Liver Fat, Hepatic Enzymes, Alkaline Phosphatase and the Risk of Incident Type 2 Diabetes: A Prospective Study of 132,377 Adults
Sean Chun-Chang Chen, Shan Pou Tsai, Jing-Yun Jhao, Wun-Kai Jiang, Chwen Keng Tsao & Ly-Yun Chang
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Scientific Reports 7, Article number: 4649 (2017)
doi:10.1038/s41598-017-04631-7
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Introduction
The prevalence and incidence of type 2 diabetes (diabetes hereafter) are rising rapidly worldwide, especially in Asia1. Diabetes has been linked to a shorter life expectancy mainly because of its complications, including heart disease, strokes, eye disease, kidney failure and bone disease2. Lifestyle changes and medications are shown to reduce the incidence of diabetes3. Therefore, identification and evaluation of risk factors for diabetes is crucial for early intervention and treatment.
The relationships between hepatic enzymes including alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyltransferase (GGT) and incident diabetes have been examined, but the results are inconsistent. Several prospective studies have reported that ALT was assocaited with incident diabetes4,5,6,7,8,9, but this association was not significant in a study of 4,201 French men and women10. Hanley et al.5, Fraser et al.4, and Schneider et al.11 found that AST independently predicted incident diabetes in 906 non-Hispanic Americans, 3,041 British women, and 9,337 Americans (7,495 white and 1,842 black), respectively. However, others showed that AST did not predict incident diabetes7, 8, 10. In a recent review of literature, Kunutsor and colleagues12 suggested that AST was associated with the risk of incident diabetes after controlling for potential confounding factors. In addition, while most of the studies showed that elevated GGT level was a strong indicator for the onset of diabetes independent of common diabetes risk factors9, 10, a study in Pima Indians found GGT not a predictor8. Several recent studies used the Mendelian randomization to estimate the causal effects of liver enzymes on incident diabetes. ALT was shown to increase the risk of diabetes13 whereas the causal role of GGT in the development of diabetes remained controversial13,14,15.
Non-alcoholic fatty liver disease (NAFLD), the accumulation of excess fat in liver cells that is not caused by alcohol, has been found to be associated with several features of insulin resistance16 and incident diabetes4, 17. Ultrasonography-diagnosed NAFLD is an independent risk factor for diabetes18,19,20,21,22,23,24. Notably, most of them were conducted in Japanese or Korean populations. Notwithstanding the interesting findings, there were concerns about these studies. First, only one of them controlled for ALT and GGT23, both of which have been associated with liver fat accumulation25 Second, most of them used a small sample size and/or a few incident cases, whereas those with a large sample size comprised primarily men22, 23.
Alkaline phosphatase (ALP), an enzyme presented primarily in bone and liver, has been found to elevate in diabetes patients compared with non-diabetes control group26. However, other studies found no significant association between ALP and incident diabetes5, 8, 27, 28.
The aims of the study were: (1) to examine whether baseline NAFLD status and ALT, AST, GGT, and ALP levels are independent risk factors for incident diabetes, and (2) to determine whether these associations vary by gender group. The study population comprised 132,377 non-type 2 nor type 1 diabetic individuals (64,875 men and 67,502 women) aged 35–79 years. They had first physical examination on 1 January 1996 or later and had one or more follow-up examinations on or before 31 December 2014. To our knowledge, this is the largest and the first prospective study that includes five liver-related factors and evaluates their individual effects on incident diabetes, adjusting for a cluster of classical risk factors.
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Full Text
Nature's scientific reports
Introduction
The prevalence and incidence of type 2 diabetes (diabetes hereafter) are rising rapidly worldwide, especially in Asia1. Diabetes has been linked to a shorter life expectancy mainly because of its complications, including heart disease, strokes, eye disease, kidney failure and bone disease2. Lifestyle changes and medications are shown to reduce the incidence of diabetes3. Therefore, identification and evaluation of risk factors for diabetes is crucial for early intervention and treatment.
The relationships between hepatic enzymes including alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyltransferase (GGT) and incident diabetes have been examined, but the results are inconsistent. Several prospective studies have reported that ALT was assocaited with incident diabetes4,5,6,7,8,9, but this association was not significant in a study of 4,201 French men and women10. Hanley et al.5, Fraser et al.4, and Schneider et al.11 found that AST independently predicted incident diabetes in 906 non-Hispanic Americans, 3,041 British women, and 9,337 Americans (7,495 white and 1,842 black), respectively. However, others showed that AST did not predict incident diabetes7, 8, 10. In a recent review of literature, Kunutsor and colleagues12 suggested that AST was associated with the risk of incident diabetes after controlling for potential confounding factors. In addition, while most of the studies showed that elevated GGT level was a strong indicator for the onset of diabetes independent of common diabetes risk factors9, 10, a study in Pima Indians found GGT not a predictor8. Several recent studies used the Mendelian randomization to estimate the causal effects of liver enzymes on incident diabetes. ALT was shown to increase the risk of diabetes13 whereas the causal role of GGT in the development of diabetes remained controversial13,14,15.
Non-alcoholic fatty liver disease (NAFLD), the accumulation of excess fat in liver cells that is not caused by alcohol, has been found to be associated with several features of insulin resistance16 and incident diabetes4, 17. Ultrasonography-diagnosed NAFLD is an independent risk factor for diabetes18,19,20,21,22,23,24. Notably, most of them were conducted in Japanese or Korean populations. Notwithstanding the interesting findings, there were concerns about these studies. First, only one of them controlled for ALT and GGT23, both of which have been associated with liver fat accumulation25 Second, most of them used a small sample size and/or a few incident cases, whereas those with a large sample size comprised primarily men22, 23.
Alkaline phosphatase (ALP), an enzyme presented primarily in bone and liver, has been found to elevate in diabetes patients compared with non-diabetes control group26. However, other studies found no significant association between ALP and incident diabetes5, 8, 27, 28.
The aims of the study were: (1) to examine whether baseline NAFLD status and ALT, AST, GGT, and ALP levels are independent risk factors for incident diabetes, and (2) to determine whether these associations vary by gender group. The study population comprised 132,377 non-type 2 nor type 1 diabetic individuals (64,875 men and 67,502 women) aged 35–79 years. They had first physical examination on 1 January 1996 or later and had one or more follow-up examinations on or before 31 December 2014. To our knowledge, this is the largest and the first prospective study that includes five liver-related factors and evaluates their individual effects on incident diabetes, adjusting for a cluster of classical risk factors.
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