HCV patients treated with DAA undergo a marked reduction of insulin resistance

Improvement of insulin sensitivity in diabetic and non diabetic patients with chronic hepatitis C treated with direct antiviral agents 
Alessandro Gualerzi, Mattia Bellan , Carlo Smirne, Margherita Tran Minh, Cristina Rigamonti, Michela Emma Burlone, Ramona Bonometti, Sara Bianco, Azzurra Re, Serena Favretto, Giorgio Bellomo, Rosalba Minisini, Gian Piero Carnevale Schianca, Mario Pirisi
Published: December 20, 2018 https://doi.org/10.1371/journal.pone.0209216 

Full-Text Article

Download PDF

View Online

Abstract

Background
The increased incidence of type 2 diabetes mellitus among hepatitis C virus (HCV) infected patients is likely due to viral-induced insulin resistance (IR). Indeed, control of diabetes in these patients benefits of successful antiviral treatment; whether the same applies to subtler alterations of glucose metabolism is unknown. We aimed to fill this gap.

Methods
The study population included 82 HCV-RNA positive patients (48 males, median age 66 years, 73 with advanced fibrosis, 41 HCV-1b), attending the liver clinic of an academic hospital to receive direct antivirals. None was previously known to be diabetic. All underwent a standard oral glucose tolerance test (OGTT) before antiviral treatment and right after its conclusion.

Results
At baseline, the majority of patients had evidence of abnormal glucose metabolism (N. = 45, 55%; impaired fasting glucose 10%, impaired glucose tolerance16%, both the above 12%, 17% diabetes), while only 37 (45%) were normally glucose tolerant (NGT). At the end of treatment, HCV-RNA quantification was below the detection threshold (HCV-RNA <12 UI/ml), for all patients enrolled. A significant decrease in glucose and insulin plasma concentrations was observed, leading to a significant reduction in Homeostasis Model Assessment (HOMA)-IR (from 3.42 [2.66–5.38] to 2.80 [1.78–3.95];p<0.001) and a corresponding increase in insulin sensitivity (ISI Belfiore from 0.49 [0.26–0.75] to 0.64 [0.42–0.91];p<0.001), despite a significant reduction in insulin secretion (EFP Stumvoll from 1363 [959–1730] to 1264 [976–1588];p = 0.027). Importantly, HOMA-IR reduction occurred also in the subgroup of NGT patients (p = 0.017). The number of NGT patients increased to 53, 65% (p = 0.013) paralleled by a reduced number of those satisfying criteria for prediabetic conditions (31 (38%) vs. 17 (21%); p = 0.025).

Conclusions

Glucose metabolism parameters of HCV infected patients improve early after antiviral treatment, with benefits that are not limited to diabetics. These findings confirm how deep and widespread is the impairment of insulin pathways exerted by HCV infection.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209216

Cirius Therapeutics Reports On Phase 2b Trial in NASH Patients with Fibrosis

Cirius Therapeutics Reports Positive Data for MSDC-0602K in Interim Analysis of Phase 2b Clinical Trial in NASH Patients with Fibrosis

- Interim analysis showed statistically significant reductions in liver enzymes, including ALT and AST, measured from baseline at six months

- In two highest dose groups, at least 50% of patients with high baseline ALT or AST improved to normal range at six months

- Statistically significant reductions in HbA1c and other measures of glycemic control and insulin resistance were observed

- Overall adverse event rate was similar across placebo and all doses of MSDC-0602K

- Largest Phase2b clinical trial including paired biopsies conducted in NASH; biopsy data after 12 months of treatment expected to be reported in the second half of 2019

SAN DIEGO and KALAMAZOO, Mich., Oct. 25, 2018 /PRNewswire/ -- Cirius Therapeutics today announced positive results from an interim analysis of exploratory endpoints from its ongoing, fully enrolled Phase 2b clinical trial (the EMMINENCE trial) evaluating MSDC-0602K in 402 patients diagnosed with non-alcoholic steatohepatitis (NASH) with fibrosis. The interim analysis, which was conducted in the first 328 patients to reach their six-month follow-up visit, showed that patients treated with MSDC-0602K had significant improvements from baseline in measures of liver function and insulin resistance at six months. MSDC-0602K, a second-generation insulin sensitizer, is designed to selectively modulate the mitochondrial pyruvate carrier (MPC), which at the cellular level mediates the effects of overnutrition, a major cause of NASH and other metabolic disorders.

The subjects included in this interim analysis had significant liver disease, as established by liver biopsy, with an average non-alcoholic fatty liver disease (NAFLD) activity score at baseline of 5.3. Almost sixty percent of these subjects had a baseline fibrosis score of 2 or 3 and approximately fifty percent also had a diagnosis of Type 2 diabetes at baseline. Overall, baseline characteristics were well-balanced across treatment groups.

Key findings from the interim analysis include improvements in liver enzymes, with placebo-corrected reductions at 6 months of 14.3 U/L (p<0.001) and 7.9 U/L (p=0.012) in ALT and AST, respectively, in the 125mg cohort, and 10.6 U/L (p=0.004) and 4.0 (NS) in ALT and AST, respectively, in the 250mg cohort. Placebo-corrected reductions, relative to baseline, were 25% and 18% in ALT and AST, respectively, in the 125mg cohort, and 19% and 9% in ALT and AST, respectively, in the 250mg cohort. Importantly, normalization of hepatic enzymes was observed across all three dose levels of MSDC-0602K. 

Percentage of patients with high baseline values who returned to normal range
	Placebo	62.5mg	125mg	250mg
ALT	15%	29%	60%	56%
AST	20%	36%	50%	52%

*ALT normal range defined as 6-34 U/L and 6-43 U/L for women and men, respectively; AST normal range defined as 9-34 U/L and 11-36 U/L for women and men, respectively) 

"We believe these interim results around improved measures of liver function and glycemic control, together with the preliminary adverse event profile, support MSDC-0602K's potential to be used in the treatment of NASH with fibrosis, including for those patients with Type 2 diabetes, a group which represents approximately 50% of patients with NASH," said Cirius' chief medical officer Howard Dittrich, M.D. "These results support the view that therapies directed toward the MPC have the potential to achieve insulin sensitizing pharmacology with an improved profile over first generation insulin sensitizers. We look forward to presenting full data to the scientific community." 

In addition to the improvement in ALT and AST, observations included significant improvement at six months in fasting glucose, HbA1c, insulin levels and HOMA-IR at the 125mg and 250mg dose levels.  Significant improvement in HbA1c was also observed in subjects with a diagnosis of Type 2 diabetes in the 125mg and 250mg cohorts.  

In this interim analysis, the overall rate of treatment emergent adverse events was similar across placebo and all MSDC-0602K cohorts. There was a higher rate of treatment emergent adverse events reported in the 250mg dose compared to placebo in the musculoskeletal and connective tissue disorders category. Within this category, arthralgia and back pain were the most frequently reported individual adverse events across the pooled 328 subjects. A modest dose-dependent increase in body weight was seen in MSDC-0602K treated subjects, a finding seen with insulin and with other therapies that seek to improve insulin resistance. The rate of peripheral edema observed at six months was similar to that observed at baseline and was comparable across placebo and all MSDC-0602K cohorts. 

"The interim results from the EMMINENCE trial, the largest Phase 2b clinical trial to include paired biopsies ever conducted in NASH, are compelling," said Stephen Harrison, M.D., the principal investigator in the EMMINENCE trial. "The improvements in hepatic enzymes observed to date are impressive, especially when combined with the meaningful improvements in glycemic control." 

About the EMMINENCE Trial

The EMMINENCE trial is a 12-month, randomized, double-blind, placebo-controlled trial evaluating three oral dose levels of MSDC-0602K. Endpoints of the clinical trial include hepatic histological changes measured by biopsy after 12 months of treatment, changes in liver and metabolic function measured by the liver enzymes ALT and AST, markers of liver fibrosis, glycemic control and safety and tolerability. Not all of these endpoints were examined in this interim analysis; rather, in addition to the safety variables of incidence of treatment-emergent adverse events and  peripheral edema grades, changes from baseline relative to placebo for a number of endpoints, including liver functions tests such as ALT and AST, among others, biomarkers and indirect measures of apoptosis and fibrosis, circulating inflammatory markers and markers of bone metabolism, serum triglycerides and fasting cholesterol, markers of insulin sensitivity, and blood pressure, were examined in an exploratory manner. 

About Cirius Therapeutics

Cirius is a clinical-stage pharmaceutical company focused on the development and commercialization of innovative therapies for the treatment of liver and metabolic diseases. Our lead product candidate, MSDC- 0602K, is a novel small molecule being developed as a once-daily oral therapy to treat NASH with fibrosis. MSDC-0602K is designed to selectively modulate the MPC, which mediates at the cellular level the effects of overnutrition, a major cause of NASH and other metabolic disorders. We are conducting a Phase 2b clinical trial of MSDC-0602K, which we have fully enrolled with 402 patients diagnosed with NASH with fibrosis. We expect to report final data from this clinical trial in the second half of 2019.

SOURCE Cirius Therapeutics

Treating Insulin Resistance in Hepatitis C-Infected Patients With Diabetes

Treating Insulin Resistance in Hepatitis C-Infected Patients With Diabetes
Elizabeth Kukielka, PharmD
Publish Date: Wednesday, January 24, 2018

Both insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are more prevalent in patients with chronic hepatitis C virus (HCV) infection compared with the general population. 

As this is one of the first studies to demonstrate the benefit of treating HCV-positive patients who also have IR with both standard HCV therapy and metformin to achieve SVR, more studies are needed to confirm the results and help determine a standard regimen for patients with HCV and IR, researchers noted.

Continue reading: https://www.specialtypharmacytimes.com/news/treating-insulin-resistance-in-hepatitis-c-infected-patients-with-diabetes

Full Text

Comparison of metformin and pioglitazone in achieving sustained virological response in chronic hepatitis C patients with insulin resistance: A quasi-experimental study

Recommended Reading
Shared by Henry E. Chang on Twitter
HCV eradication by DAA improves glucose tolerance & reduces post-load insulin resistance in nondiabetic patients with genotype 1

When liver immune cells turn bad

When liver immune cells turn bad
University Health Network
(April 21, 2017--Toronto) - A high-fat diet and obesity turn "hero" virus-fighting liver immune cells "rogue", leading to insulin resistance, a condition that often results in type 2 diabetes, according to research published today in Science Immunology.

Using cells from mice and human livers, Toronto General Hospital Research Institute researchers demonstrated for the first time how under specific conditions, such as obesity, liver CD8+ T cells, white blood cells which play an important role in the control of viral infections, become highly activated and inflammatory, reprogramming themselves into disease-driving cells.

Scientists have been trying for many years to discover why the liver continues to pump out too much glucose in people with diabetes. This paper sheds light on the markers of activation and inflammation in CD8+ T cells and the Interferon-1 pathway which helps stimulate their function.

The research is entitled, "Type 1 Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome," by first authors Magar Ghazarian, a former graduate student, Dr. Xavier Revelo, a post-doctoral fellow in the lab of Dr. Daniel Winer, and senior authors Dr. Shawn Winer, Laboratory Medicine, St. Michael's Hospital, Laboratory Medicine and Pathobiology, University of Toronto, and Dr. Daniel Winer, Diabetes Research Group and the Department of Pathology, Toronto General Hospital Research Institute and the Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto.

"We found that under conditions of obesity and a high-fat diet, the cells that typically strengthen our immune system by killing viruses and pathogens instead increase blood sugar. They become pathogenic and worsen insulin resistance," explains Dr. Dan Winer. In fact, the normal function of the immune cells becomes misdirected. The pathways they would typically use to fight infection create inflammation, unleashing a chemical cascade which impacts insulin and glucose metabolism.

"The immune system in the liver represents a key missing link in our understanding of how the liver malfunctions in obesity to dysregulate sugar levels," adds Dr. Revelo.

In the study, researchers fed mice a high-fat diet, 60% of which was saturated fat, for 16 weeks. Compared with normal chow diet-fed mice, the high-fat diet mice showed worsened blood sugar, increased triglycerides, a type of fat (lipid) in the blood, and a substantial increase in the numbers of CD8+ T cells in the liver.

Instead of responding to viruses or other foreign invaders in the body, the activated CD8+ T cells launch an inflammatory response to fat, and to bacterial components that migrate to the liver from the gut through the blood.

The activated T-cells divide rapidly, pumping out increased numbers of cytokines, proteins that assist them in an active and excessive immune response. This pro-inflammatory response in turn interferes with normal metabolism in the liver, specifically jamming up or blocking insulin signaling to the liver cells.

Since the liver stores and manufactures glucose or sugar depending upon the body's need, the hormone insulin signals whether the liver should store or release glucose. This system keeps circulating blood sugar levels in check. If that signal is disrupted or blocked, the liver continues to make more sugar, pouring it into the bloodstream. If the liver is over-producing glucose, it becomes difficult to regulate blood sugar.

"This response never manifested itself until humans started to eat high-sugar, high-fat, high-calorie diets," says Magar Ghazarian, now a medical student in Ireland.

Adds Dr. Shawn Winer: "We're moving from studying diabetes as a metabolic syndrome - a combination of nutritional and hormonal imbalances - to include the role of the immune system and inflammation. That's the developing link. Inflammation is emerging to be a major mediator of insulin resistance."

Insulin resistance is a pathological condition linked to obesity, in which cells fail to respond normally to the hormone insulin which helps the body metabolize glucose. This results in poor absorption of glucose by cells, causing a buildup of sugar in the blood. Long-term insulin resistance eventually leads to diabetes.

The findings were confirmed in genetically-modified mice, as well as in human liver cells.

The researchers found that in genetically-modified mice lacking Interferon-1, who were also fed a high-fat diet, the CD8+ T cells did not produce an inflammatory response, and the mice had near normal blood sugar levels.

In further investigations of human liver cells from nearly 50 donor tissues of humans with varying degrees of body mass index (BMI) and liver fat, higher levels of CD8+ T cells were linked with higher levels of blood sugar or more advanced fatty liver disease. Donor tissues were obtained from Saint Louis University Hospital, Washington University School of Medicine and Mid-American Transplant Services from St. Louis and University Health Network.

The researchers note that CD8 + T cells could potentially be used as markers for the progression of fatty liver disease, which is expected to become the leading indication for liver transplantation within the next one or two decades.

Type 2 diabetes is one of the fastest growing diseases in Canada with more than 60,000 new cases yearly. Nine out of ten people with diabetes have type 2 diabetes. Being overweight or obese is an important risk factor for diabetes. It is estimated that 3.5 million or about 9% of Canadians have diabetes.

The study was funded by the Canadian Institutes of Health Research, the Canadian Diabetes Association, the J.P. Bickell Foundation, and the Ontario Ministry of Research, Innovation & Science.

About Toronto General Hospital
Toronto General Hospital is a partner in University Health Network, along with Toronto Western, the Princess Margaret Cancer Centre, the Toronto Rehabilitation Institute and the Michener Institute for Education. The scope of research and complexity of cases at Toronto General Hospital have made it a national and international source for discovery, education and patient care. It has one of the largest hospital-based research programs in Canada, with major research in cardiology, transplantation, diabetes, regenerative medicine, infectious diseases, genomic medicine, psychosocial care and health systems. Toronto General Hospital is a research and teaching hospital affiliated with the University of Toronto. http://www.uhn.ca

http://immunology.sciencemag.org/content/2/10/eaai7616

Predicting severe liver disease: Obesity, insulin, diabetes, cholesterol, alcohol

Predicting severe liver disease: Obesity, insulin, diabetes, cholesterol, alcohol

ILC 2017: Type 2 diabetes is the main predictor of severe liver disease among alcohol risk drinkers

European Association for the Study of the Liver

April 22, 2017, Amsterdam, The Netherlands: A study conducted in Finland, presented today, demonstrates that in the general population, central obesity, insulin resistance, diabetes, lipid abnormalities and high alcohol consumption were the strongest predictors of severe liver disease. The study, presented at The International Liver Congress™ 2017 in Amsterdam, The Netherlands, also found that the only significant predictor of severe liver disease among individuals who consume high amounts of alcohol (more than 210 g/week in men, and more than 140 g/week in women), is diabetes.

Using metabolic and alcohol consumption data from the Finnish Health 2000 Study, a nationally representative cohort, the researchers investigated which metabolic factors best predicted severe liver complications and classified the results by the amount of alcohol consumed. For those with no or mild alcohol use, age, total cholesterol, HOMA-index (a measure of resistance to insulin and how well the cells that secrete insulin are functioning) and waist circumference predicted the development of liver disease.

According to the World Health Organization, Europe is the heaviest drinking region in the world in terms of prevalence of alcohol consumption; therefore alcoholic liver disease (ALD) is an important issue for Europe to address.1 Whilst many people who consume more than 60 g of alcohol a day (equivalent to half a bottle of wine or more than a litre of beer) will develop steatosis (accumulation of fat in the liver), only a minority will go on to develop the more serious condition of alcoholic liver inflammation (alcoholic hepatitis) and between 10 to 20% will develop cirrhosis (irreversible scarring of the liver).2 Alcohol consumption is responsible for nearly 5.9% of all deaths globally and 139 million disability-adjusted life-years (DALYs) lost due to premature death from alcohol.1

"The results of this study can help us identify which people are at risk of developing severe liver disease, so that we can work with them to reduce those risks," said Dr Fredrik Åberg, Transplantation and Liver Surgery Clinic, Helsinki University, Finland, and lead author of the study. "It's important that the risk factors identified in our study are considered for use in future risk models so that doctors can identify and counsel those patients at risk for developing liver disease."

The study included 6,732 people without known liver disease who were representative of the general Finnish population and had participated in the Health 2000 Study, which was conducted from 2000 to 2001. Follow-up data on liver related hospital admissions, deaths and liver cancer were collected over the following decade.

"These data emphasise the important role of diabetes and metabolic syndrome in the development of liver disease, reinforcing the need to consider liver disease in such patient groups," said Prof Philip Newsome, Centre for Liver Research & Professor of Experimental Hepatology, University of Birmingham, United Kingdom, and EASL Governing Board Member.

About The International Liver Congress™
This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2017 will take place from April 19 - 23, at the RAI Amsterdam, Amsterdam, The Netherlands.

About The European Association for the Study of the Liver (EASL)
Since its foundation in 1966, this not-for-profit organisation has grown to over 4,000 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European Association with international influence, with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

Onsite location reference
Session title: General session III and award ceremony II
Time, date and location of session: 10:00 - 12:00, Saturday 22 April, Hall 5
Presenter: Fredrik Åberg, Finland
Abstract: Interaction between alcohol use and metabolic components in predicting severe liver disease in the general population - a decade follow-up of a nationally representative cohort (GS015) 11:15 - 11:30

Author disclosures
Research grants from Finnish research foundations (Wilhelm and Else Stockmanns Foundation, Liv och Hälsa, and Finska Läkaresällskapet). Travel expenses to scientific conferences within the past three years: Astellas, Chiesi, Gilead.

References
1 World Health Organization. Global status report on alcohol and health 2014. Available from: http://apps.who.int/iris/bitstream/10665/112736/1/9789240692763_eng.pdf?ua=1. Last accessed: April 2017.
2 European Association for the Study of the Liver. EASL Clinical Practical Guidelines: Management of Alcoholic Liver Disease. Available from: http://www.easl.eu/medias/cpg/issue9/Report.pdf. Last accessed: April 2017.

Could maintaining a healthy weight actually improve liver health in a person with HCV?

Could maintaining a healthy weight actually improve liver health in a person with HCV?

Studies indicate that obesity and diabetes can accelerate damage caused by the hepatitis C virus, with research pointing to an increased prevalence of diabetes in people with HCV.

