RT Journal Article
SR Electronic
T1 The mechanism of chlorothiazide-induced carbohydrate intolerance.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 423
OP 430
VO 206
IS 2
A1 B Hoskins
A1 C M Jackson, 3rd
YR 1978
UL http://jpet.aspetjournals.org/content/206/2/423.abstract
AB In order to establish the mechanism(s) of chlorothiazide-induced hyperglycemia, measurements of blood glucose, plasma insulin, liver glycogen and hepatic cyclic adenosine 3':5'-monophosphate (cyclic AMP) levels, and liver phosphodiesterase activity were made in rats administered 10, 25, 50 or 100 mg/kg of the drug. Comparison of data obtained on these animals with those from controls revealed significant and dose-dependent increases in blood glucose, decreases in liver glycogen, increases in hepatic cyclic AMP and inhibition of phosphodiesterase. Although basal insulin levels were significantly increased at the two higher doses of chlorothiazide, ratios of blood glucose/plasma insulin levels showed suppression of insulin secretion at all four doses. However, this suppression was not dose-related. All effects of the drug were maximal at 2 hours after subcutaneous administration. The results of this investigation indicate that the primary mechanism of chlorothiazide-induced carbohydrate intolerance is cyclic AMP-mediated stimulation of glycogenolysis and inhibition of glycogenesis. Suppression of insulin secretion is secondary but probably contributes to the hyperglycemia.