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 (non-insulin-dependent diabetes mellitus) is related to alterations in the handling of cytosolic Ca2+ of islets of Langerhans. Using two recognized rat models of NIDDM, the GK (Goto-Kakizaki) spontaneous model and the nSTZ (neonatal streptozotocin) induced model, we could detect several common alterations in the glucose-induced [Ca2+]i cytosolic responses. First, the initial reduction of [Ca2+]i following high glucose (16.7 mM) observed routinely in islets obtained from non-diabetic Wistar rats could not be detected in GK and nSTZ islets. Second, a delayed response for glucose to induce a subsequent 3% increase of [Ca2+]i over basal level was observed in both GK (321+/-40 s, n=11) and nSTZ (326+/-38 s, n=13) islets as compared with Wistar islets (198+/-20 s, n=11), values representing means+/-s.e.m. Third, the rate of increase in [Ca2+]i in 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+](i) level reached after 10 min of perifusion with 16.7 mM glucose was lower with GK and nSTZ islets and represented respectively 60% and 90% of that of Wistar islets. Further, thapsigargin, a blocker of Ca2+/ATPases (SERCA), abolished the initial reduction in [Ca2+]i observed in response to high glucose and induced fast [Ca2+]i oscillations with high amplitude in Wistar islets. The latter effect was not seen in GK and nSTZ islets. In these two NIDDM models, several common alterations in glucose-induced Ca2+ handling were revealed which may contribute to their poor glucose-induced insulin secretion.
Laboratoire de Physiopathologie de la Nutrition, CNRS-ESA 7059, Université Paris VII/D. Diderot, 2 Place Jussieu, F-75251 Paris, France. ugh@bichat.inserm.fr
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Marie
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Bailbé
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Gylfe
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Portha
D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar
D005947:Glucose; D002118:Calcium