Diazoxide infusion at excess but not at basal hyperglycemia enhances beta-cell sensitivity to glucose in vitro in neonatally streptozotocin-diabetic rats.
The influence of chronic and moderate hyperglycemia vis-à-vis a 48-hour further elevation of blood glucose on beta-cell sensitivity to glucose was compared in an animal model of non-insulin-dependent diabetes. Neonatally streptozotocin-diabetic (n-STZ) rats infused with saline for 48 hours displayed moderate nonfasting hyperglycemia (mean, 11.5 +/- 1.5 mmol/L/48 h) and plasma insulin levels similar to those seen in normoglycemic, nondiabetic rats. In perfused pancreas, the insulin response to 27 mmol/L glucose was severely reduced to 1.60 +/- 0.45 pmol/min, ie, approximately 15% of the response in nondiabetic rats. A continuous infusion of diazoxide (5 mg/kg/h), which normally blocks glucose-induced insulin secretion, did not affect glucose and insulin levels in vivo, nor did it significantly affect the insulin response to glucose in vitro. In other experiments, "basal" hyperglycemia in n-STZ rats was doubled by glucose infusions for 48 hours to reach a mean of 23.8 +/- 0.6 mmol/L. Plasma insulin increased 3.2-fold. The in vitro insulin response to 27 mmol/L glucose was totally abolished, and the pancreatic insulin content was decreased by 81% relative to the content after saline. Addition of a diazoxide infusion inhibited the increase in plasma insulin by 93%. After the combined glucose and diazoxide infusion, the subsequent in vitro response to 27 mmol/L glucose was dramatically enhanced to 9.55 +/- 3.25 pmol/min, ie, the response was sixfold higher than after saline alone. This aftereffect of the diazoxide infusion was not significantly altered by an insulin infusion (2 U/d) added to the hyperglycemia plus diazoxide protocol to compensate for the insulin-lowering effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
Sako
Y
Y
Department of Endocrinology, Karolinska Hospital, Stockholm, Sweden.
Grill
V E
VE
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003981:Diazoxide / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D013311:Streptozocin
D001786:Blood Glucose; D007328:Insulin; D013311:Streptozocin; D005947:Glucose; D003981:Diazoxide