Chronic Inflammation Exacerbates Pancreatic B Cell Dysfunction And Apoptosis In C57BL/6J Mice Fed With High Fat Diat

PART ONE: CHRONIC INFLAMMATION EXACERBATESPANCREASTIC β CELL DYSFUNTION AND APOPTOSISIN C57BL/6J MICE FED WITH HIGH FAT DIETObjectives: Type2diabetes is closely related to obesity. However,clinically, most obese individuals failed to develop into diabetes, while theprecise cellular mechanism is largely unknown. In this study, weinvestigated whether chronic inflammation exacerbated β cell dysfunction inHFD-fed C57BL/6J mice.Methods: We used casein injection in HFD-fed C57BL/6J mice toinduce chronic inflammation. Serum was analyzed for inflammatorycytokines, lipids, glucose and insulin. Insulin sensitivities were evaluated byglucose and insulin tolerance tests. The protein expressions were detected byWestern Blot. Pancreas was taken for histomorphological and apoptoticdetection. Real-time polymerase chain reaction was used to examine thegene expression of molecules involved in insulin synthesis and secretion and β cell apoptosis in pancreas.Results:14weeks on a HFD resulted in weight gain and hyperlipidemiain C57BL/6J mice. Casein injection elevated TNF-α and SAA levels in theserum and simultaneously increased TNF-α and MCP-1levels in the adiposetissue, liver and muscle of HFD-fed mice. Inflammation induced by caseininjection further impaired glucose tolerance and insulin signaling pathway,induced hyperglycemia and insulin deficiency in mice fed with HFD.Chronic inflammation decreased islet mass and insulin content and increasedβ cell apoptosis in HFD-fed mice. Results from gene expression of insulinsynthesis and secretion and β cell apoptosis in pancreas were consistent withthese data.Conclusion: Chronic inflammation exacerbates pancreatic β celldysfunction and apoptosis in HFD-fed C57BL/6J mice, suggesting thatobese individuals with chronic inflammation are more prone to develop intohyperglycemia. PART TWO: RAPAMYCIN EXACERBATES THE DESTRUCTIONOF PANCREATIC β CELLS INDUCED BY CHRONICINFLAMMATION IN C57BL/6J MICEObjectives: To investigate the effect of Rapamycin on pancreatic β cellfunction under chronic systemic inflammation in C57BL/6J mice.Methods: Male C57BL/6J mice aged8weeks were fed with high fatdiet and were randomly assigned to receive intraperitoneal injection ofCasein plus Vehicle (Veh) and Casein plus Rapamycin (Rapa). Serum insulinlevels were measured by ELISA kits. Glucose and insulin tolerance testswere used to evaluate body glucose utilization. Pancreas was taken forhistomorphological and apoptotic detection. Real-time polymerase chainreaction was used to examine the gene expression of molecules involved ininsulin synthesis and secretion and β cell apoptosis in pancreas.Results: After glucose loading, blood glucose concentration waspersistently higher in Rapa group (30,60,120min) than in Veh group; andafter insulin challenge, blood glucose levels in Rapa group reduced slowly,and were still higher than Veh group, indicating Rapamycin aggravatedglucose intolerance and insulin insensitivity induced by chronicinflammation in C57BL/6J mice. Compared to Veh group, islet mass andinsulin content were significantly decreased in Rapa group, accompanyingwith notable lower serum insulin levels. It suggested that Rapamycin further impaired pancreatic β cells in the state of chronic inflammation. PDX-1,GLUT2and GK mRNA expression in Rapa group were obviouslydown-regulated compared to Veh group. Moreover, Rapamycin exacerbatedapoptosis of β cells and increased Bax/Bcl2mRNA levels in pancreas ofmice.Conclusion: Rapamycin exacerbates the destruction of pancreatic βcells induced by chronic inflammation in C57BL/6J mice.