HCV is associated with a broad range of conditions other than liver disease and are thought to include (but are not limited to) fatigue, depression, cryoglobulinemic vasculitis, renal disease with or without cryoglobulinemia, skin disorders including cutaneous leukocytoclastic vasculitis and porphyria cutanea tarda, lymphomas, diabetes mellitus and metabolic syndrome.

Type 2 Diabetes
The latter two, diabetes mellitus and metabolic syndrome are both detailed in a review article by Mitchell L. Shiffman, MD published in Liver International. The good doctor cited metabolic complications associated with the virus; insulin resistance and type 2 diabetes as an indication for treatment. Although, in the article, Dr. Shiffman set out to inform private insurance carriers and governmental healthcare agencies of the importance, and need to cover effective medications to treat the hepatitis C virus, the information is extremely patient friendly, one you may want read or pass along.

He wrote:

At the very least the presence of the metabolic syndrome, insulin resistance or  type 2 diabetes mellitus should be an indication for HCV therapy for all private insurance carriers and governmental healthcare agencies.

Below is the abstract, full text article here.

Abstract

Chronic hepatitis C virus (HCV) is associated with insulin resistance (IR) and leads to type 2 diabetes mellitus (T2DM) and hepatic steatosis in many patients. These metabolic complications of HCV have been shown to accelerate the progression of fibrosis to cirrhosis and increase the risk of hepatocellular carcinoma. The metabolic syndrome is a common disorder that also includes IR, T2DM and hepatic steatosis. Approximately 20%-30% of patients with chronic HCV also have co-existent metabolic syndrome. The cause of steatosis in patients with the features of both the metabolic syndrome and chronic HCV is sometime difficult to determine. Patients with metabolic syndrome and chronic HCV are also at risk of developing renal, cardiovascular and cerebrovascular disease. Recent data suggest that HCV is an independent risk factor for renal, coronary and cerebral vascular disease, and may increase mortality associated with these disorders. The treatment of HCV can now result in a sustained virological response and cure nearly all patients with chronic HCV. The eradication of HCV reduces the risk of developing IR and T2DM, improves IR and 2TDM, reduces the risk of developing chronic kidney disease, end-stage renal disease, acute cardiac syndrome and stroke in patients with 2TDM. Thus, treatment of chronic HCV can provide a significant public health benefit, but only if all patients with chronic HCV are identified and universally treated.
I highly suggest you read the full text article.

Eating Right To Control Type 2 Diabetes
Today, I found an interesting article over at PMlive, about a study published in the Journal of Clinical Endocrinology & Metabolism, which found 40% of patients with type 2 diabetes who underwent a lifestyle change including exercise and diet were able to stop taking their medications, and were left without any signs and symptoms of diabetes.

The team from McMaster University in Canada tested the idea in diabetic patients who had been symptomatic for up to three years, underwent a personalised exercise regimen, a diet reducing their calorie intake by 500 to 750 per day and continued use of glucose-controlling drugs (metformin, acarbose and in some cases basal insulin) to closely manage blood sugar levels. 

After four months 40% (11 of 27) of patients who adhered to the changes were able to cease taking their medications and stay in complete or partial remission from diabetes according to investigator Natalia McInnes.

Here is the article.

Liver Cancer, Type 2 Diabetes
In the March 2017 issue of Gut, a recent study investigated the link between high body mass index in late adolescent men, reporting it was associated with an increased risk of future severe liver disease, including HCC (liver cancer). The overweight men were more likely to develop liver disease later in life by almost 50% - than men of a normal weight. In addition the development of Type 2 diabetes during follow-up was associated with a further increased risk of severe liver disease, independent of baseline BMI. The authors call for earlier interventions and additional screening for those at risk.
Here is the article.

HCV Diet And Exercise
Although the above mentioned articles did not include people with HCV, a 2013 study published in Nutrition, found HCV patients who participated in a diet and exercise program lowered their grade of steatosis and remarkably their fibrosis score.

The present study establishes the benefits of the low-calorie diet and low-fat diet in management of patients with hepatitis C regarding improvement of insulin resistance, steatosis and also liver fibrosis. 

Overweight or obese patients with hepatitis C undergoing a lifestyle intervention (specific dietary intervention and physical activity) for 1-year had significant improvements in body weight, lipid and hepatic profiles.

Read the article here.

Off The Cuff

Published in Gastroenterol Hepatol (N Y). 2014 Jan; 10(1): 43–45.
Fibrosis and Cirrhosis in HCV Infection
An interview with Mitchell L Shiftman, MD

Gastroenterology & Hepatology: What are your thoughts about vitamin supplementation on fibrosis and risk of cirrhosis?

Mitchell L Shiftman, MD: The data are very mixed and not conclusive. The strongest data, which are consistent but sparse, suggest that vitamin E may reduce the fat content in patients with fatty liver disease. This, in turn, may reduce fibrosis progression. At this stage of the game, eating healthy and maintaining health is probably a better strategy for averting liver fibrosis than vitamin supplementation. Interestingly, the strongest data about the antifibrotic effects of food concern coffee. Data from several studies now suggest that drinking 2 cups of coffee a day reduces fibrosis progression in the liver. The most useful study on this comes from the National Institutes of Health HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial. Patients completed detailed diet questionnaires that included questions on coffee and tea consumption. A strong relationship between coffee consumption and lack of cirrhosis was found.

Read the 2014 interview here....

The bottom line
Experts agree, exercise, eating healthy, and controlling weight gain are all key elements in the management of HCV, especially for those people with both hepatitis C and type 2 diabetes.

Recommended Reading
Current level of evidence on causal association between hepatitis C virus and type 2 diabetes: A review
2017 - Management of extrahepatic manifestations of chronic hepatitis C virus infection
HCV - Fatty liver disease and genotype 3
The Liver Loving Diet 

Have a great weekend!

Tina

Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection

Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection

Download the PDF

Gastroenterology & HepatologyVolume 12, Issue 5, May 2016

Robert J. Wong, MD, MS, and Robert G. Gish, MD

Dr Wong is an assistant clinical professor of medicine at the University of California, San Francisco in San Francisco, California, and the director of research and education in the Division of Gastroenterology and Hepatology at Highland Hospital in Oakland, California. Dr Gish is a professor consultant in the Department of Medicine in the Division of Gastroenterology and Hepatology at Stanford University in Stanford, California; principal of Robert G. Gish Consultants, LLC, in San Diego, California; and senior medical director at St Joseph’s Hospital and Medical Center in Phoenix, Arizona.

 

Address correspondence to:Dr Robert J. WongHighland HospitalHighland Care Pavilion, 5th FloorEndoscopy Unit1411 East 31st StreetOakland, CA 94602Tel: 510-437-6531E-mail: Rowong@alamedahealthsystem.org

 

Abstract:

Chronic hepatitis C virus (HCV) infection is associated with many extrahepatic manifestations that contribute to morbidity and mortality. It is especially important to be aware of metabolic manifestations and serious complications that affect other organs and cancer risks. Chronic HCV infection itself contributes to de novo development of insulin resistance and hepatic steatosis, both of which increase the risk of cardiovascular diseases. Through these metabolic pathways (as well as through other hypothesized mechanisms that involve lipid metabolism, systemic inflammatory signals, and endothelial dysfunction), chronic HCV infection also contributes to significant systemic cardiovascular morbidity and mortality. While chronic HCV infection contributes to incident development of metabolic complications, the presence of concurrent metabolic diseases also contributes to disease progression, such as higher risks of hepatocellular carcinoma and progression to advanced fibrosis, among patients with chronic HCV infection. The implications of these observations are particularly important given the rising prevalence of obesity and metabolic syndrome in the United States and worldwide. Furthermore, concurrent nonalcoholic fatty liver disease, either as a result of underlying metabolic syndrome or as a direct result of HCV-induced fatty liver disease, further complicates the management of chronic HCV-infected patients. Greater awareness is needed toward the systemic manifestations of chronic HCV infection, with focused attention on the associated metabolic manifestations and complications. Successful treatment and cure of chronic HCV infection with the currently available, highly effective antiviral therapies will significantly improve long-term outcomes among these patients. It is also important to recognize and address the associated metabolic manifestations and complications to reduce cardiovascular-related morbidity and mortality.

 

Chronic hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality, with studies estimating a prevalence of 3 to 7 million persons affected in the United States.^1-4 There have been major recent advances in antiviral therapy for the management of chronic HCV infection, with the majority of current therapies achieving sustained virologic response (SVR) in over 95% of chronic HCV-infected patients. Despite these improvements, the long-term impact of these therapies on viral clearance and prevention of disease progression to cirrhosis and cirrhosis-related complications (eg, hepatocellular carcinoma [HCC], liver failure) will take time to determine. Currently, chronic HCV infection remains the leading cause of HCC and decompensated cirrhosis requiring liver transplantation in the United States (Figure).^5-7 While the impact of chronic HCV infection on liver-related complications and outcomes has been well studied, extrahepatic sequelae and complications of chronic HCV infection that result from the systemic effects of persistent viral infection are less well emphasized.⁸ The early recognition of systemic effects of chronic HCV infection provides an opportunity to advocate for early initiation of antiviral therapy in which SVR may be achieved, as well as to treat all patients, thereby preventing further, and potentially permanent, hepatic and extrahepatic consequences of chronic HCV infection. This review highlights the metabolic manifestations and complications associated with chronic HCV infection.

 

Insulin Resistance

The association between chronic HCV infection and metabolic manifestations primarily involves the potential diabetogenic effect of persistent viral infection. Several studies have investigated and demonstrated the association between chronic HCV infection and insulin resistance.^9-14 Using data from the third National Health and Nutrition Examination Survey (1988-1994), Mehta and colleagues performed a cross-sectional study of adults in the United States.¹⁴ Among a study cohort of 9841 individuals, there was an 8.4% prevalence of diabetes mellitus and a 2.1% prevalence of individuals who were anti-HCV antibody–positive. After adjusting for multiple factors (including age, body mass index, and socioeconomic status), the authors demonstrated that adults age 40 years or older with HCV infection were nearly 4 times more likely to have concurrent diabetes than those without HCV infection.¹⁴ However, as the authors acknowledged, while this study and previous cross-sectional studies have demonstrated the association of chronic HCV infection with insulin resistance, it remains unclear whether chronic HCV infection preceded the development of diabetes or whether HCV infection itself contributed to incident diabetes.

 

To better address this question, Mehta and colleagues performed a follow-up study using data from the Atherosclerosis Risk in Communities Study.¹⁵ In this prospective case-control study of men and women between the ages of 44 and 65 years, 1084 adults without diabetes at baseline were evaluated to determine the association between antecedent chronic HCV infection and the development of diabetes. After risk stratification adjustments based on factors such as age and body mass index, the authors demonstrated that among individuals at high risk for developing diabetes, the presence of chronic HCV infection was associated with a greater than 11-fold higher risk of developing diabetes over 9 years of follow-up (hazard ratio [HR], 11.58; 95% CI, 1.39-96.6).¹⁵ Further supporting the increased risk of chronic HCV infection on insulin resistance, additional studies have demonstrated that successful clearance of HCV infection with antiviral therapy can lead to improved insulin resistance.^16-24 In a study by Romero-Gomez and colleagues, 1059 patients with chronic HCV infection were evaluated to determine the impact of achieving SVR on insulin resistance as measured by the homeostasis model assessment of insulin resistance.²⁴ The authors demonstrated that achieving SVR was an independent predictor of impaired fasting glucose or diabetes.²⁴

 

However, another study by Giordanino and colleagues evaluated 202 chronic HCV-infected patients without pretreatment glucose abnormalities to determine whether antiviral treatment response affected the incidence of developing glucose abnormalities.²⁵ After a median follow-up period of 8 years, the authors found no significant difference between patients who achieved long-term virologic response and those who were nonresponders with respect to their incidence of developing glucose abnormalities.²⁵ Another study of 2842 chronic HCV-infected patients treated with interferon monotherapy or in combination with ribavirin evaluated the impact of antiviral treatment on incident diabetes.²³ The investigators demonstrated a two-thirds reduction in the risk of developing incident diabetes associated with interferon treatment. Despite this seemingly conflicting study, the majority of studies continue to demonstrate the association of chronic HCV infection and insulin resistance, further emphasizing the potential metabolic benefit of achieving and maintaining viral clearance.

 

Cardiovascular Diseases

The association between chronic HCV infection and cardiovascular diseases has been well studied, and while potential mechanisms have been hypothesized, the current literature demonstrates variations in the degree of this association.^26-34 Mechanistically, the potential increased risk of cardiovascular diseases among patients with chronic HCV infection may stem from insulin resistance, hepatic steatosis contributing to increased systemic inflammatory markers, and/or endothelial dysfunction.^31,35-39 In addition, insulin resistance and hepatic steatosis are tightly linked and may further contribute to the development of other metabolic syndrome components such as hypertension and dyslipidemia.^39-41 However, a recent systematic review that evaluated published studies from 1995 to 2013 included a total of 5 studies that met inclusion and exclusion criteria.²⁶ The authors found 1 cohort study of US veterans that demonstrated a significantly increased risk of cardiovascular disease among patients with chronic HCV infection (HR, 1.27; 95% CI, 1.22-1.31); however, additional studies that also used US Veterans Affairs data, although from an earlier period, demonstrated a protective effect of chronic HCV infection on the development of cardiovascular disease.^30,32 The remaining studies included in this systematic review did not demonstrate a clear clinical association between chronic HCV infection and cardiovascular disease, leading the authors to conclude that more prospective studies are needed to better evaluate this association before more definitive statements regarding chronic HCV infection and its impact on cardiovascular disease can be made.²⁶

 

The difficulties in evaluating cardiovascular associations of chronic HCV infection are multifold. Different studies utilize varying definitions, categorizations, and surrogates of cardiovascular disease (eg, carotid artery intima-media thickness, subclinical atherosclerosis, congestive heart failure) and span large periods of time, during which antiviral treatment regimens have significantly improved with better efficacy and fewer side effects.²⁶ Furthermore, while several hypotheses have been discussed, it is likely that chronic HCV infection and clearance of HCV infection with treatment impart a multitude of systemic metabolic changes that may affect cardiovascular disease risk in multidirectional ways. For example, as previously discussed, clearance of HCV infection improves insulin resistance, which may contribute to reducing cardiovascular disease risk.^16-24 However, studies have also postulated that chronic HCV infection itself may be associated with lower serum lipid levels, and patients who achieve SVR may develop a significant rebound rise in lipid levels in the blood that may contribute to increased cardiovascular disease risks.^39-41 Thus, the cumulative impact of persistent viral infection and subsequent viral clearance with antiviral therapy is a complex interplay of different mechanistic pathways, and while not all studies demonstrate clear and convincing evidence supporting the association between chronic HCV infection and cardiovascular diseases, it cannot be argued that viral clearance has an overall beneficial effect. Large prospective studies that include -multivariate -analysis and sensitivity testing would permit a more refined understanding of this issue.

 

Nonalcoholic Fatty Liver Disease

The interplay between chronic HCV infection and nonalcoholic fatty liver disease (NAFLD) is complex. As discussed above, chronic HCV infection can contribute to metabolic derangements (including insulin resistance and dyslipidemia) that subsequently increase the risk of developing concurrent NAFLD. In addition, several studies have reported that chronic HCV infection itself may contribute to the development of hepatic steatosis, the presence of which feeds into the cycle of metabolic diseases contributing to disease progression and complications among patients with chronic HCV infection.^31,35,37,42 The strong association between chronic HCV infection and de novo hepatic steatosis is seen most prominently in patients with HCV genotype 3 infection.^35,42-45 In a large meta-analysis, Leandro and colleagues evaluated 3068 patients with histologically confirmed chronic HCV infection from 10 centers in Italy, Switzerland, France, Australia, and the United States, among whom 50.9% had histologic evidence of hepatic steatosis.⁴³ Hepatic steatosis was more commonly found, and was more severe, in patients with HCV genotype 3 infection. Interestingly, subsequent studies demonstrated that hepatic steatosis was significantly improved, and in some cases completely resolved, after antiviral therapy in patients with HCV genotype 3 infection.^42,45-47 However, patients with non–genotype 3 infection did not demonstrate the same improvement in hepatic steatosis, even among those who achieved SVR with antiviral therapy.^45-47 While the exact etiologies underlying these observations are not clear, several hypotheses have been raised. Studies have described the potential de novo lipogenic role of chronic HCV infection through activation of in vitro sterol regulatory element-binding proteins 1c and 2, both of which are transcription factors involved in lipogenesis.⁴⁸ Further studies observed an inhibition of fatty acid oxidation by HCV infection, contributing to triglyceride accumulation.^49-51 Other hypotheses have implicated impaired assembly and secretion of very low–density lipoprotein.^52,53 Although the exact mechanisms of HCV-induced fatty liver disease are likely multifactorial and involve multiple systemic pathways, the implications of HCV-induced fatty liver are paramount to fully appreciating the systemic metabolic effects of chronic HCV infection. While clearance of chronic HCV infection with antiviral treatment will be important not only to address the hepatic and extrahepatic manifestations associated with persistent viral replication, increased awareness of associated metabolic derangements is also critical to prevent complications such as diabetes and cardiovascular diseases.

 

Impact of Metabolic Diseases on the Natural History of Chronic Hepatitis C Virus Infection

Understanding whether chronic HCV infection increases the risk of developing metabolic complications deserves greater attention. However, it is also important to understand the impact of underlying metabolic diseases on the natural history of chronic HCV infection. Recognizing the impact of obesity and insulin resistance on disease progression among patients with chronic HCV infection is especially important given the rising prevalence of obesity and metabolic syndrome observed in the United States.^54,55

 

In a recent systematic review evaluating the impact of metabolic diseases on disease progression among patients with chronic HCV infection, Dyal and colleagues looked at literature from 2001 to 2014 and identified 20 cohort studies that met inclusion criteria.⁵⁶ Focusing primarily on obesity, diabetes mellitus, and hepatic steatosis, the authors evaluated the association of these concurrent risk factors with the development of advanced fibrosis in patients with chronic HCV infection.⁵⁶ The authors demonstrated that the presence of concurrent diabetes among patients with chronic HCV infection was associated with a significantly higher risk of developing advanced fibrosis, with effect measures ranging from odds ratios (ORs) of 2.25 to 9.24. The presence of hepatic steatosis was also significantly associated with an increased risk of developing advanced fibrosis, with effect measures ranging from ORs of 1.80 to 14.3.⁵⁶ While the authors found 7 studies showing an increased risk of advanced fibrosis associated with obesity, 4 additional studies in the systematic review failed to show a significant association between the 2 conditions.

 

Disease progression to advanced fibrosis and cirrhosis is an important outcome among chronic HCV-infected patients. The development of HCC is another feared complication of chronic HCV infection. In a follow-up study, Dyal and colleagues performed a systematic review to evaluate the impact of obesity, diabetes mellitus, and hepatic steatosis on the risk of HCC among patients with chronic HCV infection.⁵⁷ A total of 9 studies from 2001 to 2014 met inclusion criteria and were included in the analysis. The authors demonstrated that concurrent diabetes was significantly associated with higher risk of HCC among chronic HCV-infected patients, with effect measures ranging from a HR of 1.73 to a risk ratio of 3.52.⁵⁷ The study also demonstrated an increased risk of HCC associated with obesity and hepatic steatosis, although the evidence supporting these associations were less robust, and larger studies with longer-term follow-up are needed to further explore these associations.

