Diazoxide causes recovery of beta-cell glucose responsiveness in 90% pancreatectomized diabetic rats.
Chronic hyperglycemia causes near-total disappearance of glucose-induced insulin secretion. The etiology has been suggested to be a nonsustainable stimulation of insulin release that causes beta-cells to become unresponsive to glucose through an undefined mechanism. We used an inhibitor of insulin secretion, diazoxide, to test this hypothesis in 90% pancreatectomized (Px) rats. Px rats were given 5 days of diazoxide (30 mg/kg orally twice a day) or tap water starting on postoperative day 8, 15, or 22. In vitro pancreas perfusions were conducted 36 h posttreatment (2, 3, or 4 weeks after surgery) using a protocol of 15 min of 16.7 mM glucose followed by 15 min of 16.7 mM glucose plus 10 mM arginine. In 2-week Px rats, insulin responses to 16.7 mM glucose and to glucose/arginine were both appropriate for the reduced beta-cell mass, i.e., no defect in beta-cell glucose responsiveness had yet occurred. Diazoxide had no affect on insulin release at this time. Between 2 and 3 weeks after pancreatectomy, insulin output to 16.7 mM glucose fell 75%, and that to glucose/arginine fell 50%. Diazoxide given at this time partially blocked the fall in glucose-induced insulin secretion and totally prevented that with arginine. The increased insulin secretion caused by diazoxide was accompanied by 1) lower nonfasting plasma glucose values, 2) improved glucose tolerance after oral glucose load, and 3) a 50% increase in pancreatic insulin content. Our results support the concept that excessive insulin secretion is a major cause of the hyperglycemia-induced loss of beta-cell glucose responsiveness. A leading candidate for the mechanism of this effect is depleted pancreatic insulin stores. Overstimulation of insulin secretion provides a new target for pharmacological therapy aimed at reducing glucose intolerance in non-insulin-dependent diabetes mellitus.
Leahy
J L
JL
Endocrine Division, New England Medical Center, Boston, MA 02111.
Bumbalo
L M
LM
Chen
C
C
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology*; D003981:Diazoxide / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010180:Pancreatectomy; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D007328:Insulin; D001120:Arginine; D005947:Glucose; D003981:Diazoxide