Deteriorated high-fat diet-induced diabetes caused by pancreatic beta-cell-specific overexpression of Reg3 beta gene in mice

摘要

Reg family proteins have long been implicated in islet beta-cell proliferation, survival, and regeneration. In our previous study, we reported that Reg3 beta overexpression did not increase islet growth but prevented streptozotocin-induced islet damage by inducing specific genes. In order to explore its role in type 2 diabetes (T2D), we established high-fat diet (HFD)-induced obesity and diabetes in RIP-I/Reg3 beta mice. Glucose and insulin tolerance tests, immunofluorescence for insulin, eIF2 alpha, and GLUT2 in islets, Western blots on phosphorylated AMPK alpha and hepatic histology were performed. Both RIP-I/Reg3 beta and wild-type mice gained weight rapidly and became hyperglycemic after 10 weeks on the HFD. However, the transgenic mice exhibited more significant acceleration in blood glucose levels, further deterioration of glucose intolerance and insulin resistance, and a lower intensity of insulin staining. Immunofluorescence revealed similar magnitude of islet compensation to a wild-type HFD. The normal GLUT2 distribution in the transgenic beta-cells was disrupted and the staining was obviously diminished on the cell membrane. HFD feeding also caused a further decrease in the level of AMPK alpha phosphorylation in the transgenic islets. Our results suggest that unlike its protective effect against T1D, overexpressed Reg3 beta was unable to protect the beta-cells against HFD-induced damage.