Nonalcoholic Fatty Liver Disease Is a Risk Factor for Type 2 Diabetes in Middle-Aged Japanese Men

Abstract

OBJECTIVE -To determine the association between nonalcoholic fatty liver disease and the risk for development of diabetes.RESEARCH DESIGN AND METHODS -We conducted an observational cohort study in male workers Ն40 years old in a Japanese company from 1997 to 2005. We excluded workers with alcohol intake Ն20 g/day and those with impaired glucose tolerance by a 75-g oral glucose tolerance test. The remaining 3,189 workers were classified into fatty liver (FL) and non-FL group based on the findings of abdominal ultrasonography. Both groups were followed for the development of diabetes. Hazard ratio (HR) was determined in Cox proportional hazard analysis. A nested case-control study was conducted to determine the odds ratio (OR).RESULTS -The average age of participants was 48.0 years at the entry, and the average follow-up period was 4.0 years. The incidence of diabetes in the FL group was 2,073 per 100,000 person-years (65 cases), whereas 452 per 100,000 person-years (44 cases) in the non-FL group. The age-and BMI-adjusted HR of diabetes associated with FL was 5.5 (95% CI 3.6 -8.5, P Ͻ 0.001). In the nested case-control analysis, the OR adjusted for age and BMI was 4.6 (3.0 -6.9, P Ͻ 0.001).CONCLUSIONS -Nonalcoholic fatty liver disease significantly increases the risk of diabetes in middle-aged Japanese men. Diabetes Care 30:2940-2944, 2007N onalcoholic fatty liver disease (NAFLD) has become the most common disease of chronic liver damage, with increased prevalence of obesity, diabetes, and metabolic syndrome in the U.S. (1-3). The prevalence of NAFLD is increasing in Japan because of the westernization of the lifestyle, such as a high-fat and high-calorie diet and less physical activity (4). The high prevalence of fatty liver in association with type 2 diabetes has been reported (5,6).NAFLD is characterized by significant lipid deposition in hepatocytes in patients without history of excessive alcohol intake and is often associated with obesity (7), type 2 diabetes (8,9), dyslipidemia (10), and hypertension (11). Although they are often categorized as the insulin resistance syndrome or the metabolic syndrome (12), each of these individual abnormalities carries a risk of cardiovascular disease. In addition, diabetes, insulin resistance, and increased plasma fatty acids are considered to increase the risk for NAFLD (13,14), and each of these metabolic factors is also characteristic of type 2 diabetes. It has been reported that NAFLD influences severity of hepatic insulin resistance in type 2 diabetes (15). Moreover, NAFLD was correlated with hepatic insulin resistance independently of obesity and intra-abdominal adiposity among nonobese men without type 2 diabetes (16).Increased prevalence of NAFLD in relation to the development of diabetes has been reported in a cross-sectional study (17), and a close relationship between liver enzymes and diabetes has been reported in cohort studies (18 -23). However, the former does not prove a causal relationship, and the latter does not directly pay attention to NAFLD. There is...

Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon?

“…There are now about 20 observational studies that have assessed the association between NAFLD and the risk of new-onset type 2 diabetes [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25].…”

“…The risk of diabetes among these published studies varied markedly from a 33% increase [14] to a 5.5 fold increase in risk [11]. This wide inter-study variation in risk might reflect differences in NAFLD severity, since the study by Park et al [15] showed that the 5-year incidence rate of type 2 diabetes increased progressively according to the ultrasonographic severity of NAFLD at baseline (normal: 7.0%, mild: 9.8%, moderate-to-severe: 17.8%) in a cohort of 25,232 South Korean nondiabetic middle-aged men.…”

“…Collectively, although there is now convincing evidence that NAFLD is associated with an increased risk of new-onset type 2 diabetes [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], and there is emerging evidence that this risk varies according to the severity of NAFLD (as detected either by ultrasonography or by use of non-invasive fibrosis scoring systems) [9,[12][13][14], further evidence is unquestionably needed in non-Asian populations, as nearly all of the studies summarised in Table 1 have been conducted in various Asian populations, and most of the evidence obtained to date has been obtained in South Korean individuals. However, a recent analysis from the Multi-Ethnic Study of Atherosclerosis study involving more than 3,000 United States nondiabetic individuals has confirmed that NAFLD as detected by computed tomography was independently associated with a two-fold increased risk of developing type 2 diabetes [25].…”

“…Additional follow-up studies with a larger panel of established and emerging diabetes risk factors (e.g., higher serum ferritin and lower adiponectin levels that have been also associated with the presence and severity of NAFLD) are needed to firmly establish an independent contribution of NAFLD per se to the risk of new-onset type 2 diabetes. Finally, it is important to underline that in none of the published studies, except for the studies by Shibata et al [11] and by Ming et al [23], the diagnosis of diabetes was based on 2-hour post-load plasma glucose concentrations.…”

“…In NAFLD and insulin resistance, dysfunction of glucagon-like peptide (GLP-1) secretion and altered short chain fatty acid (SCFA) production may also adversely influence hepatic gluconeogenesis and lipogenesis. 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 19 [11] Retrospective cohort study with a nested case-control analysis n=3,189 male Japanese workers with normal glucose tolerance, no viral hepatitis, no alcohol ; 4 years; liver ultrasonography Fasting glucose ≥7.0 mmol/l or 2-h glucose ≥11.1 mmol/l on 75-g OGTT n=109 incident cases 1.8% vs. 8.1%…”