Uric Acid-Induced Decrease in Rat Insulin Secretion 1 2

Abstract

Interest in the relationship of uric acid (UA) to insulin stems from reports of a possible association between gout and development of glucose intolerance as well as the structural similarity between uric acid and the diabetogen, alloxan. Previous attempts to examine this relationship using experimental animals possessing a potent uricase have produced inconsistent results. In order to examine the effects of elevated UA concentrations on serum-immunoreactive insulin (IRI), lactic acid, and glucose, we used rats treated with potassium oxonate (KOx), a competitive inhibitor of uricase, to prevent rapid degradation of UA. Male Wistar rats fed 3.5% KOx or 3.5% KOx plus 2% UA in a modified AIN-76 diet for 1 week had serum UA and whole blood lactic acid increased twofold. Hyperuricemic rats drank more water and weighed less than controls. In the 1-week experiments we describe here, animals treated with KOx alone (endogenous UA) did not become hypoinsulinemic compared to controls whereas those fed KOx and UA (endogenous plus exogenous UA) showed a decrease in serum IRI of 44%. In longer-term experiments (4 weeks), it was sufficient to feed 4.5% KOx alone to observe a 26% decrease in insulin. Thus, it appeared that the effect was dose and time dependent. Serum glucose increased (24-38%) in animals fed KOx/UA for 1 week. As a result, insu1in:glucose ratios also decreased in the KOx/UA-fed group suggesting abnormal insulin secretion. Results from in vitro studies using isolated neonatal rat pancreatic islets indicated that UA, unlike KOx, rapidly suppressed insulin secretion by up to 65%. The rapidity of the suppression and subsequent reversal of the effect by removing UA from the medium further suggested that UA interferes with insulin secretion. These data indicate a reexamination is warranted of the possible cytostatic if not cytotoxic effects of U A toward the β-cells of the pancreas.