Heterotrimeric Gai2 protein function in insulin-secreting beta-cells and insulin-sensitive adipocytes

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Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder, which affects more than 300 million people globally. The prominent feature of uncontrolled T2DM is hyperglycemia, which results from beta-cell dysfunction and insulin resistance. In most people suffering T2DM a characteristic set of symptoms is found, which is known as metabolic syndrome: insulin resistance, hyperlipidemia, hypertension and obesity. Lifestyle interventions such as diet and/or exercise have often limited effects. Hence, novel pharmacological interventions are needed to reduce body weight, improve insulin sensitivity and hyperlipidemia in order to prevent the progression of T2DM. G protein coupled receptors (GPCR) are quite frequent pharmacological targets. Upon ligand binding GPCRs activate heterotrimeric G proteins which in turn are eliciting cellular responses through the regulation of intracellular second messenger-generating systems. The class of inhibitory G proteins (Gi) forms one subfamily including the predominantly expressed Gi2 isoform which is found in pancreatic islets and white adipose tissue (WAT). However, the mechanisms and biological implication of Gi2-dependent pathways in insulin-secreting beta-cells and WAT remain cryptic. Within the first funding period we identified beta-cell-Gi2 as a stimulator of L arginine- and L ornithine-induced insulin secretion. Surprisingly, although Gi2 is a PTx-sensitive G protein and therefore thought to inhibit insulin secretion, Gi2 deletion in beta-cells resulted in a decreased glucose tolerance and impaired insulin secretion in vivo, a situation also found in patients suffering from T2DM. Interestingly, our studies in global Gi2-deficient mice demonstrated a lean phenotype of these mice on control (CD) and on a 45% high-fat diet (HFD). Both, CD and HFD-fed Gi2-deficient mice were significantly leaner and accumulated significantly less body fat mass than their littermate controls. First studies on adipocyte-specific Gi2-deficient mice showed also significantly reduced body weight on HFD. Therefore, we hypothesize that Gi2 is not only relevant for proper insulin secretion but also important for adipocyte differentiation and plays a role in diet-induced obesity. Consequently, on the one hand a major aim of our grant proposal is to elucidate the molecular Gi2 signalling pathway in beta-cells by analyzing beta-cell-specific Gi2-deficient islets. On the other hand we want to clarify the function of Gi2 in adipocytes. Therefore, we intend to examine global and adipocytes-specific Gi2-deficient mice. We will study adipocyte differentiation, maturation and organization in vitro and weight gain, glucose homeostasis, body consumption, fat mass distribution and energy expenditure in mice on CD and HFD. Taken together, this study will provide new insights into T2DM-relevant signalling pathways and will help to develop new pharmacological interventions for T2DM.