NIDDM IS ASSOCIATED WITH LOSS OF PANCREATIC BETA-CELL L-TYPE CA2+ CHANNEL ACTIVITY

Development of non-insulin-dependent diabetes mellitus (NIDDM) is asso ciated with defects in glucose-stimulated insulin secretion. We have i nvestigated Zucker diabetic fatty rats (ZDF), an animal model of NIDDM , and found that, compared with control islets, the expression of mRNA encoding C- and D-isoforms of alpha(1)-subunits of beta-cell L-type v oltage-dependent Ca2+ channels (VDCC) was significantly reduced in isl ets isolated from ZDF rats. This correlated with a substantial reducti on of L-type Ca2+ currents (I-Ca) in ZDF beta-cells. Intracellular Ca2 + concentration responses in ZDF islets after glucose, KCl, or BAY K 8 644 stimulation were markedly attenuated, whereas responses evoked by carbachol were unimpaired, consistent with a specific decrease in I-Ca in the diabetic islets. This reduction was accompanied by loss of pul satile insulin secretion from ZDF islets treated with oscillatory incr eases of external glucose concentration. Our findings suggest that the attenuation of I-Ca in diabetic islets may contribute to the abnormal glucose-dependent insulin secretory responses associated with NIDDM a nd indicate that this defect is caused by decreased expression of gene s encoding beta-cell VDCC alpha(1)-subunits.