Pancreatic islet-specific overexpression of reg3β protein

Reg family proteins have been implicated in islet β-cell proliferation, survival, and regeneration. Reg3β (pancreatitis-associated protein, PAP; or gene expressed in hepatocellular carcinoma-intestine-pancreas, HIP) was first reported as a pancreatic secretory protein expressed in acinar cells during the acute phase of pancreatitis. Previous studies in Dr. Liu's and other research groups have demonstrated that Reg3β was specifically induced either during islet hyperplasia in the IGF-I-deficient pancreas or as a result of GLP-1-induced islet cell growth. Reg3β has been shown to play anti-apoptotic and anti-inflammatory roles during acute pancreatitis. In the present study, we generated transgenic mice with pancreatic β-cell-specific over-expression of Reg3β and investigated the effect of Reg3β in the regulation of β-cell function during streptozotocin (STZ)-induced type 1 diabetes (T1D) and diet-induced type 2 diabetes (T2D). The data presented in Chapter II demonstrated that pancreatic islet-specific overexpression of Reg3β protein protected mice from STZ-induced T1D. The RIP-I/Reg3β mice were indistinguishable from wild-type littermates in fertility, islet morphology, β-cell mass, and insulin secretion response, yet were slightly high in glucose and low in the expression of Glut2 and insulin. These transgenic mice were significantly protected from STZ-induced hyperglycemia and weight loss that were observed in the wild-type controls. To identify the molecular networks that Reg3β is involved in, a whole genome DNA microarray analysis of isolated islet RNA samples revealed more than 45 genes whose expression were markedly up- or down-regulated as a consequence of Reg3β overexpression. We further confirmed the change in several genes, including the upregulation of islet-protective osteopontin/Spp1 and acute responsive nuclear protein Nupr1/p8 by real-time PCR, Western blots and histology. These results support the potential of Reg3β in preventing STZ-induced damage by regulating expression of specific genes.In Chapter III, mice carrying Reg3β over-expression displayed worsened T2D induced by high-fat diet (HFD), as characterized by faster and more severe development of hyperglycemia, glucose intolerance and insulin resistance. Reg3β seems to exert two opposite actions in respone to HFD: further diminishing the expression of insulin and Glut2 induced by HFD, while suppressing AMPK activity and increasing p8 expression to compensate for the loss of β-cell function. Taken together, Reg3β is a putative protector that prevents STZ-induced acute damage, but unlikely an islet growth factor and unable to protect β-cells against HFD-induced T2D. The protective effect of Reg3β is likely triggered by acute stress but ineffective against chronic stress induced by HFD.%%%%Les proteines de la famille Reg sont impliquees dans la proliferation, la survie et la regeneration des cellules pancreatiques β. Reg3β [aussi connue sous le nom de PAP (proteine associee a la pancreatite) ou encore HIP (gene exprime dans le carcinome…