Abnormal regulation of insulin secretion in the genetically obese (ob/ob) mouse

Abstract

To determine whether the abnormal insulin-secretory activity encountered in obese mice is due to an anomaly in the production of cyclic AMP, islets of lean and obese mice were incubated with forskolin under various conditions. Our data show that, in addition to the well-known quantitative differences in insulin-secretory activity between islets of lean and obese mice, there are important qualitative differences. The islets of obese mice accumulated less cyclic AMP than did those of lean mice in response to given doses of forskolin, yet their insulin secretion was enhanced to much higher values. In the islets of obese mice, but not in those of lean mice, the stimulatory effect of forskolin on insulin secretion was evident even at non-stimulatory concentrations of glucose or in Ca2+-deprived incubation media, showing that the islet of the obese mouse is less dependent on a primary stimulus (glucose) and on the provision of normal concentrations of Ca2+ in the bathing medium than is the islet of the lean mouse.

Enhanced glucose-induced intracellular signaling promotes insulin hypersecretion: Pancreatic beta-cell functional adaptations in a model of genetic obesity and prediabetes

“…5B) were found to be increased in ob/ob islets as compared to CTL. As previously documented (Black et al, 1986;Fournier et al, 1990), we observed that insulin secretion was enhanced in islets from obese mice (Supplemental Fig. S4).…”

“…The increased insulin secretory capacity in ob/ob islets has been reported long time ago (Black et al, 1986;Fournier et al, 1990). Our capacitance experiments in intact islets demonstrate that this hypersecretion may be supported by an enhanced exocytotic capacity at the single cell level.…”

“…1). Although the hyperinsulinemic characteristic of ob/ob mice has been related with morphological adaptations (Baetens et al, 1978;Gepts et al, 1960;Tomita et al, 1992), increased GSIS has been also observed in isolated ob/ob islets (Black et al, 1986;Fournier et al, 1990;Saleh et al, 2006). In the present work, we focused on the involvement of the different functional steps participating in GSIS.…”

Polyamines in pancreatic islets of obese-hyperglycemic (ob/ob) mice of different ages

“…These studies were conducted in normal mouse or rat islets and demonstrated a glucose-regulated spermine content, suggesting a stimulatory or permissive role of spermine at multiple sites of insulin production and glucosesensitive insulin release, results reproduced in the present study. Such a role is also in conformity with the present observations of an increased spermine-tospermidine ratio in conjunction with a previously reported enhanced (pro)insulin biosynthesis (2) and hypersensitive secretory response to glucose (5,11,21,40) in islets of the obese-hyperglycemic mouse.…”

EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance

“…Based on the traditional role of Gi/o proteins to block adenylate cyclase activity and reduce cAMP production, EP3γ activity may reduce NGOB β-cell cAMP levels from an even higher theoretical baseline. Numerous signaling changes have been demonstrated in β-cell compensation and failure, such as those mediated by β-cell stress pathways (6,9,38,39), many of which converge on cAMP (14,31,(40)(41)(42). In this scenario, EP3γ up-regulation may be a compensatory adaptation to dampen β-cell stress and promote β-cell survival.…”