Both of the aforementioned systematic reviews attempted to better clarify the impact of concurrent metabolic diseases on disease progression and the -natural history of chronic HCV infection; however, several limitations must be acknowledged when interpreting these results. The ideal method for exploring the impact of metabolic diseases on disease progression would be to identify patients with antecedent metabolic diseases who subsequently acquired HCV infection. However, many of these studies were observational in nature and either utilized a case-control or retrospective cohort study design, which inherently limit the true ability to understand causation.^56,57 Furthermore, the study period of the included studies spanned a period during which significant advancements in HCV therapies were introduced. Thus, improved therapies may have been a potential confounder or effect modifier that affected disease progression in chronic HCV-infected patients. Despite the general agreement that increasing rates of metabolic diseases undoubtedly contribute to worse outcomes such as cardiovascular diseases, the current studies suffer from heterogeneity in definitions of obesity and insulin resistance, and often do not take into account more accurate measures of metabolic risk such as waist circumference as a measure of visceral adiposity, which may be especially important when evaluating for metabolic diseases in ethnically diverse populations.^6,26,54,58 Nevertheless, greater awareness of underlying metabolic diseases among patients with chronic HCV infection is paramount in that targeted treatment of these diseases can translate not only into improved management of liver disease but into overall health, including cardiovascular diseases.

 

In the current era of highly effective direct-acting antiviral therapies for chronic HCV infection, the ability to eradicate HCV will not only improve HCV-related liver disease, but will likely impact the incidence and prevalence of HCV-related metabolic diseases, given the association between the 2 conditions. However, greater awareness is also needed for metabolic diseases unrelated to chronic HCV infection, including NAFLD and NAFLD-related complications.

 

Conclusion

Despite the improvements in diagnosis, linkage to care, treatment, and eradication of chronic HCV infection, this condition will continue to pose a major disease burden for the near future. Chronic HCV infection contributes to significant hepatic disease and complications; however, it is important to understand and appreciate the systemic effects of chronic HCV infection as it relates to metabolic manifestations and complications. The associations between chronic HCV infection and metabolic disease and between chronic HCV infection and cardiovascular diseases are especially important in light of the increasing prevalence of obesity and metabolic syndrome and their costs to patients, the health care system, and society.

 

Dr Wong has received research grants from and is on the advisory board for Gilead. Dr Gish has received grants/research support from AbbVie, Benitec Biopharma, Gilead, and Merck. He has served as a consultant and/or advisor to AbbVie, Akshaya Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Genentech, Gilead, F Hoffmann-La Roche, Ionis Pharmaceuticals, Janssen, Merck, Nanogen Biopharmaceutical, and Presidio Pharmaceuticals, and is currently on the scientific or clinical advisory board of AbbVie, AstraZeneca, Genentech, Gilead, Janssen, Merck, and Nanogen Biopharmaceutical. Additionally, he is a member of the speakers bureau for AbbVie, Bristol-Myers Squibb, Gilead, and Merck and is a minor stock shareholder of Cocrystal Pharma.

 

References

1. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):705-714.

2. Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011;31(8):1090-1101.

3. Ditah I, Ditah F, Devaki P, et al. The changing epidemiology of hepatitis C virus infection in the United States: National Health and Nutrition Examination Survey 2001 through 2010. J Hepatol. 2014;60(4):691-698.

4. Dominitz JA, Boyko EJ, Koepsell TD, et al. Elevated prevalence of hepatitis C infection in users of United States veterans medical centers. Hepatology. 2005;41(1):88-96.

5. Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547-555.

6. Wong RJ, Chou C, Sinha SR, Kamal A, Ahmed A. Ethnic disparities in the association of body mass index with the risk of hypertension and diabetes. J Community Health. 2014;39(3):437-445.

7. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141(4):1249-1253.

8. Gill K, Ghazinian H, Manch R, Gish R. Hepatitis C virus as a systemic disease: reaching beyond the liver. Hepatol Int. 2016;10(3):415-423.

9. Stepanova M, Lam B, Younossi Y, Srishord MK, Younossi ZM. Association of hepatitis C with insulin resistance and type 2 diabetes in US general population: the impact of the epidemic of obesity. J Viral Hepat. 2012;19(5):341-345.

10. Mangia A, Ripoli M. Insulin resistance, steatosis and hepatitis C virus. Hepatol Int. 2013;7(suppl 2):782-789.

11. Younossi ZM, Stepanova M, Nader F, Younossi Z, Elsheikh E. Associations of chronic hepatitis C with metabolic and cardiac outcomes. Aliment Pharmacol Ther. 2013;37(6):647-652.

12. Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Hepatology. 2001;33(6):1554.

13. Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol. 2007;166(2):196-203.

14. Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133(8):592-599.

15. Mehta SH, Brancati FL, Strathdee SA, et al. Hepatitis C virus infection and incident type 2 diabetes. Hepatology. 2003;38(1):50-56.

16. Romero-Gómez M, Del Mar Viloria M, Andrade RJ, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128(3):636-641.

17. Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis. 2011;52(7):889-900.

18. Thompson AJ, Patel K, Chuang WL, et al; ACHIEVE-1 and ACHIEVE-2/3 Study Teams. Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3. Gut. 2012;61(1):128-134.

19. Chien CH, Lin CL, Hu CC, Chang JJ, Chien RN. Clearance of hepatitis C virus improves insulin resistance during and after peginterferon and ribavirin therapy. J Interferon Cytokine Res. 2015;35(12):981-989.

20. Cua IH, Hui JM, Kench JG, George J. Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C. Hepatology. 2008;48(3):723-731.

21. White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol. 2008;49(5):831-844.

22. Delgado-Borrego A, Jordan SH, Negre B, et al; Halt-C Trial Group. Reduction of insulin resistance with effective clearance of hepatitis C infection: results from the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8(5):458-462.

23. Arase Y, Suzuki F, Suzuki Y, et al. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology. 2009;49(3):739-744.

24. Romero-Gómez M, Fernández-Rodríguez CM, Andrade RJ, et al. Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48(5):721-727.

25. Giordanino C, Bugianesi E, Smedile A, et al. Incidence of type 2 diabetes mellitus and glucose abnormalities in patients with chronic hepatitis C infection by response to treatment: results of a cohort study. Am J Gastroenterol. 2008;103(10):2481-2487.

26. Wong RJ, Kanwal F, Younossi ZM, Ahmed A. Hepatitis C virus infection and coronary artery disease risk: a systematic review of the literature. Dig Dis Sci. 2014;59(7):1586-1593.

27. Roed T, Lebech AM, Kjaer A, Weis N. Hepatitis C virus infection and risk of coronary artery disease: a systematic review of the literature. Clin Physiol Funct Imaging. 2012;32(6):421-430.

28. Völzke H, Schwahn C, Wolff B, et al. Hepatitis B and C virus infection and the risk of atherosclerosis in a general population. Atherosclerosis. 2004;174(1):99-103.

29. Ishizaka N, Ishizaka Y, Takahashi E, et al. Association between hepatitis C virus seropositivity, carotid-artery plaque, and intima-media thickening. Lancet. 2002;359(9301):133-135.

30. Butt AA, Xiaoqiang W, Budoff M, Leaf D, Kuller LH, Justice AC. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis. 2009;49(2):225-232.

31. Adinolfi LE, Restivo L, Zampino R, et al. Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis. Atherosclerosis. 2012;221(2):496-502.

32. Butt AA, Khan UA, McGinnis KA, Skanderson M, Kent Kwoh C. Co-morbid medical and psychiatric illness and substance abuse in HCV-infected and uninfected veterans. J Viral Hepat. 2007;14(12):890-896.

33. Forde KA, Haynes K, Troxel AB, et al. Risk of myocardial infarction associated with chronic hepatitis C virus infection: a population-based cohort study. J Viral Hepat. 2012;19(4):271-277.

34. Arcari CM, Nelson KE, Netski DM, Nieto FJ, Gaydos CA. No association between hepatitis C virus seropositivity and acute myocardial infarction. Clin Infect Dis. 2006;43(6):e53-e56.

35. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33(6):1358-1364.

36. Gastaldelli A, Kozakova M, Højlund K, et al; RISC Investigators. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology. 2009;49(5):1537-1544.

37. Volzke H, Robinson DM, Kleine V, et al. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. World J Gastroenterol. 2005;11(12):1848-1853.

38. Sanyal AJ, Contos MJ, Sterling RK, et al. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am J Gastroenterol. 2003;98(9):2064-2071.

39. Marzouk D, Sass J, Bakr I, et al. Metabolic and cardiovascular risk profiles and hepatitis C virus infection in rural Egypt. Gut. 2007;56(8):1105-1110.

40. Bilora F, Rinaldi R, Boccioletti V, Petrobelli F, Girolami A. Chronic viral hepatitis: a prospective factor against atherosclerosis. A study with echo-color Doppler of the carotid and femoral arteries and the abdominal aorta. Gastroenterol Clin Biol. 2002;26(11):1001-1004.

41. Corey KE, Kane E, Munroe C, Barlow LL, Zheng H, Chung RT. Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up. Hepatology. 2009;50(4):1030-1037.

42. Goossens N, Negro F. Is genotype 3 of the hepatitis C virus the new villain? Hepatology. 2014;59(6):2403-2412.

43. Leandro G, Mangia A, Hui J, et al; HCV Meta-Analysis (on) Individual Patients’ Data Study Group. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology. 2006;130(6):1636-1642.

44. Fartoux L, Poujol-Robert A, Guéchot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54(7):1003-1008.

45. Rubbia-Brandt L, Quadri R, Abid K, et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol. 2000;33(1):106-115.

46. Kumar D, Farrell GC, Fung C, George J. Hepatitis C virus genotype 3 is cytopathic to hepatocytes: reversal of hepatic steatosis after sustained therapeutic response. Hepatology. 2002;36(5):1266-1272.

47. Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology. 2003;38(1):75-85.

48. Waris G, Felmlee DJ, Negro F, Siddiqui A. Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress. J Virol. 2007;81(15):8122-8130.

49. Dharancy S, Malapel M, Perlemuter G, et al. Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection. Gastroenterology. 2005;128(2):334-342.

50. de Gottardi A, Pazienza V, Pugnale P, et al. Peroxisome proliferator-activated receptor-alpha and -gamma mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection. Aliment Pharmacol Ther. 2006;23(1):107-114.

51. Yamaguchi A, Tazuma S, Nishioka T, et al. Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver. Dig Dis Sci. 2005;50(7):1361-1371.

52. Mirandola S, Realdon S, Iqbal J, et al. Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology. 2006;130(6):1661-1669.

53. Perlemuter G, Sabile A, Letteron P, et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J. 2002;16(2):185-194.

54. Aguilar M, Bhuket T, Torres S, Liu B, Wong RJ. Prevalence of the metabolic syndrome in the United States, 2003-2012. JAMA. 2015;313(19):1973-1974.

55. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311(8):806-814.

56. Dyal HK, Aguilar M, Bhuket T, et al. Concurrent obesity, diabetes, and steatosis increase risk of advanced fibrosis among HCV patients: a systematic review. Dig Dis Sci. 2015;60(9):2813-2824.

57. Dyal HK, Aguilar M, Bartos G, et al. Diabetes mellitus increases risk of hepatocellular carcinoma in chronic hepatitis C virus patients: a systematic review. Dig Dis Sci. 2016;61(2):636-645.

58. Ahmed A, Wong RJ, Harrison SA. Nonalcoholic fatty liver disease review: diagnosis, treatment, and outcomes. Clin Gastroenterol Hepatol. 2015;13(12):2062-2070.

Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection-Liver: The “Musketeer” in the Spotlight

Int. J. Mol. Sci. 2016, 17(3), 355; doi:10.3390/ijms17030355

Review
http://www.mdpi.com/1422-0067/17/3/355/htm

Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection—Liver: The “Musketeer” in the Spotlight

Stefano Ballestri 1, Fabio Nascimbeni 2,3, Dante Romagnoli 2, Enrica Baldelli 3, Giovanni Targher 4 and Amedeo Lonardo 2,*

1 Operating Unit Internal Medicine, Pavullo General Hospital, Azienda USL Modena, ViaSuore di San Giuseppe Benedetto Cottolengo, 5, Pavullo, 41026 Modena, Italy
2 Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy
3 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via P. Giardini, 1355, 41126 Modena, Italy
4 Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126 Verona, Italy
* Correspondence: Tel.: +39-059-396-1807; Fax: +39-059-396-1322
Academic Editor: Giovanni Tarantino

Received: 16 February 2016 / Accepted: 2 March 2016 / Published: 9 March 2016

Abstract: The pathogenesis of type 2 diabetes (T2D) involves chronic hyperinsulinemia due to systemic and hepatic insulin resistance (IR), which if uncorrected, will lead to progressive pancreatic beta cell failure in predisposed individuals. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty (simple steatosis and steatohepatitis) and non-fatty liver changes (NASH-cirrhosis with or without hepatocellular carcinoma (HCC)) that are commonly observed among individuals with multiple metabolic derangements, notably including visceral obesity,  insulin resistance (IR) and type 2 diabetes (T2D).

Hepatitis C virus (HCV) infection is also often associated with both hepatic steatosis and features of a specific HCV-associated dysmetabolic syndrome. In recent years, the key role of the steatotic liver in the development of insulin resistance (IR) and type 2 diabetes (T2D) has been increasingly recognized. Thus, in this comprehensive review we summarize the rapidly expanding body of evidence that links type 2 diabetes (T2D) with NAFLD and HCV infection.

For each of these two liver diseases with systemic manifestations, we discuss the epidemiological burden, the pathophysiologic mechanisms and the clinical implications. To date, substantial evidence suggests that NAFLD and HCV play a key role in T2D development and that the interaction of T2D with liver disease may result in a “vicious circle”, eventually leading to an increased risk of all-cause mortality and liver-related and cardiovascular complications. Preliminary evidence also suggests that improvement of NAFLD is associated with a decreased incidence of T2D. Similarly, the prevention of T2D following HCV eradication in the era of direct-acting antiviral agents is a biologically plausible result. However, additional studies are required for further clarification of mechanisms involved.

Keywords:

epidemiology; cirrhosis; clinical implications; direct acting antivirals; fibrosis; insulin resistance; hepatocellular carcinoma; NASH; pathophysiology

1. Introduction
1.1. Definitions

Type 2 diabetes (T2D) identifies the more prevalent category of diabetes mellitus and is due to a progressive insulin secretory defect in the background of insulin resistance (IR) [1]. T2D is typically found in obese and overweight middle-aged individuals though the age of its initial manifestation has now been observed shifting towards adolescents and even children [2].

Non-alcoholic fatty liver disease (NAFLD) describes a cluster of hepatic disorders predominantly (though not exclusively) characterized by fatty changes with or without ballooning degeneration and fibrosis (i.e., simple steatosis, steatohepatitis (NASH) and advanced fibrosis), which may evolve into cirrhosis (NASH-cirrhosis will typically lose fatty changes) and hepatocellular carcinoma (HCC); NAFLD is commonly observed in insulin-resistant, dysmetabolic individuals without excessive alcohol consumption and other competing etiologies of liver disease [3,4]. There is now compelling evidence that NAFLD is a multisystem disease associated with a wide range of extra-hepatic manifestations, notably including, among others, IR, dysglycemia and premature atherosclerosis [5,6].

Hepatitis C virus (HCV) is a small enveloped RNA virus belonging to the genus Flaviviridae, of which six different genotypes are recognized and which is transmitted via the parenteral route [7]. In several countries there have been two major HCV epidemics. The first one (mostly sustained by genotype 1 HCV) took place in the 1960s as a result of HCV being transmitted via medical procedures. The second one (predominantly due to genotype 3 HCV) occurred in the 1980s owing to needle-sharing practices among intravenous illicit drug users [7].

The natural course of HCV infection is variable and modulated by the interaction of host and viral factors. Of concern, the chronicity rate following acute infection approximates 85%, giving way to dreadful sequelae, such as chronic hepatitis, cirrhosis, end-stage liver failure and HCC [7]. Similarly to NAFLD, HCV infection is increasingly identified as a systemic disease which may be conducive to metabolic disorders (including IR and T2D) and premature atherosclerosis [8].

1.2. Epidemiology and Burden of Type 2 Diabetes

The world prevalence of T2D was estimated to be 6.4% in 2010 and is projected to rise to 7.7% in 2030 [9]. Recent estimates of T2D prevalence in the main five European countries (France, Germany, Italy, Spain and UK) ranged from 4.8% in Italy to 8.9% in Germany, with rates increasing steadily over the past two decades in all these countries. Of concern, in these European countries the total direct medical costs of T2D in 2010 were estimated to range from 5.45 billion euros in Spain to 43.2 billion euros in Germany, with hospitalizations due to T2D-related complications accounting for the greatest proportion of these costs [10]. In the USA, T2D now affects up to 8%–10% of adults in the general population in whom it increases up to four-fold the risk of major cardiovascular events and is the leading cause of blindness, chronic kidney failure and non-traumatic lower extremity amputations [11]. In 2007, T2D posed on society a cost as high as 174 billion dollars in the USA [12]. Of concern, this already alarming prevalence of T2D is predicted to be increasing in all age groups, making it urgent for clinicians, researchers and health authorities to gain a better understanding of the pathophysiology of T2D aimed at preventing the further spread of its disastrous pandemic [13].

1.3. Liver and Type 2 Diabetes: Historical Overview

In the past, clinicians and pathologists viewed the hepatic fatty changes as a histological correlate of the coexistence of T2D and obesity (the so-called “diabesity”) [14], a conclusion which has been fully supported by contemporary studies [15]. Stated otherwise, the liver was essentially regarded as a target organ affected by either concurrent or pre-existent “diabesity”.

More recently, however, this perspective has been fully overturned. Several studies have now exhaustively proven that hepatic steatosis precedes the development of T2D and Metabolic Syndrome (MetS) in a large proportion of cases [16,17,18]. In tandem, epidemiological evidence has also suggested that HCV infection almost doubles the risk of incident T2D compared to both HBV infection and virus-free individuals [19]. This is of outstanding interest given that HCV infection is a systemic disease [20] that often exhibits hepatic histological changes of variable severity, including hepatic steatosis, which makes it conceptually similar to NAFLD [7,21]. Excitingly, a cure for HCV has recently become available with direct acting antivirals [22,23,24].

Collectively, all the above findings support the notion that there is a causal, bi-directional link between NAFLD and T2D [25]; that HCV infection is a diabetogenic condition [19]; and that T2D is potentially preventable by curing NAFLD [26] and HCV infection [27].

1.4. Aim of the Review and Evidence Acquisition

The liver, the skeletal muscle and the pancreas are the anatomic basis of IR and they have collectively been alluded as the “three musketeers” [28]. Along with these three organs, the adipose tissue is the “fourth musketeer” which is implicated in the pathogenesis of IR (Figure 1) [29]. Over the last decade, the liver has been put in the spotlight of research and our group has been gaining particular interest in the association between the steatotic liver and risk of incident T2D. Accordingly, the main purpose of this article was to review data linking T2D with either NAFLD or HCV infection. For each of these two liver diseases, we will discuss systematically the epidemiological burden, the pathophysiologic mechanisms and the clinical implications.

Figure 1. The “four musketeers” fighting for maintaining glucose homeostasis. Under normal conditions, muscle and pancreas improve glycemic control. However, an expanded adipose tissue will usually lead to dysglycemia. Similarly, fatty changes occurring in the liver will result in the development of insulin resistance. Hence, this review article puts the liver in the spotlight.
In order to retrieve pertinent articles, the PubMed database was extensively searched for reports published through 31 January 2016. To this end, we used the following keywords “nonalcoholic fatty liver disease” or “NAFLD” combined with “insulin resistance”, “type 2 diabetes” or “diabetes”. The same keywords were used to identify those articles in which “insulin resistance”, “type 2 diabetes” or “diabetes” were combined with either “HCV” or “hepatitis C virus”.

The selection of articles was performed based on agreement among the authors. Cross-references were taken in consideration based on the authors’ judgment.

 2. NAFLD and Type 2 Diabetes
2.1. Epidemiology

The wide spectrum of the extra-hepatic manifestations and correlates of NAFLD includes cardiovascular diseases (CVD), chronic kidney disease, colorectal cancer, obstructive sleep apnea syndrome, psoriasis, endocrine disorders, notably including IR/T2D, thyroid dysfunction, polycystic ovarian syndrome and osteoporosis (Figure 2) [5,6,30,31,32,33,34,35,36]. Epidemiological data fully support a bi-directional relationship between NAFLD and T2D [25]. Stated otherwise, NAFLD is associated with established T2D in cross-sectional studies and precedes the development of T2D in follow-up studies [3,16,18].

Figure 2. The spectrum of extra-hepatic manifestations and correlates of both non-alcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection: type 2 diabetes is a shared feature. This figure illustrates the concept that NAFLD and HCV infection are two systemic diseases whose spectrum of clinical manifestations tends to overlap significantly. Type 2 diabetes is a feature shared among the various pathologic conditions included in the NAFLD clinical spectrum [5,6,30,31,32,33,34,35,36] as well as in the clinical spectrum of chronic HCV infection [8,37,38].

2.1.1. NAFLD as a “Manifestation” of Type 2 Diabetes

A consistent body of epidemiological evidence supports the conclusion that NAFLD is strongly associated with T2D and that T2D is a major modifier of the epidemiological features of NAFLD [3,39]. For example, the prevalence of NAFLD (assessed by ultrasonography) is approximately 25%–30% in the general adult population, and men outnumber women by 20% to 40%. In patients with T2D, the prevalence of NAFLD is considerably higher (occurring in up to 75% of these patients), and, remarkably, T2D abrogates sex differences among patients with NAFLD [3,39]. The prevalence of NAFLD in patients with T2D ranges widely from 45% to 75% in large hospital-based studies and from 30% to 70% in population-based studies; this wide inter-study variability is largely due to differences in the ethnicity, population characteristics and criteria adopted for the diagnosis of diabetes [39]. The prevalence of histologically diagnosed NASH, i.e., the more rapidly progressive form of NAFLD [40], is estimated to occur in 2%–3% of the general adult population [6]; conversely, it ranges from 56% to 76% in hospital-based studies [41,42] and from 22% to 83% in outpatient cohort-based studies among individuals with T2D [15,43,44]. Notably, a recent study reported a high prevalence of NAFLD (76%) and NASH (56%) in obese T2D patients with normal serum aminotransferase levels [42]. The finding that many T2D patients with NAFLD have fairly normal serum transaminase concentrations is not reassuring given that NASH, advanced fibrosis and even cirrhosis may occur in such patients with “normal” serum aminotransferases [39,45,46]. Taken together, these studies suggest that the “normal” range of serum liver enzymes needs to be lowered to capture more NAFLD cases.

 2.1.2. NAFLD as a Precursor of Type 2 Diabetes

Accumulating data from observational prospective studies indicate that NAFLD (as diagnosed by serum liver enzymes or imaging) is strongly associated with an increased incidence of both T2D and MetS [3,45]. Two large meta-analytic studies have provided further evidence for a strong association between NAFLD and increased risk of incident T2D [17,18]. The first of such meta-analyses, published by Musso et al., [17] found an approximately two-fold increased risk of incident T2D among patients with NAFLD. The second one, recently published by our group, confirmed that NAFLD was associated with an almost two-fold increased risk of developing both T2D and MetS over a median period of five years. Worryingly, our meta-analysis is first in suggesting that the risk of developing MetS was much higher in those in whom NAFLD was identified by ultrasonography compared to those in whom NAFLD was identified based on abnormal liver enzymes [18]. In agreement with these findings, a retrospective cohort study by Sung et al. [47] showed that individuals in whom ultrasonography-assessed NAFLD developed or worsened over five years had a marked increase in T2D risk, suggesting that more severe NAFLD is associated with a higher risk of incident T2D [47]. Conversely, individuals in whom NAFLD resolved over five years did not show an increased T2D risk [47]. Similarly, a recent retrospective study reported a strong and independent association between NAFLD improvement and reduced incidence of T2D [48]. Moreover, another recent study has shown that non-overweight individuals with NAFLD had a substantially increased risk of incident T2D compared with both overweight and non-overweight NAFLD-free individuals [49]. Finally, the Multi-Ethnic Study of Atherosclerosis [50] has shown that NAFLD, assessed by computed tomography, was associated with an increased risk of incident T2D independent of common risk factors of T2D.

To date, there is a paucity of published data regarding the association between biopsy proven-NAFLD and the risk of incident T2D or MetS. In a retrospective cohort of 129 Swedish adults with histologically confirmed NAFLD and elevated liver enzymes, the baseline prevalence of T2D was 8.5% and approximately 80% of cases developed T2D (58%) or pre-diabetes (20%) at the end of a 14-year follow-up period [51].

In conclusion, a large body of epidemiological evidence supports the notion that the prevalence of NAFLD is remarkably increased in patients with T2D and that NAFLD is closely associated with an increased risk of incident T2D and MetS.

 2.2. Pathophysiology
The pathogenic mechanisms linking NAFLD and T2D encompass a complex cross-talk among different organ systems, notably including the gut and the nervous system further to the previously alluded “four musketeers”: the adipose tissue, the skeletal muscle, the liver and the pancreas.

 2.2.1. Remodeling of White Adipose Tissue

Excess visceral adiposity is a key factor in connecting NAFLD and T2D. The expansion of white adipose tissue (WAT) is associated with hypoxia and adipocytes necrosis [52,53,54,55]. The former causes the release of hypoxia inducible factor 1α (HIF1α), while adipocytes necrosis induces infiltration and M1-polarization of macrophages, thus producing WAT dysfunction, inflammation and fibrosis [53,55,56,57,58,59,60,61,62]. Such a WAT remodeling causes a dysregulation of multiple endocrine and lipid storage functions [54,62]. Dysfunctional WAT, in its turn, is associated with an imbalanced cytokine release, i.e., over-production of multiple pro-inflammatory adipocytokines, such as tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1/C-C chemokine receptor-2 (MCP-1/CCR-2), and reduction of adiponectin, which contribute to worsen local and systemic metabolic derangements [62,63,64,65,66,67,68,69,70,71,72]. Increased interstitial fibrosis in WAT limits adipose tissue expandability [52,53,62]. Reduction in lipid storage capacity also contributes to ectopic lipid accumulation in the liver, skeletal muscles and pancreas where lipotoxicity triggers multiple pathways that hinder insulin signaling [53,62,73,74]. All of these mechanisms may contribute to the development of IR in the adipose tissue with its inherent failure to suppress adipose lipolysis that results in an overflow of free fatty acids (FFAs) to the liver [74].

2.2.2. Role of Skeletal Muscle and Brown Adipose Tissue

Muscle IR, due to intra-myocellular lipid accumulation, occurs early in the course of T2D. It has been suggested that intra-myocellular diacylglycerol (DAG) accumulation activates protein kinase C-θ (PKCθ), which impairs insulin signaling, impeding muscle glucose uptake and leading to increased delivery of glucose to the liver, where it becomes substrate for hepatic de-novo lipogenesis (DNL) [74,75,76,77]. Accordingly, it has recently been shown that skeletal muscle steatosis is associated with NAFLD [78].

The myokines, i.e., cytokines produced by the skeletal muscle, have been recently identified as another piece in the interplay linking NAFLD to T2D. Irisin is produced by the skeletal muscle in response to physical exercise and exerts beneficial metabolic effects by recruiting brown adipose tissue (BAT) and triggering thermogenesis [79,80]. Evidence has recently shown that BAT is recruitable post-natally within either WAT or skeletal muscle [81,82,83,84,85]. BAT, through the expression of uncoupling C protein-1 (UCP-1), generates heat and regulates energy expenditure, lipid and glucose metabolism [81,86,87]. For these reasons, both irisin and BAT could be potential targets for the treatment of obesity-related complications. Interestingly, low levels of irisin have been associated with NAFLD and T2D in humans, thus confirming the important role of this myokine in the regulation of energy homeostasis and preservation of a healthy metabolism [88,89,90].

 2.2.3. Intrahepatic Fat Accumulation, Hepatic Insulin Resistance and Hepatokines

In NAFLD, steatogenesis results mainly from increased hepatic esterification of FFAs originating from dysfunctional/inflamed WAT (60%), DNL (25%) and diet (15%) [91,92]. Increased lipolysis drives hepatic lipid synthesis through esterification of FFAs and stimulates hepatic gluconeogenesis [92,93,94], thus promoting hepatic IR [74,95]. Muscle IR increases glucose delivery to the liver, thus enhancing DNL. Moreover, dietary monosaccharides, particularly fructose, directly promotes hepatic lipogenesis by increasing sterol regulatory element binding protein 1c (SREBP1c), carbohydrate-responsive element-binding protein (chREBP), peroxisome proliferator-activated receptor (PPAR)-γ coactivator 1-β, and liver X receptor expression [74,96,97,98,99,100,101].

The resulting intrahepatic ectopic storage of lipids has been specifically associated with hepatic IR [74,102]. However, hepatic triglyceride accumulation per se is not always harmful. Experimentally, the inhibition of diacylglycerol acyltransferase 2 (DGAT2), an enzyme devoted to hepatocyte triglyceride biosynthesis, decreases hepatic steatosis, but increases markers of lipid peroxidation/oxidant stress, hepatic lobular necro-inflammation and fibrosis [103]. Several lines of evidence support that intrahepatic diacylglycerol (DAG), via activation of PKCε, and ceramides, by impairing Akt2 action and inducing endoplasmic-reticulum stress and mitochondrial dysfunction, are the two major lipid mediators of hepatic IR [74,102,104,105,106,107,108,109,110,111,112,113,114]. Also intracellular localization of lipids in the liver matters [102]. A common single-nucleotide polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3), a lipid droplet protein with triglyceride lipase activity, has been strongly associated with NAFLD, but not with IR [114,115,116,117,118,119,120]. This dissociation between hepatic steatosis and IR is likely due to the accumulation of metabolically inert polyunsaturated triacylglycerols in lipid droplets caused by the PNPLA3 I148M variant [114,121,122]. Other underlying mechanisms clearly implicated in the development of hepatic IR and in the progression of NAFLD are low-grade chronic inflammation, elevated production of reactive oxygen species, activation of unfolded protein response and endoplasmic-reticulum stress, activation of Jun N-terminal kinase (JNK)-1, increased hepatocyte apoptosis and lipo-autophagy [25,92,102,123,124,125,126,127].

Finally, the liver releases several endocrine mediators, the so-called hepatokines, able to impact glucose metabolism, insulin action and secretion. Fetuin-A, which is abundantly secreted by steatotic hepatocytes, mediates IR by inhibiting the insulin receptor, reducing adiponectin expression, and enhancing WAT inflammation and dysfunction, and is independently associated with T2D development [128,129,130,131,132]. More recently, also fetuin-B has emerged as a potentially major player in T2D pathogenesis. Indeed, in their seminal study, Meex et al. [133], have shown that 32 hepatokines are differently secreted in steatotic versus non-steatotic hepatocytes. By inducing inflammation and IR in macrophages and skeletal muscles, these changes in the secretory products may contribute to the development of metabolic dysfunction in other cell types. These authors have identified higher levels of fetuin-B in the altered hepatokine secretory profile of steatotic livers in obese patients, and have also experimentally demonstrated that fetuin-B impairs insulin sensitivity in myotubes and hepatocytes and causes glucose intolerance in mice [133]. Fibroblast growth factor (FGF)-21 acts as a potent activator of glucose uptake and inhibitor of WAT lipolysis, recruits BAT and is associated with obesity, NAFLD and T2D [134,135,136,137,138,139,140]. Finally, serpinB1 increases pancreatic β-cell proliferation and its deficiency leads to maladaptive β-cell proliferation in IR [141,142].

 2.2.4. Gut-Liver Axis

Compelling evidence links gut microbiota, intestinal barrier integrity and NAFLD. Dysbiosis and impaired gut permeability favor the occurrence of endotoxemia and toll like receptor (TLR) 4-mediated inflammation, thereby contributing to the development of IR and other metabolic complications in obese individuals [143,144,145]. Other interactions between the gut and the liver may occur through the production of multiple gut hormones and the entero-hepatic circulation of bile acids that activate farnesoid X receptor in the liver [26].

Although further research is needed, these findings underline the importance of NAFLD as a precursor for the development of hepatic and systemic IR. However, the presence of long-standing IR per se is not sufficient to lead to the development of T2D. Gluco-lipotoxicity and genetic factors are additional requirements, which induce T2D through the development of pancreatic β-cell failure [25,74,146].

2.3. Clinical Implications
2.3.1. NASH and Fibrosis

Several studies have shown that T2D patients with NAFLD are at a high risk of NASH and cirrhosis [39,147,148,149]. Data from cross sectional studies [15,150,151,152,153] and longitudinal retrospective studies with sequential liver biopsies [154,155,156] clearly indicate that T2D strongly predicts fibrosis severity and progression in NAFLD patients. Consistently, two studies have demonstrated that poor glycemic control was associated with an increased risk of fibrosis in NASH [157,158].

Interestingly, one study showed that T2D and IR were strongly associated with NASH and severe fibrosis in patients with normal serum liver enzymes [159]. This finding provides further evidence to the clinical wisdom that “normal” serum liver enzyme levels are not a sufficient reason for excluding from liver biopsy those “high-risk” patients in whom advanced liver disease is strongly suggested by non-invasive evaluation. To this end, transient elastography and semi-quantitative ultrasound or non-invasive clinical scores (such as the US-FLI, the NAFLD fibrosis or the Fib4 scores) may be used in most patients with T2D [39,45,160,161].

 2.3.2. Cirrhosis and Hepatocellular Carcinoma

Many studies have reported T2D as an established risk factor for cirrhosis [162,163] and HCC [164,165,166]. Worryingly, a significant proportion of NAFLD patients with HCC have no evidence of cirrhosis [164], implying that they have escaped the normal surveillance strategies implemented in patients with cirrhosis of viral or alcoholic origin, and thus are diagnosed too late to receive radical treatment [167,168].

The presence of NAFLD among patients with T2D is also an important risk factor of increased all-cause and cause-specific mortality. Patients with T2D have an increased mortality risk from cirrhosis of any aetiology [39]. Accordingly, a recent cohort study showed that, compared to the age- and sex-matched general population, patients with T2D had a two- to three-fold higher risk of dying of non-viral and non-alcoholic chronic liver disease, largely attributable to NAFLD [169]. Consistently, a recent Scottish national retrospective cohort study reported that T2D was associated with an increased risk of hospital admissions or deaths for all common chronic liver diseases and, among them, NAFLD had the strongest association with T2D [170]. In agreement, a retrospective USA cohort study on 132 NAFLD patients found that T2D patients with NAFLD were at risk for the development of poor clinical outcomes, such as increased all-cause and liver-related mortality or morbidity after adjusting for potential confounding factors [162]. Finally, NAFLD was associated with a two-fold increased risk of all-cause mortality (mainly due to malignancy (33%), liver-related complications (19%) or ischemic heart disease (19%)) in a cohort study of 337 T2D patients followed-up for a mean period of 11 years [171].

 2.3.3. Atherosclerosis

Accumulating evidence indicates that NAFLD is strongly associated not only with liver-related morbidity or mortality, but also with an excess risk of CVD, which is the most common cause of death in T2D [39]. Several studies have reported a strong association between NAFLD and early subclinical or advanced atherosclerosis among patients with and without T2D [172]. These findings have been further confirmed by multiple prospective studies that showed an increased risk of fatal and non-fatal CVD events in patients with and without T2D, independently of several cardiometabolic risk factors [39,172,173,174]. The association between NAFLD and risk of CVD mortality has been further supported by a milestone meta-analysis [17], although some recent follow-up studies are conflicting [172,175].

Emerging evidence also indicates that NAFLD is independently associated with the development of microvascular diabetic complications, i.e., chronic kidney disease and advanced diabetic retinopathy [5].

Collectively, the above-mentioned studies convincingly show that T2D is strongly associated with an increased risk of progressive NAFLD and an excess risk of overall and cause-specific mortality, including not only liver-related but also CVD-related mortality. These findings fully support careful monitoring and screening for NAFLD and/or advanced fibrosis among patients with T2D.

3. HCV and Type 2 Diabetes
3.1 Epidemiology
3.1.1. HCV and Diabetes: A Non-chance Association

The notion that cirrhosis is a potentially diabetogenic condition dates back to as early as 1906 [176]. More recently, such a view was confirmed in the pre-HBV and pre-HCV age [177]. It was more than 20 years ago that Allison et al., [178] by comparing the rates of T2D among cirrhotic patients undergoing evaluation for liver transplantation, showed that T2D prevalence was 50% in patients with HCV-related versus 9% in those with non-HCV-related cirrhosis. Since that pioneering report, this topic has developed into a major line of research and, at the time of this writing, more than 1340 articles can be retrieved [179].

3.1.2. The Burden

Licensing of oral direct acting antivirals (DAA), which deliver sustained virological response (SVR) rates >90%, has led to the revolutionary expectation that HCV infection will possibly be the first chronic viral infection totally eradicated [22]. However, such an inference is premature and, for the time being, HCV still infects from 150,000,000 to 185,000,000 people worldwide, namely up to 2.8% of the world population [180,181]. Moreover, in developing countries, the case-finding and management have not improved in tandem, suggesting that continued refinement of epidemiology, cost-utility models and targeted diagnostic strategies remain an unmet need [182]. Worldwide, chronic HCV infection remains a significant public health burden, given that it can lead to cirrhosis in approximately 15% to 20% of those infected within 20 years, resulting in end-stage liver disease and HCC [182]. In Europe, although the iatrogenic HCV transmission was enormously reduced over the last 20 years, transmission related to intravenous recreational drug use is on the increase, especially in Eastern Europe, and the high HCV prevalence in the migrant populations is a challenge [183]. Moreover, HCV-related morbidity and mortality are projected to increase in Europe until 2030 [183]. In the USA, up to 35% of patients on the liver-transplant waiting list are infected with HCV, and global HCV-associated mortality estimates approximate 500,000 deaths per year [184,185].

3.1.3. Extra-Hepatic Manifestations of HCV Infection: Type 2 Diabetes

The clinical spectrum of chronic HCV infection is not limited to liver disease but also includes major extra-hepatic conditions, affecting eyes, salivary glands, skin, kidneys, genital tract, endocrine, neurologic, cardiovascular and immune systems (Figure 2) [8,37,38].

Among the extra-hepatic manifestations of HCV, a mutual and bi-directional relationship connects T2D with HCV infection. HCV infection is more common in patients with T2D than in those without T2D and, conversely, T2D abounds among patients with chronic HCV infection [177]. That said, however, the usual clinical scenario depicts a vignette in which, in predisposed individuals, HCV infection precedes and accelerates the development of new-onset T2D by approximately 10 years [38,186]. This finding suggests that HCV infection observed in T2D patients does not result from the risk of HCV infection associated with medical procedures in the highly medicalized T2D population but is the primary event which may adversely affect the subsequent development of T2D [187].

3.1.4. Heterogeneity in the Distribution of HCV and Type 2 Diabetes and Differential Features of Hepatitis C-Associated Dysmetabolic Syndrome and MetS

There are 170,000,000 individuals with T2D worldwide, namely the same number of individuals with HCV infection [177]. However, HCV infection has undergone epidemiological diffusion in certain age groups and geographical areas as a result of specific lifestyle risk behaviors or transmission via medical practices, whereas T2D reaches its zenith among 45-to-64 year old individuals, particularly in obese and sedentary individuals [177]. Stated otherwise, the epidemiological distribution of HCV infection and T2D does not identify the same geographical areas and groups of individuals. Accordingly, screening campaigns to identify either HCV infection among T2D patients or T2D among those with HCV infection are not justifiable at this time and more accurate strategies are needed in screening selected cohorts of individuals [188].

