Evidence for defective glucose sensing by islets of fa/fa obese Zucker rats.
The hypothesis that a defect in glucose sensing by islets of fa/fa Zucker rats contributes to hyperinsulinemia in these animals was tested. Islets from lean and fa/fa rats were isolated by collagenase digestion and step-density gradient purification and then cultured overnight in Dulbecco's modified Eagle's medium containing 12.5 mM glucose. Obese rat islets were more sensitive to hypoglycemic glucose levels with half-maximal effective concentration (EC50) of 5.6 mM compared with an EC50 of 8.2 mM for lean rat islets. In contrast, responsiveness of both phenotypes to alpha-ketoisocaproate and quinine was similar. Mannoheptulose did not inhibit insulin secretion from fa/fa islets, although inhibitors of later events in the stimulus-secretion coupling pathway were normally inhibited by iodoacetate and diazoxide. Finally, starvation in vivo and culture of islets in low glucose concentrations (5 mM) in vitro both decreased glucose-stimulated insulin secretion from lean but not fa/fa rat islets. We conclude that fa/fa rat islets have an exaggerated insulin response to hypoglycemic stimuli, possibly as a result of a defect in B-cell glucokinase function.
Department of Anatomy and Physiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, P.E.I., Canada.
C B
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Chan
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MacPhail
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Mitton
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D005260:Female; D005941:Glucokinase / Q000037:antagonists & inhibitors; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007461:Iodoacetates / Q000494:pharmacology; D019807:Iodoacetic Acid; D007515:Islets of Langerhans / Q000378:metabolism*; D008356:Mannoheptulose / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism*; D009924:Organ Culture Techniques; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D013217:Starvation / Q000378:metabolism
D000596:Amino Acids; D001786:Blood Glucose; D007328:Insulin; D007461:Iodoacetates; D008356:Mannoheptulose; D000255:Adenosine Triphosphate; D011803:Quinine; D005941:Glucokinase; D005947:Glucose; D003981:Diazoxide; D019807:Iodoacetic Acid