Prevention of Pancreatic β-Cell Failure in Type 2 Diabetes. By Targeting a Mitochondrial Voltage Gated Channel 1 and a Novel class of GPCRs
Sammanfattning: It has been long known that hyperglycaemia-induced β-cell dysfunction precipitates type 2 diabetes (T2D) in insulin-resistant obesity, although the underlying mechanisms are still poorly defined. The few frequently used antidiabetic drugs on the market have still not satisfactorily demonstrated any long-lasting improvements of β-cell function and prevention of the disease. Islets synthesise and secrete numerous peptides, many of which having important impact on the regulation of metabolism, in particular blood glucose control. In paper I, we quantified mRNAs encoding all peptide ligands of islet G protein-coupled receptors (GPCRs) in isolated human and mouse islets. The study will allow accurate translation of mouse islet functional studies relevant for human physiology, which may pave the way to novel treatment of diabetes. In paper II, we show that ADGRG1 (GPR56) is the most abundant GPCR transcript in both human and mouse islets, and its expression in human islets strongly correlate with genes important for β-cell function. ADGRG1 was reduced in islets of T2D donors, in db/db mouse islets, and in isolated human non-diabetic islets exposed to chronic hyperglycaemia (high glucose concentration in vitro). ADGRG1 activation increased cAMP generation and exerted ant-apoptotic effects. In paper III, we show that long-lasting exposure to high glucose (glucotoxicity) impairs ATP production in β-cells, due to overexpression and coll of the mitochondrial membrane protein VDAC1 to the cell surface. This causes ATP loss, whose attenuation with VDAC1 inhibitors restores β-cell function. Daily injections of a VDAC1 inhibitor prevent the onset of hyperglycaemia in db/db mice. Thus, β-cell function is preserved by targeting the novel diabetes executer protein VDAC1.In paper IV, we show that Adgrg1/GPR56 knock-down (KD) in mouse islets increases the activity of P70S6K, JNK, AKT, NFkb, STAT3 and STAT5. Similar to the hyperglycaemia-induced β-cell dysfunction, the Adgrg1-KD induced β-cell dysfunction seems to be associated with translocation of mitochondrial Vdac1 to the cell membrane resulting in an increased loss of cellular ATP.In paper V, we studied the role of GPR142, expressed in both mouse and human islets. Gpr142 activation by specific agonists increases the generation of cAMP in mouse islets and long-term exposure to high glucose also reduces the expression of Gpr142. Gpr142-KD was associated with increase in Vdac1 expression in mouse islets and INS-1 cells.Taken together the information presented in the current thesis identified the involvement of the novel diabetes executer protein VDAC1 in β-cell dysfunction and suggests VDAC1 as a new target for the prevention of T2D. Keeping the heterogeneity of T2D in mind, additional opportunities i.e. targeting two newly deorphanized GPCRs i.e. ADGRG1 (GPR56) and GPR142 has also been highlighted as novel therapies for the prevention of human T2D.
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