Insulin secretion, myo-inositol transport, and Na(+)-K(+)-ATPase in glucose-desensitized rat islets.
Glucose-induced insulin secretion is desensitized during long-term exposure of pancreatic islet beta-cells to elevated glucose levels. This study characterizes an in vitro model of glucose-induced desensitization in cultured isolated islets of the rat. Insulin secretion in desensitized islets cultured with 11 mM glucose for 4-7 days was progressively reduced compared with the normal freshly isolated (fresh) islets. When desensitized islets were returned to a basal concentration of glucose (5.5 mM) for up to 2 h, the glucose sensitivity of insulin secretion was restored to normal (recovered islets). Carbachol and L-arginine also reversed the effects of desensitization. However, basal insulin release was elevated in desensitized and recovered islets. Sodium-dependent myo-inositol uptake was reduced during desensitization by up to 49% within 4 days. myo-Inositol uptake was restored to normal in a time-dependent manner during recovery of islets at 5.5 mM glucose. The recovery of myo-inositol uptake paralleled that of insulin release. The apparent transport constant for myo-inositol uptake was significantly increased during desensitization, whereas the maximum uptake was not changed. myo-Inositol supplementation (35 or 250 microM) during islet culture did not alter myo-inositol uptake or insulin secretion in desensitized islets. Na(+)-K(+)-ATPase activity, but not 5'-nucleotidase activity, in desensitized islets was also inhibited by 65 and 47% when compared with fresh islet and recovered islet Na(+)-K(+)-ATPase activity, respectively. Thus, cultured islets represent an appropriate model to study biochemical parameters associated with the onset and reversibility of glucose desensitization of insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Therapeutics, State University of New York at Buffalo, School of Medicine.
M
M
Xia
S G
SG
Laychock
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001692:Biological Transport; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism; D007294:Inositol / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors; D014316:Tritium
D007328:Insulin; D014316:Tritium; D007294:Inositol; D002217:Carbachol; D001120:Arginine; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose