Coupling of beta-cell desensitization by hyperglycemia to excessive stimulation and circulating insulin in glucose-infused rats.
Nondiabetic rats were infused with glucose for 48 h to maintain moderate or marked hyperglycemia (mean blood glucose 13.2 +/- 0.7 or 22.8 +/- 0.3 mM, respectively). The two levels of hyperglycemia increased plasma insulin levels severalfold but decreased the insulin response to 27 mM glucose by 19 and 95%, respectively, versus saline infusion. Diazoxide (5 mg.kg-1.h-1), when continuously infused during the hyperglycemia protocols, completely inhibited the glucose-induced rise in plasma insulin levels. Diazoxide transformed beta-cell insensitivity to stimulation: glucose-induced insulin release was thus increased 318% after moderate hyperglycemia and 707% after marked hyperglycemia. These stimulatory effects of diazoxide were reversed by exogenous insulin infusion (8 or 2 U/24 h) in a dose-dependent manner. It is concluded that excessive beta-cell stimulation rather than glucotoxicity underlies hyperglycemia-induced beta-cell insensitivity. Effects of hyperinsulinemia can form part of the mechanisms whereby excessive stimulation affects beta-cell secretion.
Sako
Y
Y
Department of Endocrinology, Karolinska Hospital, Stockholm, Sweden.
Grill
V E
VE
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003981:Diazoxide / Q000494:pharmacology; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D006943:Hyperglycemia / Q000473:pathology* / Q000503:physiopathology; D007262:Infusions, Intravenous; D007328:Insulin / Q000032:analysis / Q000097:blood / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D010179:Pancreas / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D012965:Sodium Chloride / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D012965:Sodium Chloride; D014044:Tolbutamide; D005947:Glucose; D003981:Diazoxide