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...

UMIN000001818; Results.

Transforming growth factor-b (TGF-b) is an important cytokine in the fibrogenesis in many organs, including the pancreas. Using an adenoviral vector expressing the entire extracellular domain of type II human TGF-b receptor (AdTb-ExR), we investigated whether inhibition of TGF-b action is effective against persistent pancreatic fibrosis, and whether it exerts a beneficial effect on the pancreas in the process of chronic injury. To induce chronic pancreatic injury and pancreatic fibrosis, mice were subjected to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 lg/kg body weight cerulein at hourly intervals, per week for 3 consecutive weeks. Mice were infected once with AdTb-ExR, or with a control adenoviral vector expressing bacterial b-galactosidase (AdLacZ). Pancreatic fibrosis was evaluated by histology and hydroxyproline content. Activation of pancreatic stellate cells (PSCs) was assessed by immunostaining for a-smooth muscle actin. Apoptosis and proliferation of acinar cells were assessed by immunostaining of ssDNA and Ki-67, respectively. Three-week cerulein injection induced pancreatic fibrosis and pancreatic atrophy with proliferation of activated PSCs. In AdTb-ExR-injected mice, but not AdLacZ-injected mice, pancreatic fibrosis was significantly attenuated. This finding was accompanied by a reduction of activated PSCs. AdTb-ExR, but not AdLacZ, significantly increased pancreas weight after chronic pancreatic injury. AdTb-ExR did not change the proportion of proliferating acinar cells, whereas it reduced the number of apoptotic acinar cells. Our results demonstrate that inhibition of TGF-b action not only decreases pancreatic fibrosis but also protects the pancreas against chronic injury by preventing acinar cell apoptosis.

Local tissue pressure is higher in chronic pancreatitis than in the normal pancreas. We reported recently that pressure application induces synthesis of extracellular matrix (ECM) and cytokines in pancreatic stellate cells (PSCs) and that epigallocatechin gallate (EGCG), a potent antioxidant, inhibits the transformation of PSCs from quiescent to activated phenotype and ethanol-induced synthesis of ECM and cytokines in PSCs. These results suggest that oxidative stress and reactive oxygen species (ROS) are important in PSC activation. The aim of this study was to clarify the effects of ROS on activation and functions of pressure-stimulated PSCs. We used freshly isolated rat PSCs and culture-activated PSCs. Pressure was applied on rat cultured PSCs by adding compressed helium gas into a pressure-loading apparatus. PSCs were cultured with or without antioxidants (EGCG and N-acetyl cysteine) under normal or elevated pressure. Externally applied high pressure (80 mmHg) resulted in a gradual decrease of superoxide dismutase activity in PSCs and increased intracellular ROS generation as early as 30 s, reaching a peak level at 1 h. Antioxidants significantly inhibited ROS generation. Pressure increased the expression levels of alpha-smooth muscle actin, alpha(1)(I)-procollagen, and TGF-beta1 in PSCs. EGCG suppressed these alterations, abolished pressure-induced phosphorylation of p38 MAPK, and suppressed pressure-induced PSC transformation to activated phenotype. Our results indicated that ROS is a key player in pressure-induced PSC activation and ECM synthesis. Antioxidants could be potentially effective against the development of pancreatic fibrosis in patients with chronic pancreatitis.

Our results suggest that green tea and polyphenols could prevent pancreatic fibrosis by inhibiting PSC activation through the antioxidative effect.