Hyperresponse in calcium-induced insulin release from electrically permeabilized pancreatic islets of diabetic GK rats and its defective augmentation by glucose

Abstract

In spontaneously diabetic GK rats, insulin secretion from pancreatic beta cells in response to glucose is selectively impaired, probably due to deficient intracellular metabolism of glucose and impaired closure of KATP channels during glucose stimulation. By using electrically permeabilized islets of GK rats, we explored the functional modulations in exocytotic steps distal to the rise in [Ca2+]i in the diabetic condition. At 30 nmol/l Ca2+ (basal conditions) insulin release was similar between GK and non-diabetic control Wistar rats. In response to 3.0 mumol/l Ca2+ (maximum stimulatory conditions), insulin release was significantly augmented in permeabilized GK islets (p < 0.01). Raising glucose concentrations from 2.8 to 16.7 mmol/l further augmented insulin release induced by 3.0 mumol/l Ca2+ from permeabilized control islets (p < 0.001), but had no effect on that from permeabilized GK islets. The stimulatory effect of glucose on insulin release from permeabilized control islets was partly inhibited by 2,4-dinitrophenol, an inhibitor of mitochondrial oxidative phosphorylation (p < 0.01). The hyperresponse to Ca2+ in GK islets may play a physiologically compensatory role on the putative functional impairment both in [Ca2+]i rise and energy state in response to glucose in diabetic beta cells, and may explain the relative preservation of insulin release induced by non-glucose depolarizing stimuli, such as arginine, from pancreatic islets in non-insulin-dependent diabetes mellitus.

Modulation of L-Type Ca2+ Channels by Distinct Domains Within SNAP-25

“…These results have the potential to elucidate how SNARE proteins may not only regulate physiological insulin exocytosis but also be of pathophysiological significance in the dysregulation of Ca 2ϩ influx-mediated islet ␤-cell injury in diabetes (1)(2)(3). In fact, SNARE protein expression levels were diminished in islets of type 2 diabetic models, including Zucker fa/fa and GK rats (34,35), which exhibit abnormal regulation of Ca 2ϩ influx and insulin exocytosis (36). Reconstitution of these SNARE proteins, particularly SNAP-25 and syntaxin, partially restored insulin secretion to normal levels (35), likely by restoring the diabetic dysregulation of the distal components of the insulin exocytotic machinery, in particular the L C excitosome.…”

(Patho)physiological implications of the novel epithelial Ca2+ channels TRPV5 and TRPV6

“…Involvement of ion channels in this process is widely accepted and an increase in intracellular Ca 2+ levels is necessary to trigger exocytosis and release of insulin [68,76]. Furthermore, in isolated pancreatic islets of diabetic rats, impairment of insulin secretion is due to the inability of glucose to eventually increase the intracellular Ca 2+ concentration and trigger exocytosis [48,49]. The localization of TRPV5 suggests that it may play a role in the regulation of intracellular Ca 2+ homeostasis and insulin secretion.…”

A Review of Islet of Langerhans Degeneration in Rodent Models of Type 2 Diabetes

“…Desensitization of the K ATP channel to ATP has been reported (Tsuura et al, 1994), but is not believed to be a major cause of reduced insulin secretion. Indeed, studies have shown a hyperresponsiveness to Ca 2+ in Goto-Kakizaki rat electropermeabilized β cells (Katayama et al, 1995;Okamoto et al, 1995), which may represent a compensatory adaptation to decreased ATP production.…”