Showing posts with label diabetes-insulin resistance. Show all posts
Showing posts with label diabetes-insulin resistance. Show all posts

Wednesday, January 24, 2018

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.

Full Text

Saturday, April 22, 2017

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

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.

Saturday, March 18, 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

Monday, May 9, 2016

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.
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Sunday, March 20, 2016

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

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].
 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
 
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