Glyburide and tolbutamide induce desensitization of insulin release in rat pancreatic islets by different mechanisms.

Abstract

Insulin secretion was studied in rat pancreatic islets after 24-h exposure to various glyburide or tolbutamide concentrations. Glucose-induced insulin release was significantly (P < 0.05) reduced in islets cultured with 0.1 microM glyburide or 100 microM tolbutamide (2098 +/- 187, 832 +/- 93, and 989 +/- 88 pg/islet.h in control, glyburide-exposed, and tolbutamide-exposed islets, respectively). When glyburide-treated islets were stimulated with glyburide or tolbutamide, insulin release was also impaired compared to that in control islets (P < 0.05). In contrast, tolbutamide-exposed islets showed an impaired response to tolbutamide, but a normal response to glyburide. To investigate the mechanism of the sulfonylurea-induced impairment of insulin secretion, we measured insulin release and Rb+ efflux (a marker of the K+ channel activity) in a perifusion system and islet Ca2+ uptake under static conditions. Insulin release in response to 16.7 mM glucose increased in control islets from 9.4 +/- 1.1 to 131 +/- 19 pg/islet.min (first phase secretion peak). Simultaneously, the fractional 86Rb+ efflux declined from 0.015 +/- 0.002% to 0.006 +/- 0.001% (change in decrement, -63.5%). Glucose-induced insulin release in glyburide- and tolbutamide-treated islets was significantly reduced (first phase peak, 22.1 +/- 5 and 39.7 +/- 8 pg/islet.min, respectively; P < 0.05), and the fractional 86Rb+ efflux decrement was -21 +/- 6% for glyburide (P < 0.005 vs. control islets) and -65 +/- 4% (not different from control) for tolbutamide. When glyburide- or tolbutamide-exposed islets were stimulated with the corresponding sulfonylurea, insulin release was impaired compared to that in control islets (P < 0.05), but, again, 86Rb+ efflux was impaired (P < 0.05) only in glyburide-exposed islets. When 45Ca2+ uptake was studied, the increase in glucose concentration from 2.8 to 16.7 mM increased calcium uptake in control islets from 1.76 +/- 0.58 to 7.27 +/- 1.36 pmol/islet.2 min (n = 4). Preexposure to 0.1 microM glyburide did not change calcium uptake at a glucose concentration of 2.8 mM (1.44 +/- 0.45 pmol/islet.2 min) but significantly reduced calcium uptake stimulated by 16.7 mM glucose (3.21 +/- 0.35 pmol/islet.2 min; n = 4; P < 0.005 compared to control islets). In contrast, preexposure to 100 microM tolbutamide did not change either basal or glucose-stimulated calcium uptake (1.44 +/- 0.45 and 6.90 +/- 0.81 pmol/islet.2 min, respectively; n = 4). These data show that in vitro chronic exposure of pancreatic islets to the sulfonylureas glyburide and tolbutamide impairs their ability to respond to a subsequent glucose or sulfonylurea stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity

“…It was demonstrated that 1 μmol/L GB acutely promoted basal insulin secretion by approximately 250% in isolated islets, while markedly reduced GSIS in the presence of 16.7 mmol/L glucose. This observation is in good agreement with previous reports [2,23] . The suppressed GSIS might partly result from the reduction of K ATP channel activity induced by chronic exposure to GB and/or the depletion of insulin stores, reflecting the controversy of β-cell desensitization vs β-cell exhaustion [3,24] .…”

“…Moreover, chronic SUs therapy may lead to a selective desensitization of pancreatic β cells to SUs [1,2] . In the present study, the insulinotropic effect of berberine on rat islets was compared with GB, a classical SU derivative.…”

“…The SU receptor-1 on the ATP-sensitive potassium channels (K ATP channels) is occupied by SU leading to closure of the potassium channels and subsequent opening of calcium channels, resulting in exocytosis of insulin granules [1] . Yet, the maintenance of satisfactory long-term glycaemic control in patients undergoing SU therapy is usually restricted by increased risk of hypoglycemia coupled with declined insulinotropic activity due to desensitized β cells to the agents [2,3] . Therefore, new types of insulinotropic substances with an alternative action profile are in demand.…”

Actions of glucagon-like peptide-1 on KATP channel-dependent and -independent effects of glucose, sulphonylureas and nateglinide

“…In vitro data confirm that over time, prolonged exposure of insulinsecreting cells to sulphonylureas dramatically decreases their ability to stimulate insulin secretion (Rabuazzo et al 1992, Ball et al 2000a,b, 2004a. These findings highlight the need for a new generation of insulin-releasing drugs.…”

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

“…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). The mechanism underlying the -cell hyporesponsivity is not clear.…”