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...

Cholecystokinin (CCK) acting through its G protein-coupled receptor is now known to activate a variety of intracellular signaling mechanisms and thereby regulate a complex array of cellular functions in pancreatic acinar cells. The best studied mechanism is the coupling through heterotrimeric G proteins of the G q family to activate a phospholipase C leading to an increase in inositol trisphosphate and release of intracellular Ca 2π . This pathway along with protein kinase C activation in response to the increase in diacylglycerol stimulates the secretion of digestive enzymes by the process of exocytosis. CCK also activates signaling pathways in acini more related to other processes. The three mitogen activated protein kinase cascades leading to ERKs, JNKs and p38 MAPK are all activated by CCK. CCK activates the ERK cascade by PKC activation of Raf which in turn activates MEK and ERKs. JNKs are activated by a distinct mechanism whish requires higher concentrations of CCK. Both ERKs and JNKs are presumed to regulate gene expression. CCK activation of p38 MAPK also plays a role in regulating the actin cytoskeleton through phosphorylation of the small heat shock protein HSP27. The PI3K-PKB-mTOR pathway is activated by CCK and plays a major role in regulating protein synthesis at the translational level. This includes both activation of p70 S6K leading to phosphorylation of ribosomal protein S6 and the phosphorylation of the binding protein for initiation factor 4E leading to formation of the mRNA cap binding complex. Other signaling pathways activated by CCK receptors include NF-kB and a variety of tyrosine kinases. Further work is needed to understand how CCK receptors activate most of the above pathways and to better understand the biological events regulated by these diverse signaling pathways.

Arginine induced acute pancreatitis was evaluated as a novel and distinct form of experimental pancreatitis with particular attention to the actin cytoskeleton and expression of heat shock or stress proteins. Arginine induced a dose related necrotising pancreatitis in rats, as shown by histological evaluation, and an increase in serum amylase. Severe pancreatitis induced by 4.5 g/kg arginine was accompanied by dramatic changes in the actin cytoskeleton, as visualised with rhodamine phallodin. Intermediate filaments were also disrupted, as visualised by cytokeratin 8/18 immunocytochemistry. Arginine pancreatitis was accompanied by a stress response with a large increase in the small heat shock protein HSP27, as well as HSP70, peaking at 24 hours and localised to acinar cells. There was a lower increase in HSP60 and HSP90 and no eVect on GRP78. HSP27 was also shifted to phosphorylated forms during pancreatitis. A lower dose of arginine (3.0 g/kg) induced less pancreatitis but a larger increase in HSP70 and HSP27 expression and phosphorylation of HSP27. Thus HSP expression can be overwhelmed by severe damage. The present work in conjunction with earlier work on caerulein induced pancreatitis indicates that changes in the actin cytoskeleton are an early component in experimental pancreatitis. (Gut 2001;49:241-250)

Background Recent investigations suggest that activation of coagulation and fibrinolysis occurs in patients with ulcerative colitis (UC). activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), serum concentrations of von Willebrand factor (vWF), activated factors XII, XI, X, IX, VIII, VII, V, II, fibrinogen, prothrombin fragments 1+2 (F1+2), thrombin-antithrombin complexes (TAT), protein S, protein C, plasminogen, α-2 plasminogen inhibitor (α-2PI) and D-dimer (D-D). Results Median serum vWF concentrations, F1+2, TAT, fibrinogen, activated factor XI, IX, VIII and V were significantly elevated in patients with active UC and IC compared to those in patients with

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.