Finally, it should be pointed out that while T2D is a prominent feature of the MetS which is bi-directionally associated with NAFLD [3], HCV infection is also associated with a specific hepatitis C-associated dysmetabolic syndrome (HCADS), which was first described by Lonardo et al. [189].

Table 1 schematically compares the main features of the MetS with those of the HCADS [3,7,168,190,191,192,193].

        

Table 1. Metabolic Syndrome versus Hepatitis C-Associated Dysmetabolic Syndrome (HCADS)—A comparison at a glance.

Criteria	Metabolic Syndrome	HCADS	Reference(s)
T2D	Yes	Yes	[3]
Hypertension	Yes	Yes	[3]
Visceral Obesity	Yes	Preliminary evidence suggests that HCV patients have abdominal fat distribution	[3]
Atherogenic dyslipidemia	Yes	Acquired, reversible hypocholesterolemia	[6]
Hepatic steatosis	Not included among diagnostic criteria but often found as a concurrent or precursor finding	In chronic HCV patients, steatosis is two- to three-fold more prevalent than in chronic hepatitides of other etiologies. HCV genotype 3 is associated with a higher prevalence and more severe steatosis	[3,6]
Hyperuricemia	Not included in diagnostic criteria but often associated on pathophysiological grounds	Strongly associated with severity of steatosis	[3,190]
Accelerated atherogenesis	Whether the full-blown MetS adds to the risk of its individual components, particularly T2D, is controversial	Individuals with HCV infection (particularly those with T2D and hypertension) have an excess of cardiovascular morbidity and mortality	[3,191]
HCC risk	Both the MetS and T2D increase the risk of HCC. This likely results via NAFLD/NASH even in non-cirrhotic livers	Concurrent T2D and chronic HCV infection lead to increased risk of HCC. Steatosis and overweight/obesity possibly play a role	[168,192,193]

3.2. Pathophysiology

 3.2.1. HCV Increases T2D Risk via Insulin Resistance

Consistent with the development of new-onset T2D observed in the setting of NAFLD, HCV promotes a state of IR that leads, over time, to pancreatic beta-cell dysfunction, eventually culminating in the irreversible damage of such cells and the development of overt T2D [177].

 3.2.2. IR Associated with HCV: Antigens, Sites and Determinants

HCV antigens, such as the core protein, play a key role in determining post-receptor defects causing IR by interfering with the AKT signaling pathway via cytokines (such as TNF-α and interleukin-6) and the suppressors of cytokine signaling [194,195,196,197]. Strong evidence suggests that the site of IR is not only hepatic but also extra-hepatic [198], predominantly in the skeletal muscle, correlates with subcutaneous, rather than visceral adiposity, and is independent of liver fat content [199]. These findings conflict with the notion that HCV predominantly infects hepatocytes and suggest that either HCV-infected hepatocytes release a soluble mediator capable of inducing IR in skeletal muscles [38] or, alternatively, that HCV directly infects myocytes. This latter hypothesis appears to be conceptually sustainable based on the findings of a recent case-control study, which provided evidence for a significant association between inclusion body myositis and HCV infection [200].

3.2.3. T2D in the Setting of the HCADS

T2D is not the only metabolic disease observed in the setting of HCV infection. Over time, several features of what is now alluded to as the HCADS have been increasingly identified. For example, hepatic steatosis, which is one of such features, was first identified as a distinct disease entity [7,21,201]. Data comparing hepatic steatosis due to varying viral (HIV-related) and non-viral (NAFLD) steatogenic disorders suggest that IR is a prominent feature specifically associated with HCV infection [202].

Over time, several features have been added to the initial description of the HCADS [203,204,205], which, presently, is deemed to characterize hyperuricemia, reversible hypocholesterolemia, IR, hypertension and visceral obesity [189]. Collectively, these dysmetabolic disorders may best be interpreted as a Darwinian survival strategy favoring the survival of HCV at the expenses of the host’s metabolism [189]. The finding of expanded visceral adipose tissue in patients with HCV infection is consistent with the hepatic and extra-hepatic origin of IR discussed above and prompts further research as to the potential ability of HCV infection to localize directly within adipocytes [206,207].

3.3. Clinical Implications
3.3.1. Risk of Fibrosis

A consistent body of evidence supports the notion that T2D is closely associated with fibrosis in the setting of chronic HCV infection [188]. More recently, a large study conducted in USA in approximately 10,000 patients with hepatitis C found that age, sex, race, HCV genotype, HIV co-infection, alcohol abuse, antiviral therapy and T2D were independently associated with the risk of cirrhosis [208]. Moreover, a recent meta-analysis of 14 studies, involving 3659 participants with HCV infection, reported a significant association between IR and advanced hepatic fibrosis among patients with HCV genotype 1 infection but not among those with HCV genotype 3 [209]. These findings are consistent with those of previous studies reporting that IR was strongly associated with HCV genotypes 1 and 4 [210,211].

3.3.2. Risk of Hepatocellular Carcinoma

Population-based studies fully support T2D being as an emerging risk factor for HCC [192]. In a recent meta-analysis, Dyal et al., [193] have reported that concurrent T2D is strongly associated with an increased risk of HCC among chronic HCV patients. It may be argued, however, that, in these patients, T2D may either be a proxy of more advanced metabolic derangement which leads to excess fibrosis via NASH or that T2D per se exposes these individuals to higher risk of developing HCC via increased oxidative stress and hormonal changes (e.g., IR, increased IGF-1 and activation of the renin-angiotensin-aldosterone system) [193,212,213].

An Italian study conducted in 163 consecutive HCV-positive patients with cirrhosis followed-up for a median period of 10.7 years found that HCV genotype 1b was strongly associated with a higher risk of developing HCC [214].

Further studies are needed to control accurately for all viral and host’s confounders, such as genotype, obesity and ethnicity, given that an improved understanding of HCC risk factors may provide specific areas of targeted interventions to reduce HCC risk in chronic HCV patients [193].

3.3.3. Risk of Atherosclerosis

The strong association between HCV infection and T2D development is one of the most important mechanisms that may lead to accelerated atherogenesis in chronic HCV patients [215]. Three studies showed that HCV infection is a strong risk factor for carotid subclinical atherosclerosis [216,217,218]. Consistent with the notion that HCV infection is a systemic disease, the risk of major CVD events is higher in patients with HCV infection than in HCV-negative controls, independently of traditional CVD risk factors and other potential confounding variables [219,220]. In a recent meta-analysis conducted on 22 studies, Petta et al. [191] showed that patients with chronic HCV infection had an increased risk of CVD-related morbidity and mortality, especially those with T2D and hypertension. On these grounds, all chronic HCV patients should be non-invasively screened for atherosclerosis [215].

4. Conclusions

Among the “four musketeers” fighting for controlling glucose homeostasis, the liver is now in the spotlight of basic, epidemiological and clinical investigations (Figure 1). Indeed, by reviewing the role of HCV and NAFLD in the development of T2D, we found that there is a substantial body of evidence indicating that the liver plays a pathogenic role in T2D development and that the close inter-connections connecting T2D with liver disease may result in a “vicious circle” eventually leading to an excess risk of liver-related and CVD complications (Figure 3).

Figure 3.

Non-alcoholic fatty liver disease, hepatitis C virus infection and type 2 diabetes: the “vicious circle”.
The liver plays a pathogenic role in the development of type 2 diabetes both in the context of non-alcoholic fatty liver disease and hepatitis C virus infection through the development of systemic and hepatic insulin resistance, partly mediated by the release of multiple pro-inflammatory cytokines, diabetogenic hepatokines and reactive oxygen species. If left uncorrected, insulin resistance will eventually lead to progressive pancreatic beta cell failure in predisposed individuals. Moreover, the strong interconnection between type 2 diabetes and liver disease may result into a “vicious circle” [25] eventually leading to liver disease progression with an excess risk of liver-related, i.e., cirrhosis and hepatocellular carcinoma (HCC), and cardiovascular complications, i.e., atherosclerosis.

NAFLD and HCV infection are two multisystem diseases whose spectrum of clinical manifestations, seemingly as a result of their sharing hepatic steatosis and IR as prominent features (Figure 2) [205], tends to overlap more and more. Basic research is very active in the arena of NAFLD pathophysiology and extrapolation of notions from the NAFLD to the HCV research field appears to be justified and potentially fruitful [21].

However, several questions remain largely unanswered. For instance: is NAFLD treatment able to reduce the development of T2D and its major complications? Based on preliminary evidence [47,48] one may be tempted to answer affirmatively, though this remains to be fully proven by studies ad hoc. Does T2D impair SVR in the era of new direct-acting antivirals? While T2D was associated with a lower SVR rate following interferon-based therapy [7], regimens based on new direct-acting antiviral agents do not appear to be affected by coexisting T2D [221]. Moreover, whether HCV eradication may also have an impact on the future morbidity and mortality due to T2D is a clinically relevant and biologically plausible outcome. However, further studies with new direct-acting antivirals are needed to ultimately settle this issue [27].

In the meantime, it is important to underline that lifestyle changes are the mainstay of treatment for all patients with NAFLD and T2D [173,222]. It has been reported that a combination of educational, behavioral and motivational strategies may help patients with NAFLD in achieving lifestyle changes [223,224,225]. Preliminary evidence also suggests that body weight reduction may improve liver histology in those patients in whom HCV infection is associated with hepatic steatosis [226]. However, future studies are required to better define effective weight loss strategies in these patients.

Acknowledgments
Giovanni Targher is supported in part by grants from the University School of Medicine of Verona. We are indebted to Ms. Elisa Gibertini for her helping us as a graphic artist.

Author Contributions

Amedeo Lonardo conceived the idea of this article, wrote the first draft of Chapters 1 and 4, the Table and, with Dante Romagnoli, Chapter 3; Amedeo Lonardo also drew the figures in collaboration with Giovanni Targher and Fabio Nascimbeni; Stefano Ballestri and Fabio Nascimbeni wrote the first draft of Abstract and Chapter 2; Giovanni Targher and Enrica Baldelli contributed to the discussion and reviewed the manuscript. All the Authors took part in the bibliographic research, discussed, edited and approved the final version of the article.

Conflicts of Interest

Stefano Ballestri, Fabio Nascimbeni, Enrica Baldelli, Giovanni Targher and Amedeo Lonardo have nothing to disclose. Dante Romagnoli serves as a consultant for AbbVie.

Abbreviations

The following abbreviations are used in this manuscript:

CCR-2	C-C chemokine receptor-2
CHD	coronary heart disease
chREBP	carbohydrate-responsive element-binding protein
CVD	cardiovascular disease
DAA	direct acting antivirals
DAG	diacylglycerol
DGAT2	diacylglycerolacyltransferase 2
DNL	de-novo lipogenesis
FA	fatty acids
FGF-21	fibroblast growth factor 21
FXR	farnesoid X receptor
HCC	hepatocellular carcinoma
HIF1α	hypoxia inducible factor 1α
HCV	hepatitis C virus
IR	insulin resistance
MCP-1	monocyte chemoattractant protein-1
MetS	metabolic syndrome
PNPLA3	patatin-like phospholipase domain-containing protein 3
PPAR-γ	peroxisome proliferator–activated receptor γ
ROS	reactive oxygen species
SREBP1c	sterol regulatory element binding protein 1c
T2D	type 2 diabetes
TLR-4	toll-like receptor 4
TNFα	tumor necrosis factor α
UCP-1	uncoupling protein-1
WAT	white adipose tissue

 

References

 

