DIABETES-INDUCED REDUCTION IN THE HEPATIC ACCUMULATION OF 70-KDA DEXTRAN - ROLE OF HYPERGLYCEMIA AND HYPOINSULINEMIA

In vivo studies were conducted in rats to determine the role of hyperg lycemia and hypoinsulinemia in the previously reported reduction in th e hepatic accumulation and increase in the serum concentrations of 70- kDa fluorescein-dextran (FD-70) in diabetic (D) rats. The serum, urine ; and hepatic concentrations of FD-70 were measured by size exclusion chromatography after iv administration of single doses (5 mg/kg) of FD -70. Intravenous administration of a single 2 IU/kg dose of insulin to D rats at time zero or 4 h after the administration of FD-70 resulted in an increase in some and no change in other animals in their rate o f elimination of fD-70 from serum. The presence or absence of a signif icant insulin effect on the disposition of FD-70 in these animals was, respectively, associated with the presence or absence of a significan t insulin-induced hypoglycemic effect. Fasting D rats for 24 h caused normoglycemia, and subsequently, the disposition of FD-70 became simil ar to that in nondiabetic (ND) rats. Likewise, ip injections of glucos e to ND rats rendered them hyperglycemic, and the disposition of FD-70 in these rats became similar to that in untreated D animals. However, iv injection of glucose, which did not result in sustained hyperglyce mia, did not change the disposition of FD-70 in ND rats. Further, the disposition of FD-70 remained unaffected by an iv 2 IU/kg dose of insu lin administered to ND rats at time zero. Considering all animals, the re was a significant negative relationship between the 12-h hepatic re covery of FD-70 and the area under the serum concentration-time curves of glucose. It is concluded that the reduction in the hepatic accumul ation of FD-70 in D rats is due to hyperglycemia and not hypoinsulinem ia.