Desensitization of the pancreatic beta-cell: effects of sustained physiological hyperglycemia and potassium.
The impact of modest but prolonged (3 h) exposure to high physiological glucose concentrations and hyperkalemia on the insulin secretory and phospholipase C (PLC) responses of rat pancreatic islets was determined. In acute studies, glucose (5-20 mM) caused a dose-dependent increase in secretion with maximal release rates 25-fold above basal secretion. When measured after 3 h of exposure to 5-10 mM glucose, subsequent stimulation of islets with 10-20 mM glucose during a dynamic perifusion resulted in dose-dependent decrements in secretion and PLC activation. Acute hyperkalemia (15-30 mM) stimulated calcium-dependent increases in both insulin secretion and PLC activation; however, prolonged hyperkalemia resulted in a biochemical and secretory lesion similar to that induced by sustained modest hyperglycemia. Glucose- (8 mM) desensitized islets retained significant sensitivity to stimulation by either carbachol or glucagon-like peptide-1. These findings emphasize the vulnerability of the beta-cell to even moderate sustained hyperglycemia and provide a biochemical rationale for achieving tight glucose control in diabetic patients. They also suggest that PLC activation plays a critically important role in the physiological regulation of glucose-induced secretion and in the desensitization of release that follows chronic hyperglycemia or hyperkalemia.
Yamazaki
Hanae
H
Yale University School of Nursing, New Haven, CT 06536-0740, USA.
Zawalich
Kathleen C
KC
Zawalich
Walter S
WS
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000503:physiopathology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017275:Isradipine / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000378:metabolism
D002121:Calcium Channel Blockers; D007202:Indicators and Reagents; D007295:Inositol Phosphates; D007328:Insulin; D018721:Muscarinic Agonists; D011189:Potassium Chloride; D052216:Glucagon-Like Peptide 1; D002217:Carbachol; D010738:Type C Phospholipases; D005947:Glucose; D017275:Isradipine