1. Inzucchi, S.E. Clinical practice. Diagnosis of diabetes. N. Engl. J. Med. 2012, 367, 542–550. [Google Scholar] [CrossRef] [PubMed]
2. Cameron, F.J.; Wherrett, D.K. Care of diabetes in children and adolescents: Controversies, changes, and consensus. Lancet 2015, 385, 2096–2106. [Google Scholar] [CrossRef]
3. Lonardo, A.; Ballestri, S.; Marchesini, G.; Angulo, P.; Loria, P. Nonalcoholic fatty liver disease: Aprecursor of the metabolic syndrome. Dig. Liver Dis. 2015, 47, 181–190. [Google Scholar] [CrossRef] [PubMed]
4. Nascimbeni, F.; Pais, R.; Bellentani, S.; Day, C.P.; Ratziu, V.; Loria, P.; Lonardo, A. From NAFLD in clinical practice to answers from guidelines. J. Hepatol. 2013, 59, 859–871. [Google Scholar] [CrossRef] [PubMed]
5. Byrne, C.D.; Targher, G. NAFLD: A multisystem disease. J. Hepatol. 2015, 62, S47–S64. [Google Scholar] [CrossRef] [PubMed]
6. Petta, S.; Valenti, L.; Bugianesi, E.; Targher, G.; Bellentani, S.; Bonino, F.; Special Interest Group on Personalised Hepatology of the Italian Association for the Study of the Liver (AISF). A “systems medicine” approach to the study of non-alcoholic fatty liver disease. Dig. Liver Dis. 2016, 48, 333–342. [Google Scholar] [CrossRef] [PubMed]
7. Lonardo, A.; Loria, P.; Adinolfi, L.E.; Carulli, N.; Ruggiero, G. Hepatitis C and steatosis: A reappraisal. J. Viral Hepat. 2006, 13, 73–80. [Google Scholar] [CrossRef] [PubMed]
8. Negro, F.; Forton, D.; Craxi, A.; Sulkowski, M.S.; Feld, J.J.; Manns, M.P. Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology 2015, 149, 1345–1360. [Google Scholar] [CrossRef] [PubMed]
9. Shaw, J.E.; Sicree, R.A.; Zimmet, P.Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract. 2010, 87, 4–14. [Google Scholar] [CrossRef] [PubMed]
10. Kanavos, P.; van den Aardweg, S.; Schurer, W. Diabetes Expenditure, Burden of Disease and Management in 5 EU Countries. Available online here:  (accessed on 8 February 2016).
11. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States; U.S. Department of Health and Human Services, Centers for Disease Control and Prevention: Atlanta, GA, USA, 2011.
12. American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diabetes Care 2008, 31, 596–615. [Google Scholar]
13. Sherwin, R.; Jastreboff, A.M. Year in diabetes 2012: The diabetes tsunami. J. Clin. Endocrinol. Metab. 2012, 97, 4293–4301. [Google Scholar] [CrossRef] [PubMed]
14. Zimmerman, H.J.; Mac, M.F.; Rappaport, H.; Alpert, L.K. Studies on the liver in diabetes mellitus. II. The significance of fatty metamorphosis and its correlation with insulin sensitivity. J. Lab. Clin. Med. 1950, 36, 922–928. [Google Scholar] [PubMed]
15. Ballestri, S.; Nascimbeni, F.; Romagnoli, D.; Lonardo, A. The independent predictors of NASH and its individual histological features. Insulin resistance, serum uric acid, metabolic syndrome, alt and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment. Hepatol. Res. 2016. [Google Scholar] [CrossRef] [PubMed]
16. Zhang, Y.; Zhang, T.; Zhang, C.; Tang, F.; Zhong, N.; Li, H.; Song, X.; Lin, H.; Liu, Y.; Xue, F. Identification of reciprocal causality between non-alcoholic fatty liver disease and metabolic syndrome by a simplified bayesian network in a chinese population. BMJ Open 2015, 5, e008204. [Google Scholar] [CrossRef] [PubMed]
17. Musso, G.; Gambino, R.; Cassader, M.; Pagano, G. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann. Med. 2011, 43, 617–649. [Google Scholar] [CrossRef] [PubMed]
18. Ballestri, S.; Zona, S.; Targher, G.; Romagnoli, D.; Baldelli, E.; Nascimbeni, F.; Roverato, A.; Guaraldi, G.; Lonardo, A. Nonalcoholic fatty liver disease is associated with an almost two-fold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J. Gastroenterol. Hepatol. 2015. [Google Scholar] [CrossRef] [PubMed]
19. White, D.L.; Ratziu, V.; El-Serag, H.B. Hepatitis Cinfection and risk of diabetes: A systematic review and meta-analysis. J. Hepatol. 2008, 49, 831–844. [Google Scholar] [CrossRef] [PubMed]
20. Cacoub, P.; Gragnani, L.; Comarmond, C.; Zignego, A.L. Extrahepatic manifestations of chronic hepatitis Cvirus infection. Dig. Liver Dis. 2014, 46, S165–S173. [Google Scholar] [CrossRef] [PubMed]
21. Lonardo, A.; Adinolfi, L.E.; Loria, P.; Carulli, N.; Ruggiero, G.; Day, C.P. Steatosis and hepatitis Cvirus: Mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004, 126, 586–597. [Google Scholar] [CrossRef] [PubMed]
22. Asselah, T.; Boyer, N.; Saadoun, D.; Martinot-Peignoux, M.; Marcellin, P. Direct-acting antivirals for the treatment of hepatitis Cvirus infection: Optimizing current IFN-free treatment and future perspectives. Liver Int. 2016, 36, 47–57. [Google Scholar] [CrossRef] [PubMed]
23. Ilyas, J.A.; Vierling, J.M. An overview of emerging therapies for the treatment of chronic hepatitis C. Med. Clin. N. Am. 2014, 98, 17–38. [Google Scholar] [CrossRef] [PubMed]
24. Welsch, C.; Jesudian, A.; Zeuzem, S.; Jacobson, I. New direct-acting antiviral agents for the treatment of hepatitis Cvirus infection and perspectives. Gut 2012, 61, i36–i46. [Google Scholar] [CrossRef] [PubMed]
25. Loria, P.; Lonardo, A.; Anania, F. Liver and diabetes. A vicious circle. Hepatol. Res. 2013, 43, 51–64. [Google Scholar] [CrossRef] [PubMed]
26. Ballestri, S.; Nascimbeni, F.; Romagnoli, D.; Baldelli, E.; Lonardo, A. The role of nuclear receptors in the pathophysiology, natural course, and drug treatment of NAFLDin humans. Adv. Ther. 2016. [Google Scholar] [CrossRef] [PubMed]
27. Vanni, E.; Bugianesi, E.; Saracco, G. Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: Myth or reality? Dig. Liver Dis. 2016, 48, 105–111. [Google Scholar] [CrossRef] [PubMed]
28. Klip, A.; Vranic, M. Muscle, liver, and pancreas: Three musketeers fighting to control glycemia. Am. J. Physiol. Endocrinol. Metab. 2006, 291, E1141–E1143. [Google Scholar] [CrossRef] [PubMed]
29. Reaven, G.M. The fourth musketeer—From Alexandre Dumas to Claude Bernard. Diabetologia 1995, 38, 3–13. [Google Scholar] [CrossRef] [PubMed]
30. Armstrong, M.J.; Adams, L.A.; Canbay, A.; Syn, W.K. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 2014, 59, 1174–1197. [Google Scholar] [CrossRef] [PubMed]
31. Carulli, L.; Ballestri, S.; Lonardo, A.; Lami, F.; Violi, E.; Losi, L.; Bonilauri, L.; Verrone, A.M.; Odoardi, M.R.; Scaglioni, F.; et al. Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels? Intern. Emerg. Med. 2013, 8, 297–305. [Google Scholar] [CrossRef] [PubMed]
32. Nascimbeni, F.; Ballestri, S.; Di Tommaso, L.; Piccoli, M.; Lonardo, A. Inflammatory hepatocellular adenomatosis, metabolic syndrome, polycystic ovary syndrome and non-alcoholic steatohepatitis: Chance tetrad or association by necessity? Dig. Liver Dis. 2014, 46, 288–289. [Google Scholar] [CrossRef] [PubMed]
33. Loria, P.; Carulli, L.; Bertolotti, M.; Lonardo, A. Endocrine and liver interaction: The role of endocrine pathways in NASH. Nat.Rev. Gastroenterol. Hepatol. 2009, 6, 236–247. [Google Scholar] [CrossRef] [PubMed]
34. Targher, G.; Rossini, M.; Lonardo, A. Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: Anovel hepato-ovarian axis? Endocrine 2016, 51, 211–221. [Google Scholar] [CrossRef] [PubMed]
35. Targher, G.; Lonardo, A.; Rossini, M. Nonalcoholic fatty liver disease and decreased bone mineral density: Is there a link? J. Endocrinol. Investig. 2015, 38, 817–825. [Google Scholar] [CrossRef] [PubMed]
36. Mantovani, A.; Gisondi, P.; Lonardo, A.; Targher, G. Relationship between non-alcoholic fatty liver disease and psoriasis: A novel hepato-dermal axis? Int. J. Mol. Sci. 2016, 17, 217. [Google Scholar] [CrossRef] [PubMed]
37. Vigano, M.; Colombo, M. Extrahepatic manifestations of hepatitis C virus. Gastroenterol. Clin. N. Am. 2015, 44, 775–791. [Google Scholar] [CrossRef] [PubMed]
38. Negro, F. Facts and fictions of HCV and comorbidities: Steatosis, diabetes mellitus, and cardiovascular diseases. J. Hepatol. 2014, 61, S69–S78. [Google Scholar] [CrossRef] [PubMed]
39. Lonardo, A.; Bellentani, S.; Argo, C.K.; Ballestri, S.; Byrne, C.D.; Caldwell, S.H.; Cortez-Pinto, H.; Grieco, A.; Machado, M.V.; et al. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Dig Liver Dis. 2015, 47, 997–1006. [Google Scholar]
40. Singh, S.; Allen, A.M.; Wang, Z.; Prokop, L.J.; Murad, M.H.; Loomba, R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: Asystematic review and meta-analysis of paired-biopsy studies. Clin. Gastroenterol. Hepatol. 2015, 13, 643–654. [Google Scholar] [CrossRef] [PubMed]
41. Leite, N.C.; Villela-Nogueira, C.A.; Pannain, V.L.; Bottino, A.C.; Rezende, G.F.; Cardoso, C.R.; Salles, G.F. Histopathological stages of nonalcoholic fatty liver disease in type 2 diabetes: Prevalences and correlated factors. Liver Int. 2011, 31, 700–706. [Google Scholar] [CrossRef] [PubMed]
42. Portillo Sanchez, P.; Bril, F.; Maximos, M.; Lomonaco, R.; Biernacki, D.; Orsak, B.; Subbarayan, S.; Webb, A.; Hecht, J.; Cusi, K. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J. Clin. Endocrinol. Metab. 2015, 100, 2231–2238. [Google Scholar] [CrossRef] [PubMed]
43. Williams, C.D.; Stengel, J.; Asike, M.I.; Torres, D.M.; Shaw, J.; Contreras, M.; Landt, C.L.; Harrison, S.A. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: Aprospective study. Gastroenterology 2011, 140, 124–131. [Google Scholar] [CrossRef] [PubMed]
44. Kwok, R.; Choi, K.C.; Wong, G.L.; Zhang, Y.; Chan, H.L.; Luk, A.O.; Shu, S.S.; Chan, A.W.; Yeung, M.W.; Chan, J.C.; et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: Aprospective cohort study. Gut 2015. [Google Scholar] [CrossRef] [PubMed]
45. Anstee, Q.M.; Targher, G.; Day, C.P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat.Rev. Gastroenterol. Hepatol. 2013, 10, 330–344. [Google Scholar] [CrossRef] [PubMed]
46. Maximos, M.; Bril, F.; Portillo Sanchez, P.; Lomonaco, R.; Orsak, B.; Biernacki, D.; Suman, A.; Weber, M.; Cusi, K. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology 2015, 61, 153–160. [Google Scholar] [CrossRef] [PubMed]
47. Sung, K.C.; Wild, S.H.; Byrne, C.D. Resolution of fatty liver and risk of incident diabetes. J. Clin. Endocrinol. Metab. 2013, 98, 3637–3643. [Google Scholar] [CrossRef] [PubMed]
48. Yamazaki, H.; Tsuboya, T.; Tsuji, K.; Dohke, M.; Maguchi, H. Independent association between improvement of nonalcoholic fatty liver disease and reduced incidence of type 2 diabetes. Diabetes Care 2015, 38, 1673–1679. [Google Scholar] [CrossRef] [PubMed]
49. Fukuda, T.; Hamaguchi, M.; Kojima, T.; Hashimoto, Y.; Ohbora, A.; Kato, T.; Nakamura, N.; Fukui, M. The impact of non-alcoholic fatty liver disease on incident type 2 diabetes mellitus in non-overweight individuals. Liver Int. 2016, 36, 275–283. [Google Scholar] [CrossRef] [PubMed]
50. Shah, R.V.; Allison, M.A.; Lima, J.A.; Bluemke, D.A.; Abbasi, S.A.; Ouyang, P.; Jerosch-Herold, M.; Ding, J.; Budoff, M.J.; Murthy, V.L. Liver fat, statin use, and incident diabetes: The multi-ethnic study of atherosclerosis. Atherosclerosis 2015, 242, 211–217. [Google Scholar] [CrossRef] [PubMed]
51. Ekstedt, M.; Franzen, L.E.; Mathiesen, U.L.; Thorelius, L.; Holmqvist, M.; Bodemar, G.; Kechagias, S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006, 44, 865–873. [Google Scholar] [CrossRef] [PubMed]
52. Buechler, C.; Krautbauer, S.; Eisinger, K. Adipose tissue fibrosis. World J. Diabetes 2015, 6, 548–553. [Google Scholar] [PubMed]
53. Sun, K.; Tordjman, J.; Clement, K.; Scherer, P.E. Fibrosis and adipose tissue dysfunction. Cell Metab. 2013, 18, 470–477. [Google Scholar] [CrossRef] [PubMed]
54. Sun, K.; Kusminski, C.M.; Scherer, P.E. Adipose tissue remodeling and obesity. J. Clin. Investig. 2011, 121, 2094–2101. [Google Scholar] [CrossRef] [PubMed]
55. Cinti, S.; Mitchell, G.; Barbatelli, G.; Murano, I.; Ceresi, E.; Faloia, E.; Wang, S.; Fortier, M.; Greenberg, A.S.; Obin, M.S. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 2005, 46, 2347–2355. [Google Scholar] [CrossRef] [PubMed]
56. Cancello, R.; Henegar, C.; Viguerie, N.; Taleb, S.; Poitou, C.; Rouault, C.; Coupaye, M.; Pelloux, V.; Hugol, D.; Bouillot, J.L.; et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 2005, 54, 2277–2286. [Google Scholar] [CrossRef] [PubMed]
57. Halberg, N.; Khan, T.; Trujillo, M.E.; Wernstedt-Asterholm, I.; Attie, A.D.; Sherwani, S.; Wang, Z.V.; Landskroner-Eiger, S.; Dineen, S.; Magalang, U.J.; et al. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol. Cell. Biol. 2009, 29, 4467–4483. [Google Scholar] [CrossRef] [PubMed]
58. Jiang, C.; Qu, A.; Matsubara, T.; Chanturiya, T.; Jou, W.; Gavrilova, O.; Shah, Y.M.; Gonzalez, F.J. Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice. Diabetes 2011, 60, 2484–2495. [Google Scholar] [CrossRef] [PubMed]
59. Sun, K.; Halberg, N.; Khan, M.; Magalang, U.J.; Scherer, P.E. Selective inhibition of hypoxia-inducible factor 1alpha ameliorates adipose tissue dysfunction. Mol. Cell. Biol. 2013, 33, 904–917. [Google Scholar] [CrossRef] [PubMed]
60. Lumeng, C.N.; Bodzin, J.L.; Saltiel, A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Investig. 2007, 117, 175–184. [Google Scholar] [CrossRef] [PubMed]
61. Lumeng, C.N.; DelProposto, J.B.; Westcott, D.J.; Saltiel, A.R. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008, 57, 3239–3246. [Google Scholar] [CrossRef] [PubMed]
62. Suganami, T.; Tanaka, M.; Ogawa, Y. Adipose tissue inflammation and ectopic lipid accumulation. Endocr. J. 2012, 59, 849–857. [Google Scholar] [CrossRef] [PubMed]
63. Berg, A.H.; Scherer, P.E. Adipose tissue, inflammation, and cardiovascular disease. Circ. Res. 2005, 96, 939–949. [Google Scholar] [CrossRef] [PubMed]
64. Rocha, V.Z.; Libby, P. Obesity, inflammation, and atherosclerosis. Nat. Rev. Cardiol. 2009, 6, 399–409. [Google Scholar] [CrossRef] [PubMed]
65. Hotamisligil, G.S.; Shargill, N.S.; Spiegelman, B.M. Adipose expression of tumor necrosis factor-α: Direct role in obesity-linked insulin resistance. Science 1993, 259, 87–91. [Google Scholar] [CrossRef] [PubMed]
66. Uysal, K.T.; Wiesbrock, S.M.; Marino, M.W.; Hotamisligil, G.S. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997, 389, 610–614. [Google Scholar] [PubMed]
67. Kanda, H.; Tateya, S.; Tamori, Y.; Kotani, K.; Hiasa, K.; Kitazawa, R.; Kitazawa, S.; Miyachi, H.; Maeda, S.; Egashira, K.; et al. Mcp-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Investig. 2006, 116, 1494–1505. [Google Scholar] [CrossRef] [PubMed]
68. Kamei, N.; Tobe, K.; Suzuki, R.; Ohsugi, M.; Watanabe, T.; Kubota, N.; Ohtsuka-Kowatari, N.; Kumagai, K.; Sakamoto, K.; Kobayashi, M.; et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J. Biol. Chem. 2006, 281, 26602–26614. [Google Scholar] [CrossRef] [PubMed]
69. Weisberg, S.P.; Hunter, D.; Huber, R.; Lemieux, J.; Slaymaker, S.; Vaddi, K.; Charo, I.; Leibel, R.L.; Ferrante, A.W., Jr. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Investig. 2006, 116, 115–124. [Google Scholar] [CrossRef] [PubMed]
70. Yamauchi, T.; Kamon, J.; Waki, H.; Terauchi, Y.; Kubota, N.; Hara, K.; Mori, Y.; Ide, T.; Murakami, K.; Tsuboyama-Kasaoka, N.; et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 2001, 7, 941–946. [Google Scholar] [CrossRef] [PubMed]
71. Maeda, N.; Shimomura, I.; Kishida, K.; Nishizawa, H.; Matsuda, M.; Nagaretani, H.; Furuyama, N.; Kondo, H.; Takahashi, M.; Arita, Y.; et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP 30. Nat. Med. 2002, 8, 731–737. [Google Scholar] [CrossRef] [PubMed]
72. Wernstedt Asterholm, I.; Tao, C.; Morley, T.S.; Wang, Q.A.; Delgado-Lopez, F.; Wang, Z.V.; Scherer, P.E. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab. 2014, 20, 103–118. [Google Scholar] [CrossRef] [PubMed]
73. Divoux, A.; Tordjman, J.; Lacasa, D.; Veyrie, N.; Hugol, D.; Aissat, A.; Basdevant, A.; Guerre-Millo, M.; Poitou, C.; Zucker, J.D.; et al. Fibrosis in human adipose tissue: Composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes 2010, 59, 2817–2825. [Google Scholar] [CrossRef] [PubMed]
74. Samuel, V.T.; Shulman, G.I. The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux. J. Clin. Investig. 2016, 126, 12–22. [Google Scholar] [CrossRef] [PubMed]
75. Yu, C.; Chen, Y.; Cline, G.W.; Zhang, D.; Zong, H.; Wang, Y.; Bergeron, R.; Kim, J.K.; Cushman, S.W.; Cooney, G.J.; et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 2002, 277, 50230–50236. [Google Scholar] [CrossRef] [PubMed]
76. Griffin, M.E.; Marcucci, M.J.; Cline, G.W.; Bell, K.; Barucci, N.; Lee, D.; Goodyear, L.J.; Kraegen, E.W.; White, M.F.; Shulman, G.I. Free fatty acid-induced insulin resistance is associated with activation of protein kinase Ctheta and alterations in the insulin signaling cascade. Diabetes 1999, 48, 1270–1274. [Google Scholar] [CrossRef] [PubMed]
77. Szendroedi, J.; Yoshimura, T.; Phielix, E.; Koliaki, C.; Marcucci, M.; Zhang, D.; Jelenik, T.; Muller, J.; Herder, C.; Nowotny, P.; et al. Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans. Proc. Natl. Acad. Sci. USA 2014, 111, 9597–9602. [Google Scholar] [CrossRef] [PubMed]
78. Kitajima, Y.; Hyogo, H.; Sumida, Y.; Eguchi, Y.; Ono, N.; Kuwashiro, T.; Tanaka, K.; Takahashi, H.; Mizuta, T.; Ozaki, I.; et al. Severity of non-alcoholic steatohepatitis is associated with substitution of adipose tissue in skeletal muscle. J. Gastroenterol. Hepatol. 2013, 28, 1507–1514. [Google Scholar] [CrossRef] [PubMed]
79. Arias-Loste, M.T.; Ranchal, I.; Romero-Gomez, M.; Crespo, J. Irisin, a link among fatty liver disease, physical inactivity and insulin resistance. Int. J. Mol. Sci. 2014, 15, 23163–23178. [Google Scholar] [CrossRef] [PubMed]
80. Bostrom, P.; Wu, J.; Jedrychowski, M.P.; Korde, A.; Ye, L.; Lo, J.C.; Rasbach, K.A.; Bostrom, E.A.; Choi, J.H.; Long, J.Z.; et al. A PGC 1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012, 481, 463–468. [Google Scholar] [CrossRef] [PubMed]
81. Schulz, T.J.; Tseng, Y.H. Brown adipose tissue: Development, metabolism and beyond. Biochem. J. 2013, 453, 167–178. [Google Scholar] [CrossRef] [PubMed]
