Defective glucose-dependent cytosolic Ca2+ handling in islets of GK and nSTZ rat models of Type 2 diabetes

We examined to what extent the abnormal glucose-dependent insulin secretion observed in NIDDM (noninsulin-dependent diabetes mellitus) is related to a lterations in the handling of cytosolic Ca2+ of islets of Langerhans. Using two recognized rat models of NIDDM, the GK (Goto-Kakizaki) spontaneous mod el and the nSTZ (neonatal streptozotocin) induced model, we could detect se veral common alterations in the glucose-induced [Ca2+] cytosdic responses. First, the initial reduction of [Ca2+](i) following high glucose (16.7 mM) observed routinely in islets obtained from Iron-diabetic Wistar rats could not be detected ill GK and nSTZ islets. Second, a delayed response for gluc ose to induce a subsequent 3% increase of [Ca2+]i over basal level was obse rved in both GK (321 +/- 40 s, n = 11) and nSTZ (336 +/- 38 s, n=13) islets as compared with Wistar islets (198 +/- 20 s, n=11), increase in [Ca2+], i n response to a high glucose challenge was 25% and 40% lower in GK and nSTZ respectively, as compared with Wistar islets. Fourth, the maximal [Ca2+], level reached after 10 min of perifusion with 16.7 mM glucose was lower wit h GK and nSTZ islets and represented respectively 60% and 90% of that of Wi star islets. Further, thapsigargin, a blocker of Ca2f-ATPases (SERCA), abol ished the initial reduction in [Ca2+](i) observed in response to high gluco se and induced fast [Ca2+](i) oscillations with high amplitude in Wister id ets. The latter effect was not seen in GK and nSTZ islets. In these two NID DM models, several common alterations ill glucose-induced Ca2+ handling wer e revealed which may contribute to their poor glucose-induced insulin secre tion.