Role of glucose in chronic desensitization of isolated rat islets and mouse insulinoma (betaTC-3) cells to glucose-dependent insulinotropic polypeptide.
It is well documented that the release of insulin from isolated perifused islets attenuates over time, despite a continued glucose stimulation. In the current study we have shown that potentiation of insulin release by the intestinal hormone glucose-dependent insulinotropic polypeptide (GIP) is also attenuated after its continuous application. In less than 20 h of maintained stimulus with either hyperglycaemia (11.0 mM glucose) or GIP (10 nM) under 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 chronic GIP desensitization was examined in cultured mouse insulinoma (betaTC-3) cells. GIP-stimulated cAMP production was not greatly affected by the prevailing glucose conditions, suggesting that the glucose dependence of GIP-stimulated insulin release occurs distally to the increase in intracellular cAMP in betaTC-3 cells. The GIP-stimulated cAMP response curve after desensitization was of similar magnitude at all glucose concentrations, but GIP pretreatment did not affect forskolin-stimulated cAMP production. Desensitization of the cAMP response in betaTC-3 cells was shown not to involve induction of dipeptidyl peptidase IV or pertussis toxin-sensitive G-proteins, activation of protein kinase C or protein kinase A, or modulation of phosphodiesterase activity. Homologous desensitization of the insulin-potentiating activity of GIP was found to affect both GIP-stimulated and forskolin-stimulated insulin release, indicating desensitization of distal steps in the stimulus-exocytosis cascade.
Hinke
S A
SA
Department of Physiology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Pauly
R P
RP
Ehses
J
J
Kerridge
P
P
Demuth
H U
HU
McIntosh
C H
CH
Pederson
R A
RA
D000704:Analysis of Variance; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000096:biosynthesis*; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D007328:Insulin; D005576:Colforsin; D005749:Gastric Inhibitory Polypeptide; D000242:Cyclic AMP; D005947:Glucose