82. Seale, P.; Bjork, B.; Yang, W.; Kajimura, S.; Chin, S.; Kuang, S.; Scime, A.; Devarakonda, S.; Conroe, H.M.; Erdjument-Bromage, H.; et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 2008, 454, 961–967. [Google Scholar] [CrossRef] [PubMed]
83. Ishibashi, J.; Seale, P. Medicine. Beige can be slimming. Science 2010, 328, 1113–1114. [Google Scholar] [CrossRef] [PubMed]
84. Enerback, S. The origins of brown adipose tissue. N. Engl. J. Med. 2009, 360, 2021–2023. [Google Scholar] [CrossRef] [PubMed]
85. Scheja, L.; Heeren, J. Metabolic interplay between white, beige, brown adipocytes and the liver. J. Hepatol. 2016. [Google Scholar] [CrossRef] [PubMed]
86. Guerra, C.; Navarro, P.; Valverde, A.M.; Arribas, M.; Bruning, J.; Kozak, L.P.; Kahn, C.R.; Benito, M. Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. J. Clin. Investig. 2001, 108, 1205–1213. [Google Scholar] [CrossRef] [PubMed]
87. Bartelt, A.; Bruns, O.T.; Reimer, R.; Hohenberg, H.; Ittrich, H.; Peldschus, K.; Kaul, M.G.; Tromsdorf, U.I.; Weller, H.; Waurisch, C.; et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 2011, 17, 200–205. [Google Scholar] [CrossRef] [PubMed]
88. Assyov, Y.; Gateva, A.; Tsakova, A.; Kamenov, Z. Irisin in the glucose continuum. Exp. Clin. Endocrinol. Diabetes 2016, 124, 22–27. [Google Scholar] [CrossRef] [PubMed]
89. Liu, J.J.; Wong, M.D.; Toy, W.C.; Tan, C.S.; Liu, S.; Ng, X.W.; Tavintharan, S.; Sum, C.F.; Lim, S.C. Lower circulating irisin is associated with type 2 diabetes mellitus. J. Diabetes Complicat. 2013, 27, 365–369. [Google Scholar] [CrossRef] [PubMed]
90. Zhang, H.J.; Zhang, X.F.; Ma, Z.M.; Pan, L.L.; Chen, Z.; Han, H.W.; Han, C.K.; Zhuang, X.J.; Lu, Y.; Li, X.J.; et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. J. Hepatol. 2013, 59, 557–562. [Google Scholar] [CrossRef] [PubMed]
91. Donnelly, K.L.; Smith, C.I.; Schwarzenberg, S.J.; Jessurun, J.; Boldt, M.D.; Parks, E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Investig. 2005, 115, 1343–1351. [Google Scholar] [CrossRef] [PubMed]
92. Haas, J.T.; Francque, S.; Staels, B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Ann. Rev. Physiol. 2016, 78, 181–205. [Google Scholar] [CrossRef] [PubMed]
93. Seppala-Lindroos, A.; Vehkavaara, S.; Hakkinen, A.M.; Goto, T.; Westerbacka, J.; Sovijarvi, A.; Halavaara, J.; Yki-Jarvinen, H. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J. Clin. Endocrinol. Metab. 2002, 87, 3023–3028. [Google Scholar] [CrossRef] [PubMed]
94. Bugianesi, E.; Gastaldelli, A.; Vanni, E.; Gambino, R.; Cassader, M.; Baldi, S.; Ponti, V.; Pagano, G.; Ferrannini, E.; Rizzetto, M. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: Sites and mechanisms. Diabetologia 2005, 48, 634–642. [Google Scholar] [CrossRef] [PubMed]
95. Vatner, D.F.; Majumdar, S.K.; Kumashiro, N.; Petersen, M.C.; Rahimi, Y.; Gattu, A.K.; Bears, M.; Camporez, J.P.; Cline, G.W.; Jurczak, M.J.; et al. Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids. Proc. Natl. Acad. Sci. USA 2015, 112, 1143–1148. [Google Scholar] [CrossRef] [PubMed]
96. Matsuzaka, T.; Shimano, H.; Yahagi, N.; Amemiya-Kudo, M.; Okazaki, H.; Tamura, Y.; Iizuka, Y.; Ohashi, K.; Tomita, S.; Sekiya, M.; et al. Insulin-independent induction of sterol regulatory element-binding protein-1c expression in the livers of streptozotocin-treated mice. Diabetes 2004, 53, 560–569. [Google Scholar] [CrossRef] [PubMed]
97. Stanhope, K.L.; Schwarz, J.M.; Keim, N.L.; Griffen, S.C.; Bremer, A.A.; Graham, J.L.; Hatcher, B.; Cox, C.L.; Dyachenko, A.; Zhang, W.; et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J. Clin. Investig. 2009, 119, 1322–1334. [Google Scholar] [CrossRef] [PubMed]
98. Uyeda, K.; Repa, J.J. Carbohydrate response element binding protein, chrebp, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006, 4, 107–110. [Google Scholar] [CrossRef] [PubMed]
99. Erion, D.M.; Popov, V.; Hsiao, J.J.; Vatner, D.; Mitchell, K.; Yonemitsu, S.; Nagai, Y.; Kahn, M.; Gillum, M.P.; Dong, J.; et al. The role of the carbohydrate response element-binding protein in male fructose-fed rats. Endocrinology 2013, 154, 36–44. [Google Scholar] [CrossRef] [PubMed]
100. Nagai, Y.; Yonemitsu, S.; Erion, D.M.; Iwasaki, T.; Stark, R.; Weismann, D.; Dong, J.; Zhang, D.; Jurczak, M.J.; Loffler, M.G.; et al. The role of peroxisome proliferator-activated receptor gamma coactivator-1 β in the pathogenesis of fructose-induced insulin resistance. Cell Metab. 2009, 9, 252–264. [Google Scholar] [CrossRef] [PubMed]
101. Bindesboll, C.; Fan, Q.; Norgaard, R.C.; MacPherson, L.; Ruan, H.B.; Wu, J.; Pedersen, T.A.; Steffensen, K.R.; Yang, X.; Matthews, J.; et al. Liver Xreceptor regulates hepatic nuclear O-GlcNAc signaling and carbohydrate responsive element-binding protein activity. J. Lipid Res. 2015, 56, 771–785. [Google Scholar] [CrossRef] [PubMed]
102. Samuel, V.T.; Shulman, G.I. Mechanisms for insulin resistance: Common threads and missing links. Cell 2012, 148, 852–871. [Google Scholar] [CrossRef] [PubMed]
103. Yamaguchi, K.; Yang, L.; McCall, S.; Huang, J.; Yu, X.X.; Pandey, S.K.; Bhanot, S.; Monia, B.P.; Li, Y.X.; Diehl, A.M. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007, 45, 1366–1374. [Google Scholar] [CrossRef] [PubMed]
104. Samuel, V.T.; Liu, Z.X.; Wang, A.; Beddow, S.A.; Geisler, J.G.; Kahn, M.; Zhang, X.M.; Monia, B.P.; Bhanot, S.; Shulman, G.I. Inhibition of protein kinase cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J. Clin. Investig. 2007, 117, 739–745. [Google Scholar] [CrossRef] [PubMed]
105. Qu, X.; Seale, J.P.; Donnelly, R. Tissue and isoform-selective activation of protein kinase Cin insulin-resistant obese zucker rats—Effects of feeding. J. Endocrinol. 1999, 162, 207–214. [Google Scholar] [CrossRef] [PubMed]
106. Kumashiro, N.; Erion, D.M.; Zhang, D.; Kahn, M.; Beddow, S.A.; Chu, X.; Still, C.D.; Gerhard, G.S.; Han, X.; Dziura, J.; et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc. Natl. Acad. Sci. USA 2011, 108, 16381–16385. [Google Scholar] [CrossRef] [PubMed]
107. Magkos, F.; Su, X.; Bradley, D.; Fabbrini, E.; Conte, C.; Eagon, J.C.; Varela, J.E.; Brunt, E.M.; Patterson, B.W.; Klein, S. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology 2012, 142, 1444–1446. [Google Scholar] [CrossRef] [PubMed]
108. Schmitz-Peiffer, C.; Craig, D.L.; Biden, T.J. Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKBpathway in C2C12 skeletal muscle cells pretreated with palmitate. J. Biol. Chem. 1999, 274, 24202–24210. [Google Scholar] [CrossRef] [PubMed]
109. Stratford, S.; Hoehn, K.L.; Liu, F.; Summers, S.A. Regulation of insulin action by ceramide: Dual mechanisms linking ceramide accumulation to the inhibition of AKT/protein kinase B. J. Biol. Chem. 2004, 279, 36608–36615. [Google Scholar] [CrossRef] [PubMed]
110. Turinsky, J.; O′Sullivan, D.M.; Bayly, B.P. 1,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo. J. Biol. Chem. 1990, 265, 16880–16885. [Google Scholar] [PubMed]
111. Chavez, J.A.; Summers, S.A. A ceramide-centric view of insulin resistance. Cell Metab. 2012, 15, 585–594. [Google Scholar] [CrossRef] [PubMed]
112. Hla, T.; Kolesnick, R. C16:0-ceramide signals insulin resistance. Cell Metab. 2014, 20, 703–705. [Google Scholar] [CrossRef] [PubMed]
113. Turpin, S.M.; Nicholls, H.T.; Willmes, D.M.; Mourier, A.; Brodesser, S.; Wunderlich, C.M.; Mauer, J.; Xu, E.; Hammerschmidt, P.; Bronneke, H.S.; et al. Obesity-induced CERS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 2014, 20, 678–686. [Google Scholar] [CrossRef] [PubMed]
114. Luukkonen, P.K.; Zhou, Y.; Sadevirta, S.; Leivonen, M.; Arola, J.; Oresic, M.; Hyotylainen, T.; Yki-Jarvinen, H. Ceramides dissociate steatosis and insulin resistance in the human liver in non-alcoholic fatty liver disease. J. Hepatol. 2016. [Google Scholar] [CrossRef] [PubMed]
115. Jenkins, C.M.; Mancuso, D.J.; Yan, W.; Sims, H.F.; Gibson, B.; Gross, R.W. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J. Biol. Chem. 2004, 279, 48968–48975. [Google Scholar] [CrossRef] [PubMed]
116. Romeo, S.; Kozlitina, J.; Xing, C.; Pertsemlidis, A.; Cox, D.; Pennacchio, L.A.; Boerwinkle, E.; Cohen, J.C.; Hobbs, H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2008, 40, 1461–1465. [Google Scholar] [CrossRef] [PubMed]
117. Kantartzis, K.; Peter, A.; Machicao, F.; Machann, J.; Wagner, S.; Konigsrainer, I.; Konigsrainer, A.; Schick, F.; Fritsche, A.; Haring, H.U.; et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 2009, 58, 2616–2623. [Google Scholar] [CrossRef] [PubMed]
118. Kotronen, A.; Johansson, L.E.; Johansson, L.M.; Roos, C.; Westerbacka, J.; Hamsten, A.; Bergholm, R.; Arkkila, P.; Arola, J.; Kiviluoto, T.; et al. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 2009, 52, 1056–1060. [Google Scholar] [CrossRef] [PubMed]
119. Speliotes, E.K.; Butler, J.L.; Palmer, C.D.; Voight, B.F.; Consortium, G.; Consortium, M.I.; Nash, C.R.N.; Hirschhorn, J.N. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010, 52, 904–912. [Google Scholar] [CrossRef] [PubMed]
120. Kumari, M.; Schoiswohl, G.; Chitraju, C.; Paar, M.; Cornaciu, I.; Rangrez, A.Y.; Wongsiriroj, N.; Nagy, H.M.; Ivanova, P.T.; Scott, S.A.; et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab. 2012, 15, 691–702. [Google Scholar] [CrossRef] [PubMed]
121. Smagris, E.; BasuRay, S.; Li, J.; Huang, Y.; Lai, K.M.; Gromada, J.; Cohen, J.C.; Hobbs, H.H. PNPLA3I148Mknockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 2015, 61, 108–118. [Google Scholar] [CrossRef] [PubMed]
122. Wu, J.W.; Yang, H.; Mitchell, G.A. Potential mechanism underlying the PNPLA3^I148M-hepatic steatosis connection. Hepatology 2016, 63, 676–677. [Google Scholar] [CrossRef] [PubMed]
123. Puri, P.; Mirshahi, F.; Cheung, O.; Natarajan, R.; Maher, J.W.; Kellum, J.M.; Sanyal, A.J. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008, 134, 568–576. [Google Scholar] [CrossRef] [PubMed]
124. Malhi, H.; Gores, G.J. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin. Liver Dis. 2008, 28, 360–369. [Google Scholar] [CrossRef] [PubMed]
125. Singh, R.; Kaushik, S.; Wang, Y.; Xiang, Y.; Novak, I.; Komatsu, M.; Tanaka, K.; Cuervo, A.M.; Czaja, M.J. Autophagy regulates lipid metabolism. Nature 2009, 458, 1131–1135. [Google Scholar] [CrossRef] [PubMed]
126. Wang, Y.; Singh, R.; Xiang, Y.; Czaja, M.J. Macroautophagy and chaperone-mediated autophagy are required for hepatocyte resistance to oxidant stress. Hepatology 2010, 52, 266–277. [Google Scholar] [CrossRef] [PubMed]
127. Czaja, M.J. Autophagy in health and disease. 2. Regulation of lipid metabolism and storage by autophagy: Pathophysiological implications. Am. J. Physiol. Cell Physiol. 2010, 298, C973–C978. [Google Scholar] [CrossRef] [PubMed]
128. Pal, D.; Dasgupta, S.; Kundu, R.; Maitra, S.; Das, G.; Mukhopadhyay, S.; Ray, S.; Majumdar, S.S.; Bhattacharya, S. Fetuin-Aacts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 2012, 18, 1279–1285. [Google Scholar] [CrossRef] [PubMed]
129. Chatterjee, P.; Seal, S.; Mukherjee, S.; Kundu, R.; Mukherjee, S.; Ray, S.; Mukhopadhyay, S.; Majumdar, S.S.; Bhattacharya, S. Adipocyte fetuin-Acontributes to macrophage migration into adipose tissue and polarization of macrophages. J. Biol. Chem. 2013, 288, 28324–28330. [Google Scholar] [CrossRef] [PubMed]
130. Ix, J.H.; Shlipak, M.G.; Brandenburg, V.M.; Ali, S.; Ketteler, M.; Whooley, M.A. Association between human fetuin-Aand the metabolic syndrome: Data from the heart and soul study. Circulation 2006, 113, 1760–1767. [Google Scholar] [CrossRef] [PubMed]
131. Ix, J.H.; Wassel, C.L.; Kanaya, A.M.; Vittinghoff, E.; Johnson, K.C.; Koster, A.; Cauley, J.A.; Harris, T.B.; Cummings, S.R.; Shlipak, M.G.; et al. Fetuin-Aand incident diabetes mellitus in older persons. JAMA 2008, 300, 182–188. [Google Scholar] [CrossRef] [PubMed]
132. Stefan, N.; Hennige, A.M.; Staiger, H.; Machann, J.; Schick, F.; Krober, S.M.; Machicao, F.; Fritsche, A.; Haring, H.U. Alpha2-heremans-schmid glycoprotein/fetuin-Ais associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 2006, 29, 853–857. [Google Scholar] [CrossRef] [PubMed]
133. Meex, R.C.; Hoy, A.J.; Morris, A.; Brown, R.D.; Lo, J.C.; Burke, M.; Goode, R.J.; Kingwell, B.A.; Kraakman, M.J.; Febbraio, M.A.; et al. Fetuin Bis a secreted hepatocyte factor linking steatosis to impaired glucose metabolism. Cell Metab. 2015, 22, 1078–1089. [Google Scholar] [CrossRef] [PubMed]
134. Kharitonenkov, A.; Shiyanova, T.L.; Koester, A.; Ford, A.M.; Micanovic, R.; Galbreath, E.J.; Sandusky, G.E.; Hammond, L.J.; Moyers, J.S.; Owens, R.A.; et al. FGF-21 as a novel metabolic regulator. J. Clin. Investig. 2005, 115, 1627–1635. [Google Scholar] [CrossRef] [PubMed]
135. Zhang, X.; Yeung, D.C.; Karpisek, M.; Stejskal, D.; Zhou, Z.G.; Liu, F.; Wong, R.L.; Chow, W.S.; Tso, A.W.; Lam, K.S.; et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008, 57, 1246–1253. [Google Scholar] [CrossRef] [PubMed]
136. Itoh, N. FGF21 as a hepatokine, adipokine, and myokine in metabolism and diseases. Front. Endocrinol. (Lausanne) 2014, 5, 107. [Google Scholar] [CrossRef] [PubMed]
137. Chavez, A.O.; Molina-Carrion, M.; Abdul-Ghani, M.A.; Folli, F.; Defronzo, R.A.; Tripathy, D. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 2009, 32, 1542–1546. [Google Scholar] [CrossRef] [PubMed]
138. Dushay, J.; Chui, P.C.; Gopalakrishnan, G.S.; Varela-Rey, M.; Crawley, M.; Fisher, F.M.; Badman, M.K.; Martinez-Chantar, M.L.; Maratos-Flier, E. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 2010, 139, 456–463. [Google Scholar] [CrossRef] [PubMed]
139. Li, H.; Dong, K.; Fang, Q.; Hou, X.; Zhou, M.; Bao, Y.; Xiang, K.; Xu, A.; Jia, W. High serum level of fibroblast growth factor 21 is an independent predictor of non-alcoholic fatty liver disease: A3-year prospective study in china. J. Hepatol. 2013, 58, 557–563. [Google Scholar] [CrossRef] [PubMed]
140. Li, H.; Fang, Q.; Gao, F.; Fan, J.; Zhou, J.; Wang, X.; Zhang, H.; Pan, X.; Bao, Y.; Xiang, K.; et al. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J. Hepatol. 2010, 53, 934–940. [Google Scholar] [CrossRef] [PubMed]
141. El Ouaamari, A.; Dirice, E.; Gedeon, N.; Hu, J.; Zhou, J.Y.; Shirakawa, J.; Hou, L.; Goodman, J.; Karampelias, C.; Qiang, G.; et al. SerpinB1 promotes pancreatic beta cell proliferation. Cell Metab. 2016, 23, 194–205. [Google Scholar] [CrossRef] [PubMed]
142. Tarasov, A.I.; Rorsman, P. Dramatis personae in beta-cell mass regulation: Enter serpinB1. Cell Metab. 2016, 23, 8–10. [Google Scholar] [CrossRef] [PubMed]
143. Boursier, J.; Mueller, O.; Barret, M.; Machado, M.; Fizanne, L.; Araujo-Perez, F.; Guy, C.D.; Seed, P.C.; Rawls, J.F.; David, L.A.; et al. The severity of NAFLD is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016, 63, 764–775. [Google Scholar] [CrossRef] [PubMed]
144. Le Roy, T.; Llopis, M.; Lepage, P.; Bruneau, A.; Rabot, S.; Bevilacqua, C.; Martin, P.; Philippe, C.; Walker, F.; Bado, A.; et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2013, 62, 1787–1794. [Google Scholar] [CrossRef] [PubMed]
145. Musso, G.; Gambino, R.; Cassader, M. Gut microbiota as a regulator of energy homeostasis and ectopic fat deposition: Mechanisms and implications for metabolic disorders. Curr. Opin. Lipidol. 2010, 21, 76–83. [Google Scholar] [CrossRef] [PubMed]
146. Nolan, C.J.; Damm, P.; Prentki, M. Type 2 diabetes across generations: From pathophysiology to prevention and management. Lancet 2011, 378, 169–181. [Google Scholar] [CrossRef]
147. Shima, T.; Uto, H.; Ueki, K.; Takamura, T.; Kohgo, Y.; Kawata, S.; Yasui, K.; Park, H.; Nakamura, N.; Nakatou, T.; et al. Clinicopathological features of liver injury in patients with type 2 diabetes mellitus and comparative study of histologically proven nonalcoholic fatty liver diseases with or without type 2 diabetes mellitus. J.Gastroenterol. 2013, 48, 515–525. [Google Scholar] [CrossRef] [PubMed]
148. Goh, G.B.; Pagadala, M.R.; Dasarathy, J.; Unalp-Arida, A.; Sargent, R.; Hawkins, C.; Sourianarayanane, A.; Khiyami, A.; Yerian, L.; Pai, R.K.; et al. Clinical spectrum of non-alcoholic fatty liver disease in diabetic and non-diabetic patients. BBA Clin. 2015, 3, 141–145. [Google Scholar] [CrossRef] [PubMed]
149. Nascimbeni, F.; Aron-Wisniewsky, J.; Pais, R.; Tordjman, J.; Poitou, C.; Charlotte, F.; Bedossa, P.; Poynard, T.; Clement, K.; Ratziu, V. Statins, antidiabetic medications and liver histology in diabetic patients with non-alcoholic fatty liver disease. BMJ Open Gastroenterol. 2016. in press. [Google Scholar]
150. Angulo, P.; Keach, J.C.; Batts, K.P.; Lindor, K.D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999, 30, 1356–1362. [Google Scholar] [CrossRef] [PubMed]
151. De Ledinghen, V.; Ratziu, V.; Causse, X.; Le Bail, B.; Capron, D.; Renou, C.; Pilette, C.; Oules, V.; Gelsi, E.; Oberti, F.; et al. Diagnostic and predictive factors of significant liver fibrosis and minimal lesions in patients with persistent unexplained elevated transaminases. A prospective multicenter study. J. Hepatol. 2006, 45, 592–599. [Google Scholar] [CrossRef] [PubMed]
152. Hossain, N.; Afendy, A.; Stepanova, M.; Nader, F.; Srishord, M.; Rafiq, N.; Goodman, Z.; Younossi, Z. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 2009, 7, 1224–1229. [Google Scholar] [CrossRef] [PubMed]
153. Nakahara, T.; Hyogo, H.; Yoneda, M.; Sumida, Y.; Eguchi, Y.; Fujii, H.; Ono, M.; Kawaguchi, T.; Imajo, K.; Aikata, H.; et al. Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients. J. Gastroenterol. 2014, 49, 1477–1484. [Google Scholar] [CrossRef] [PubMed]
154. McPherson, S.; Hardy, T.; Henderson, E.; Burt, A.D.; Day, C.P.; Anstee, Q.M. Evidence of NAFLDprogression from steatosis to fibrosing-steatohepatitis using paired biopsies: Implications for prognosis and clinical management. J. Hepatol. 2015, 62, 1148–1155. [Google Scholar] [CrossRef] [PubMed]
155. Pais, R.; Charlotte, F.; Fedchuk, L.; Bedossa, P.; Lebray, P.; Poynard, T.; Ratziu, V.; Group, L.S. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J. Hepatol. 2013, 59, 550–556. [Google Scholar] [CrossRef] [PubMed]
