Chronic exposure to glibenclamide impairs insulin secretion in isolated rat pancreatic islets

Abstract

We investigated the effect of 24 h exposure to 100 nmol/l glibenclamide on insulin secretion in isolated rat pancreatic islets. The insulin content was similar in control islets and in islets preincubated with 100 nmol/l glibenclamide for 24 h. In islets preexposed to glibenclamide: 1) the subsequent response to a maximal glibenclamide stimulatory concentration (10 mumol/l, 1 h at 37 C) was greatly reduced in comparison to control islets (0.69 +/- 0.20% vs 2.16 +/- 0.41%; mean +/- SE; n = 14; p less than 0.001); 2) the response to 100 mumol/l tolbutamide stimulation was also reduced (0.55 +/- 0.15% vs 2.38 +/- 0.44%; n = 8; p less than 0.001); 3) the response to 16.7 mmo/l glucose, both in the presence or in the absence of 1 mmol/l IBMX, a phosphodiesterase inhibitor, was also diminished by about 50% (1.79 +/- 0.39% vs. 3.22 +/- 0.42%; n = 14, p less than 0.001). In glibenclamide pretreated islets, blunted responses to stimuli were confirmed also by dynamic studies using a perifusion system. The effect of glibenclamide preincubation was fully reversible: when islets cultured in the presence of glibenclamide were transferred to a glibenclamide-free medium for further 24 h, insulin release in response to glibenclamide stimulation returned to control values. We conclude that prolonged exposure of rat pancreatic islets to glibenclamide induces a reversible desensitization to a variety of metabolic stimuli. The inhibition by prolonged glibenclamide exposure of a common pathway in the mechanism of insulin release is one possible explanation for these results.

Glibenclamide but not other sulphonylureas stimulates release of neuropeptide Y from perifused rat islets and hamster insulinoma cells

“…This observation was confirmed using isolated perifused rat islets. Both tolbutamide and glibenclamide, however, increased insulin release in rat islets to levels comparable with those reported in other islet studies (Gullo et al 1991, Rabuazzo et al 1992. Our observation that among the sulphonylureas only glibenclamide is able to stimulate NPY release may be related to several possibilities.…”

“…The cause of this 'secondary-failure' has been the subject of several investigations and have been ascribed to ' -cell exhaustion' (Schauder et al 1977, Gullo et al 1991, Rabuazzo et al 1992) and/or ' -cell desensitization' to glucose (Hoenig et al 1986, Bolaffi et al 1988, Purrello et al 1989 or other secretagogues (Grodsky 1989). An in vitro experiment (Gullo et al 1991) has shown that 24 h exposure of islets to 100 nmol/l glibenclamide did not deplete the insulin content, suggesting that mechanisms other than insulin depletion are operative which contribute to the reduced insulin.…”

“…One interpretation of the lower insulin content in this context is that it is secondary to excessive stimulation of -cell function. A study reporting the effect of chronic exposure of sulphonylureas on insulin secretion shows a reversible impairment of insulin release in isolated rat islets after a 24 h pre-exposure to glibenclamide (Gullo et al 1991). Furthermore, desensitization of insulin release in rat islets has been demonstrated to occur secondarily to alterations in ionic fluxes in islets pre-exposed to glibenclamide but not tolbutamide (Rabuazzo et al 1992).…”

β‐cell hyperexcitability: from hyperinsulinism to diabetes

“…In many patients, sulphonylureas effectively control glycaemia for an extended period [63], but over the long term (months to years), sulphonylurea therapies may fail [64]. Studies in normal rats [65][66][67], isolated normal islets [68] and cell lines [69] have shown that long-term glibenclamide treatment may impair glucose tolerance and GSIS. Our studies with chronic glibenclamide dosing of normal mice show an impaired secretory response that can be rapidly reversed following removal of the drug in vitro.…”

Sulfonylurea Receptor 1 Mutations That Cause Opposite Insulin Secretion Defects with Chemical Chaperone Exposure

“…Insulin release during a 2-h static incubation in basal (3 mM) or high (12 mM) glucose was compared for the same experimental groups tested in the above electrophysiology studies. Because prolonged tolbutamide pretreatment to rescue mutant channel surface expression may desensitize cells to subsequent glucose stimulation by affecting their insulin secretory capacity (36,37) and confound data interpretation, we optimized the tolbutamide pretreatment such that no reduction in subsequent glucose stimulated insulin secretion was observed in uninfected control cells. We found that pretreating INS-1 cells with tolbutamide for 4 h rescued mutant surface expression without affecting insulin secretory capacity.…”