Role of glucose in chronic desensitization of isolated rat islets and mouse insulinoma (beta TC-3) cells to glucose-dependent insulinotropic polypeptide

It is well documented that the release of insulin from isolated perifused i slets attenuates over time, despite a continued glucose stimulation. In the current study we have shown that potentiation of insulin release by the in testinal hormone glucose-dependent insulinotropic polypeptide (GIP) is also attenuated after its continuous application In less than 20 h of maintaine d stimulus with either hyperglycaemia (11.0 mM glucose) or GIP (10 nM) unde r hyperglycaemic conditions, insulin release returned to basal values. This was not due to loss of islet viability or reduction in the releasable pool of insulin granules, as 1 mM isobutylmethylxanthine was able to stimulate equivalent insulin release under both conditions. Further examination of ch ronic GIP desensitization was examined in cultured mouse insulinoma (beta T C-3) cells. GIP-stimulated cAMP production was not greatly affected by the prevailing glucose conditions, suggesting that the glucose dependence of GI P-stimulated insulin release occurs distally to the increase in intracellul ar cAMP in beta TC-3 cells. The GIP-stimulated cAMP response curve after de sensitization was of similar magnitude at all glucose concentrations, but G IP pretreatment did not affect forskolin-stimulated cAMP production. Desens itization of the cAMP response in beta TC-S cells was shown not to involve induction of dipeptidyl pepidase IV or pertussis toxin-sensitive G-proteins , activation of protein kinase C or protein kinase A, or modulation of phos phodiesterase activity. Homologous desensitization of the insulin-potentiat ing activity of GIP was found to affect both GIP-stimulated and forskolin-s timulated insulin release, indicating desensitization of distal steps in th e stimulus-exocytosis cascade.