The impact of glucotoxicity on pancreatic β-cell function

Abstract: Type 2 diabetes mellitus is connected with elevated plasma glucose levels which negatively influence β-cells and cause impaired glucose-stimulated insulin secretion (GSIS). The aim of present thesis was to investigate the impact of long-term hyperglycemia on the pancreatic islet β-cell function.
The data showed abnormally increased expression of inducible nitric oxide synthase (iNOS) protein in the islets from diabetic donors as well as in the islets exposed to chronic hyperglycemia. cAMP analogue or PDE inhibitors counteract these abnormalities and restore β-cell function at least in part, by activating cyclic AMP/PKA system. Using two different diabetic animal models i.e. mild hyperlipidemic ZDF (fa/fa) and hyperglycemic GK rat, we found that chronic hyperglycemia in the absence of hyperlipidemia almost abolish GPR40 expression in the islet cells and abrogate the FFA-induced secretory effects. We suggest that this might be an important contributing factor for dysfunction of β-cells seen in human type 2 diabetes (T2D).
Furthermore we also observed that prolonged exposure of INS-1E and INS-1 832/13 cells or isolated human islets to high glucose concentration are associated with increased level of VDAC1 and reduced level of VDAC2 accompanied with marked reduction of GSIS. Similar to glucose, 2-deoxy-glucose also increased the expression of VDAC1. Addition of glycogen synthase kinase 3β (GSK-3β) inhibitor reversed the alteration in VDAC1/VADC2 expression and improved GSIS. Islets of type 2 diabetic donors showed increased expression of VDAC1 and a marked reduction of VDAC2. Diabetic islets also displayed increased expression of ChREBP and TXNIP. Down-regulation of ChREBP and TXNIP in INS-1 832/13 cells cultured at high glucose suppressed high glucose-induced increase in VDAC1 expression. The cultured INS-1 832/13 cells also exhibited a reduced expression of VADC1 when resveratrol (a polyphenolic compound) was present.
The data suggest that an increased expression of iNOS, increased expression of VDAC1 and reduced expression of VDAC2 are the main causative factors in the pathogenesis of glucotoxicity. The GPR40 protein is interactively modulated by both hyperlipidemia and hyperglycemia. Taken together, these contributing signaling factors are promising targets for pharmacotherapy in different variants of type 2 diabetes.