156. Adams, L.A.; Sanderson, S.; Lindor, K.D.; Angulo, P. The histological course of nonalcoholic fatty liver disease: A longitudinal study of 103 patients with sequential liver biopsies. J. Hepatol. 2005, 42, 132–138. [Google Scholar] [CrossRef] [PubMed]
157. Hamaguchi, E.; Takamura, T.; Sakurai, M.; Mizukoshi, E.; Zen, Y.; Takeshita, Y.; Kurita, S.; Arai, K.; Yamashita, T.; Sasaki, M.; et al. Histological course of nonalcoholic fatty liver disease in Japanese patients: Tight glycemic control, rather than weight reduction, ameliorates liver fibrosis. Diabetes Care 2010, 33, 284–286. [Google Scholar] [CrossRef] [PubMed]
158. Hashiba, M.; Ono, M.; Hyogo, H.; Ikeda, Y.; Masuda, K.; Yoshioka, R.; Ishikawa, Y.; Nagata, Y.; Munekage, K.; Ochi, T.; et al. Glycemic variability is an independent predictive factor for development of hepatic fibrosis in nonalcoholic fatty liver disease. PLoS ONE 2013, 8, e76161. [Google Scholar] [CrossRef] [PubMed]
159. Fracanzani, A.L.; Valenti, L.; Bugianesi, E.; Andreoletti, M.; Colli, A.; Vanni, E.; Bertelli, C.; Fatta, E.; Bignamini, D.; Marchesini, G.; et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: Arole for insulin resistance and diabetes. Hepatology 2008, 48, 792–798. [Google Scholar] [CrossRef] [PubMed]
160. Ballestri, S.; Romagnoli, D.; Nascimbeni, F.; Francica, G.; Lonardo, A. Role of ultrasound in the diagnosis and treatment of nonalcoholic fatty liver disease and its complications. Expert Rev. Gastroenterol. Hepatol. 2015, 9, 603–627. [Google Scholar] [CrossRef] [PubMed]
161. Nascimbeni, F.; Loria, P.; Ratziu, V. Non-alcoholic fatty liver disease: Diagnosis and investigation. Dig. Dis. 2014, 32, 586–596. [Google Scholar] [CrossRef] [PubMed]
162. Younossi, Z.M.; Gramlich, T.; Matteoni, C.A.; Boparai, N.; McCullough, A.J. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin. Gastroenterol. Hepatol. 2004, 2, 262–265. [Google Scholar] [CrossRef]
163. Hessheimer, A.J.; Forner, A.; Varela, M.; Bruix, J. Metabolic risk factors are a major comorbidity in patients with cirrhosis independent of the presence of hepatocellular carcinoma. Eur. J. Gastroenterol. Hepatol. 2010, 22, 1239–1244. [Google Scholar] [CrossRef] [PubMed]
164. Ertle, J.; Dechene, A.; Sowa, J.P.; Penndorf, V.; Herzer, K.; Kaiser, G.; Schlaak, J.F.; Gerken, G.; Syn, W.K.; Canbay, A. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int. J.Cancer 2011, 128, 2436–2443. [Google Scholar] [CrossRef] [PubMed]
165. Yasui, K.; Hashimoto, E.; Komorizono, Y.; Koike, K.; Arii, S.; Imai, Y.; Shima, T.; Kanbara, Y.; Saibara, T.; Mori, T.; et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 2011, 9, 428–433. [Google Scholar] [CrossRef] [PubMed]
166. Raff, E.J.; Kakati, D.; Bloomer, J.R.; Shoreibah, M.; Rasheed, K.; Singal, A.K. Diabetes mellitus predicts occurrence of cirrhosis and hepatocellular cancer in alcoholic liver and non-alcoholic fatty liver diseases. J. Clin. Transl. Hepatol. 2015, 3, 9–16. [Google Scholar] [CrossRef] [PubMed]
167. Giannini, E.G.; Marabotto, E.; Savarino, V.; Trevisani, F.; di Nolfo, M.A.; Del Poggio, P.; Benvegnu, L.; Farinati, F.; Zoli, M.; Borzio, F.; et al. Hepatocellular carcinoma in patients with cryptogenic cirrhosis. Clin. Gastroenterol. Hepatol. 2009, 7, 580–585. [Google Scholar] [CrossRef] [PubMed]
168. Piscaglia, F.; Svegliati-Baroni, G.; Barchetti, A.; Pecorelli, A.; Marinelli, S.; Tiribelli, C.; Bellentani, S. HCC-NAFLD Italian Study Group. Clinical patterns of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease (NAFLD): Amulticenter prospective study. Hepatology 2016, 63, 827–838. [Google Scholar] [CrossRef] [PubMed]
169. Zoppini, G.; Fedeli, U.; Gennaro, N.; Saugo, M.; Targher, G.; Bonora, E. Mortality from chronic liver diseases in diabetes. Am. J. Gastroenterol. 2014, 109, 1020–1025. [Google Scholar] [CrossRef] [PubMed]
170. Wild, S.H.; Morling, J.R.; McAllister, D.A.; Kerssens, J.; Fischbacher, C.; Parkes, J.; Roderick, P.J.; Sattar, N.; Byrne, C.D. Scottish and Southampton Diabetes and Liver Disease Group and the Scottish Diabetes Research Network Epidemiology Group. Type 2 diabetes, chronic liver disease and hepatocellular cancer: A national retrospective cohort study using linked routine data. J. Hepatol. 2016. [Google Scholar] [CrossRef] [PubMed]
171. Adams, L.A.; Harmsen, S.; St Sauver, J.L.; Charatcharoenwitthaya, P.; Enders, F.B.; Therneau, T.; Angulo, P. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: A community-based cohort study. Am. J. Gastroenterol. 2010, 105, 1567–1573. [Google Scholar] [CrossRef] [PubMed]
172. Ballestri, S.; Lonardo, A.; Bonapace, S.; Byrne, C.D.; Loria, P.; Targher, G. Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease. World J. Gastroenterol. 2014, 20, 1724–1745. [Google Scholar] [CrossRef] [PubMed]
173. Lonardo, A.; Ballestri, S.; Targher, G.; Loria, P. Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease. Expert Rev. Gastroenterol. Hepatol. 2015, 9, 629–650. [Google Scholar] [CrossRef] [PubMed]
174. Targher, G.; Bertolini, L.; Rodella, S.; Tessari, R.; Zenari, L.; Lippi, G.; Arcaro, G. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 2007, 30, 2119–2121. [Google Scholar] [CrossRef] [PubMed]
175. Mantovani, A.; Ballestri, S.; Lonardo, A.; Targher, G. Cardiovascular disease and myocardial abnormalities in nonalcoholic fatty liver disease. Dig. Dis. Sci. 2016. [Google Scholar] [CrossRef] [PubMed]
176. Naunyn, B. Der Diabetes Melitis; A Holder: Wienna, Austria, 1898. [Google Scholar]
177. Lonardo, A.; Adinolfi, L.E.; Petta, S.; Craxi, A.; Loria, P. Hepatitis C and diabetes: The inevitable coincidence? Expert Rev. Anti. Infect. Ther. 2009, 7, 293–308. [Google Scholar] [CrossRef] [PubMed]
178. Allison, M.E.; Wreghitt, T.; Palmer, C.R.; Alexander, G.J. Evidence for a link between hepatitis Cvirus infection and diabetes mellitus in a cirrhotic population. J. Hepatol. 1994, 21, 1135–1139. [Google Scholar] [CrossRef]
179. Searched on PubMed, Keywords: “HCV and diabetes”. Available online: http://www.ncbi.nlm.nih.gov/pubmed/?term=HCV+and+diabetes (accessed on 24 January 2016).
180. Kohli, A.; Shaffer, A.; Sherman, A.; Kottilil, S. Treatment of hepatitis C: Asystematic review. JAMA 2014, 312, 631–640. [Google Scholar] [CrossRef] [PubMed]
181. Hajarizadeh, B.; Grebely, J.; Dore, G.J. Epidemiology and natural history of HCVinfection. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 553–562. [Google Scholar] [CrossRef] [PubMed]
182. Shire, N.J.; Sherman, K.E. Epidemiology of hepatitis Cvirus: Abattle on new frontiers. Gastroenterol. Clin. N. Am. 2015, 44, 699–716. [Google Scholar] [CrossRef] [PubMed]
183. Dultz, G.; Zeuzem, S. Hepatitis Cvirus: An European perspective. Gastroenterol. Clin. N. Am. 2015, 44, 807–824. [Google Scholar] [CrossRef] [PubMed]
184. Lozano, R.; Naghavi, M.; Foreman, K.; Lim, S.; Shibuya, K.; Aboyans, V.; Abraham, J.; Adair, T.; Aggarwal, R.; Ahn, S.Y.; et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: Asystematic analysis for the global burden of disease study 2010. Lancet 2012, 380, 2095–2128. [Google Scholar] [CrossRef]
185. Wong, R.J.; Aguilar, M.; Cheung, R.; Perumpail, R.B.; Harrison, S.A.; Younossi, Z.M.; Ahmed, A. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the united states. Gastroenterology 2015, 148, 547–555. [Google Scholar] [CrossRef] [PubMed]
186. Mehta, S.H.; Brancati, F.L.; Strathdee, S.A.; Pankow, J.S.; Netski, D.; Coresh, J.; Szklo, M.; Thomas, D.L. Hepatitis Cvirus infection and incident type 2 diabetes. Hepatology 2003, 38, 50–56. [Google Scholar] [CrossRef] [PubMed]
187. Rudoni, S.; Petit, J.M.; Bour, J.B.; Aho, L.S.; Castaneda, A.; Vaillant, G.; Verges, B.; Brun, J.M. HCV infection and diabetes mellitus: Influence of the use of finger stick devices on nosocomial transmission. Diabetes Metab. 1999, 25, 502–505. [Google Scholar] [PubMed]
188. Lonardo, A.; Carulli, N.; Loria, P. HCV and diabetes. A two-question-based reappraisal. Dig. Liver Dis. 2007, 39, 753–761. [Google Scholar] [CrossRef] [PubMed]
189. Lonardo, A.; Adinolfi, L.E.; Restivo, L.; Ballestri, S.; Romagnoli, D.; Baldelli, E.; Nascimbeni, F.; Loria, P. Pathogenesis and significance of hepatitis C virus steatosis: An update on survival strategy of a successful pathogen. World J. Gastroenterol. 2014, 20, 7089–7103. [Google Scholar] [CrossRef] [PubMed]
190. Petta, S.; Macaluso, F.S.; Camma, C.; Marco, V.D.; Cabibi, D.; Craxi, A. Hyperuricaemia: Another metabolic feature affecting the severity of chronic hepatitis because of HCV infection. Liver Int. 2012, 32, 1443–1450. [Google Scholar] [CrossRef] [PubMed]
191. Petta, S.; Maida, M.; Macaluso, F.S.; Barbara, M.; Licata, A.; Craxi, A.; Camma, C. Hepatitis C virus infection is associated with increased cardiovascular mortality: Ameta-analysis of observational studies. Gastroenterology 2016, 150, 145–155. [Google Scholar] [CrossRef] [PubMed]
192. Singal, A.G.; El-Serag, H.B. Hepatocellular carcinoma from epidemiology to prevention: Translating knowledge into practice. Clin. Gastroenterol. Hepatol. 2015, 13, 2140–2151. [Google Scholar] [CrossRef] [PubMed]
193. Dyal, H.K.; Aguilar, M.; Bartos, G.; Holt, E.W.; Bhuket, T.; Liu, B.; Cheung, R.; Wong, R.J. Diabetes mellitus increases risk of hepatocellular carcinoma in chronic hepatitis C virus patients: Asystematic review. Dig. Dis. Sci. 2016, 61, 636–645. [Google Scholar] [CrossRef] [PubMed]
194. Lecube, A.; Hernandez, C.; Genesca, J.; Simo, R. Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: A case-control study. Diabetes Care 2006, 29, 1096–1101. [Google Scholar] [CrossRef] [PubMed]
195. Knobler, H.; Zhornicky, T.; Sandler, A.; Haran, N.; Ashur, Y.; Schattner, A. Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepatitis C virus-diabetes association. Am. J. Gastroenterol. 2003, 98, 2751–2756. [Google Scholar] [CrossRef] [PubMed]
196. Zheng, Y.Y.; Wang, L.F.; Fan, X.H.; Wu, C.H.; Huo, N.; Lu, H.Y.; Xu, X.Y.; Wei, L. Association of suppressor of cytokine signalling 3 polymorphisms with insulin resistance in patients with chronic hepatitis C. J. Viral Hepat. 2013, 20, 273–280. [Google Scholar] [CrossRef] [PubMed]
197. Pazienza, V.; Vinciguerra, M.; Andriulli, A.; Mangia, A. Hepatitis C virus core protein genotype 3a increases SOCS-7 expression through PPAR-{gamma} in Huh-7 cells. J. Gen. Virol. 2010, 91, 1678–1686. [Google Scholar] [CrossRef] [PubMed]
198. Vanni, E.; Abate, M.L.; Gentilcore, E.; Hickman, I.; Gambino, R.; Cassader, M.; Smedile, A.; Ferrannini, E.; Rizzetto, M.; Marchesini, G.; et al. Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C. Hepatology 2009, 50, 697–706. [Google Scholar] [CrossRef] [PubMed]
199. Milner, K.L.; van der Poorten, D.; Trenell, M.; Jenkins, A.B.; Xu, A.; Smythe, G.; Dore, G.J.; Zekry, A.; Weltman, M.; Fragomeli, V.; et al. Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance. Gastroenterology 2010, 138, 932–941. [Google Scholar] [CrossRef] [PubMed]
200. Uruha, A.; Noguchi, S.; Hayashi, Y.K.; Tsuburaya, R.S.; Yonekawa, T.; Nonaka, I.; Nishino, I. Hepatitis C virus infection in inclusion body myositis: A case-control study. Neurology 2016, 86, 211–217. [Google Scholar] [CrossRef] [PubMed]
201. Adinolfi, L.E.; Gambardella, M.; Andreana, A.; Tripodi, M.F.; Utili, R.; Ruggiero, G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001, 33, 1358–1364. [Google Scholar] [CrossRef] [PubMed]
202. Guaraldi, G.; Lonardo, A.; Ballestri, S.; Zona, S.; Stentarelli, C.; Orlando, G.; Carli, F.; Carulli, L.; Roverato, A.; Loria, P. Human immunodeficiency virus is the major determinant of steatosis and hepatitis C virus of insulin resistance in virus-associated fatty liver disease. Arch. Med. Res. 2011, 42, 690–697. [Google Scholar] [CrossRef] [PubMed]
203. Lonardo, A.; Loria, P.; Carulli, N. Dysmetabolic changes associated with HCV: Adistinct syndrome? Intern. Emerg. Med. 2008, 3, 99–108. [Google Scholar] [CrossRef] [PubMed]
204. Adinolfi, L.E.; Restivo, L.; Zampino, R.; Lonardo, A.; Loria, P. Metabolic alterations and chronic hepatitis C: Treatment strategies. Expert Opin. Pharmacother. 2011, 12, 2215–2234. [Google Scholar] [CrossRef] [PubMed]
205. Loria, P.; Marchesini, G.; Nascimbeni, F.; Ballestri, S.; Maurantonio, M.; Carubbi, F.; Ratziu, V.; Lonardo, A. Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology. Atherosclerosis 2014, 232, 99–109. [Google Scholar] [CrossRef] [PubMed]
206. Mostafa, A.; Mohamed, M.K.; Saeed, M.; Hasan, A.; Fontanet, A.; Godsland, I.; Coady, E.; Esmat, G.; El-Hoseiny, M.; Abdul-Hamid, M.; et al. Hepatitis Cinfection and clearance: Impact on atherosclerosis and cardiometabolic risk factors. Gut 2010, 59, 1135–1140. [Google Scholar] [CrossRef] [PubMed]
207. Zampino, R.; Coppola, N.; Cirillo, G.; Boemio, A.; Pisaturo, M.; Marrone, A.; Macera, M.; Sagnelli, E.; Perrone, L.; Adinolfi, L.E.; et al. Abdominal fat interacts with PNPLA3 I148M, but not with the APOC3 variant in the pathogenesis of liver steatosis in chronic hepatitis C. J. Viral Hepat. 2013, 20, 517–523. [Google Scholar] [CrossRef] [PubMed]
208. Gordon, S.C.; Lamerato, L.E.; Rupp, L.B.; Holmberg, S.D.; Moorman, A.C.; Spradling, P.R.; Teshale, E.; Xu, F.; Boscarino, J.A.; Vijayadeva, V.; et al. Prevalence of cirrhosis in hepatitis Cpatients in the chronic hepatitis cohort study (CHeCS): A retrospective and prospective observational study. Am. J. Gastroenterol. 2015, 110, 1169–1177. [Google Scholar] [CrossRef] [PubMed]
209. Patel, S.; Jinjuvadia, R.; Patel, R.; Liangpunsakul, S. Insulin resistance is associated with significant liver fibrosis in chronic hepatitis C patients: Asystemic review and meta-analysis. J. Clin. Gastroenterol. 2016, 50, 80–84. [Google Scholar] [CrossRef] [PubMed]
210. Moucari, R.; Asselah, T.; Cazals-Hatem, D.; Voitot, H.; Boyer, N.; Ripault, M.P.; Sobesky, R.; Martinot-Peignoux, M.; Maylin, S.; Nicolas-Chanoine, M.H.; et al. Insulin resistance in chronic hepatitis C: Association with genotypes 1 and 4, serum HCVRNA level, and liver fibrosis. Gastroenterology 2008, 134, 416–423. [Google Scholar] [CrossRef] [PubMed]
211. Serste, T.; Nkuize, M.; Moucari, R.; Van Gossum, M.; Reynders, M.; Scheen, R.; Vertongen, F.; Buset, M.; Mulkay, J.P.; Marcellin, P. Metabolic disorders associated with chronic hepatitis C: Impact of genotype and ethnicity. Liver Int. 2010, 30, 1131–1136. [Google Scholar] [CrossRef] [PubMed]
212. Wang, C.S.; Yao, W.J.; Chang, T.T.; Wang, S.T.; Chou, P. The impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses. Cancer Epidemiol. Biomarkers Prev. 2009, 18, 2054–2060. [Google Scholar] [CrossRef] [PubMed]
213. Arase, Y.; Kobayashi, M.; Suzuki, F.; Suzuki, Y.; Kawamura, Y.; Akuta, N.; Kobayashi, M.; Sezaki, H.; Saito, S.; Hosaka, T.; et al. Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C. Hepatology 2013, 57, 964–973. [Google Scholar] [CrossRef] [PubMed]
214. Bruno, S.; Crosignani, A.; Maisonneuve, P.; Rossi, S.; Silini, E.; Mondelli, M.U. Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: Aseventeen-year prospective cohort study. Hepatology 2007, 46, 1350–1356. [Google Scholar] [CrossRef] [PubMed]
215. Adinolfi, L.E.; Zampino, R.; Restivo, L.; Lonardo, A.; Guerrera, B.; Marrone, A.; Nascimbeni, F.; Florio, A.; Loria, P. Chronic hepatitis C virus infection and atherosclerosis: Clinical impact and mechanisms. World J. Gastroenterol. 2014, 20, 3410–3417. [Google Scholar] [CrossRef] [PubMed]
216. Adinolfi, L.E.; Restivo, L.; Zampino, R.; Guerrera, B.; Lonardo, A.; Ruggiero, L.; Riello, F.; Loria, P.; Florio, A. Chronic HCV infection is a risk of atherosclerosis. Role of HCVand HCV-related steatosis. Atherosclerosis 2012, 221, 496–502. [Google Scholar] [CrossRef] [PubMed]
217. Petta, S.; Torres, D.; Fazio, G.; Camma, C.; Cabibi, D.; Di Marco, V.; Licata, A.; Marchesini, G.; Mazzola, A.; Parrinello, G.; et al. Carotid atherosclerosis and chronic hepatitis C: A prospective study of risk associations. Hepatology 2012, 55, 1317–1323. [Google Scholar] [CrossRef] [PubMed]
218. Targher, G.; Bertolini, L.; Padovani, R.; Rodella, S.; Arcaro, G.; Day, C. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis Band C. J. Hepatol. 2007, 46, 1126–1132. [Google Scholar] [CrossRef] [PubMed]
219. Gill, K.; Ghazinian, H.; Manch, R.; Gish, R. Hepatitis C virus as a systemic disease: Reaching beyond the liver. Hepatol. Int. 2015. in press. [Google Scholar] [CrossRef] [PubMed]
220. Domont, F.; Cacoub, P. Chronic hepatitis C virus infection, a new cardiovascular risk factor? Liver Int. 2016. [Google Scholar] [CrossRef] [PubMed]
221. Backus, L.I.; Belperio, P.S.; Shahoumian, T.A.; Loomis, T.P.; Mole, L.A. Effectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 U.S. Veterans. Aliment. Pharmacol. Ther. 2015, 42, 559–573. [Google Scholar] [CrossRef] [PubMed]
222. Rinella, M.E. Nonalcoholic fatty liver disease: A systematic review. JAMA 2015, 313, 2263–2273. [Google Scholar] [CrossRef] [PubMed]
223. Montesi, L.; Caselli, C.; Centis, E.; Nuccitelli, C.; Moscatiello, S.; Suppini, A.; Marchesini, G. Physical activity support or weight loss counseling for nonalcoholic fatty liver disease? World J. Gastroenterol. 2014, 20, 10128–10136. [Google Scholar] [CrossRef] [PubMed]
224. Oliveira, C.P.; de Lima Sanches, P.; de Abreu-Silva, E.O.; Marcadenti, A. Nutrition and physical activity in nonalcoholic fatty liver disease. J. Diabetes Res. 2016, 2016, 4597246. [Google Scholar] [CrossRef] [PubMed]
225. Hallsworth, K.; Avery, L.; Trenell, M.I. Targeting lifestyle behavior change in adults with NAFLD during a 20-min consultation: Summary of the dietary and exercise literature. Curr. Gastroenterol. Rep. 2016, 18, 11. [Google Scholar] [CrossRef] [PubMed]
226. Hickman, I.J.; Clouston, A.D.; Macdonald, G.A.; Purdie, D.M.; Prins, J.B.; Ash, S.; Jonsson, J.R.; Powell, E.E. Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut 2002, 51, 89–94. [Google Scholar] [CrossRef] [PubMed]

© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).