Downregulation of the voltage-dependent calcium channel (VDCC) beta-subunit mRNAs in pancreatic islets of type 2 diabetic rats

The present study was undertaken to determine whether altered expression of the VDCC beta -subunits in pancreatic beta -cells could play a role in the changes in beta -cell sensitivity to glucose that occur with diabetes. App lication of competitive RT-PCR procedure revealed that in normal Wistar rat s, LETO and prediabetic OLETF rats, the beta (2)-subunit mRNA levels were 6 0-200-fold greater than the levels for the beta (3)-subunit. These findings suggest that the beta (2)-subunit as well as the beta -cell type VDCC1 alp ha (1)-subunit may be the predominant form of the VDCC expressed in pancrea tic beta -cells. The levels of mRNA encoding the beta -subunits and the bet a -cell type alpha (1)-subunit as well as insulin were significantly reduce d in diabetic rats. Perfusion experiments revealed that diabetic rats showe d the higher basal insulin secretion and profoundly impaired insulin secret ory responses to glucose compared with nondiabetic rats. Alternatively, imp aired insulin secretory responses to glucose in high dose glucose-infused r ats were recovered partly with the elevation of mRNA levels of the VDCC bet a (2)- and beta (3)-subunits as well as the alpha (1)-subunit by the treatm ent with diazoxide. Thus, considering the possibility that the most strikin g effect of the VDCC alpha (1) beta -subunit coexpression in pancreatic bet a -cells might occur on activation kinetics like the skeletal muscle, the i mpairment of further activation of the VDCCs to acute glucose challenge cau sed by the reduced expressions of the alpha (1) beta -subunits mRNAs in typ e 2 diabetic animals might be at least partly associated with the alteratio ns in beta -cell sensitivity to glucose. (C) 2001 Academic Press.