Abstract:
Type-2 diabetes is one of the main causes of morbidity and mortality worldwide. Diabetes is preceded by pre-diabetic state, which is characterized by insulin resistance in target tissues. In response to high blood glucose level, pancreatic β-cells secrete the hormone insulin, which in turn triggers glucose uptake into adipocytes and muscle cells and also reduces glucose production by liver, causing a reduction of blood glucose levels. If these tissues become insulin resistant, a compensatory increase of insulin secretion from pancreatic β-cells occurs, ultimately causing β-cell dysfunction. Additionally, recent studies indicate that macrophages as one of the major contributors to the insulin resistance in target tissues. Despite significant advances having been made in understanding those molecular events, many gaps remain to be answered. This thesis aims to identify molecular mechanisms associated with the type 2-diabetes in β-cells, adipocytes and macrophages whose proper functioning is critical for blood glucose homeostasis. In the first study, we showed that reducing α-catenin protein levels increase the glucose stimulated insulin secretion (GSIS), indicating a role for α-catenin in mechanism regulating insulin secretion. Moreover, the physiologically relevant changes in glucose concentration increases α- catenin protein levels in rat pancreatic β-cell lines. This study suggests that α-catenin protein in combination with β-catenin may act to control how much insulin is sequestered inside β-cells and hence available for release upon glucose stimulation. Furthermore, a novel regulatory role for β-catenin in glucose uptake into adipocytes was also identified during this study. Depletion or inhibition of β-catenin in adipocytes causes the reduction of insulin stimulated glucose uptake, while increased level of β-catenin increases the insulin stimulated glucose uptake, indicating the requirement of β-catenin for insulin stimulation of glucose uptake. Further supporting this, TIRF-M studies showed that β-catenin is required for insulin responsive GLUT4 trafficking process, which is critical for insulin’s effect on adipocytes. The third study suggests the glucose dependent change of α-catenin levels in macrophages, which might help to change macrophage polarization to acquire distinct functional phenotype. Altogether, here we propose novel molecular mechanisms associated with type-2 diabetes, which might help to develop novel therapeutics for this long term disease.