INCREASED HEPATIC GLUCOSE-PRODUCTION AND DECREASED HEPATIC GLUCOSE-UPTAKE AT THE PREDIABETIC PHASE IN THE OTSUKA-LONG-EVANS-TOKUSHIMA FATTYRAT MODEL

To investigate the time course of the hepatic glucose metabolism in no n-insulin-dependent diabetes (NIDDM), we measured hepatic glucose prod uction (HGP) and first-pass uptake of portal glucose infusion by the l iver (HGU) using dual-tracer methods in a NIDDM model, Otsuka Long-Eva ns Tokushima Fatty (OLETF) rats, and in normal controls, Long-Evans To kushima Otsuka (LETO) rats, at 8, 14, and 28 weeks of age (n = 5, resp ectively). The fasting plasma glucose level in OLETF rats was signific antly higher than in LETO rats at 28 weeks of age (8.9 +/- 1.7 v 6.3 /- 0.4 mmol/L, P < .01), while there was no significant difference at 8 and 14 weeks. Hyperinsulinemia in OLETF rats appeared at greater tha n or equal to 8 weeks of age. Basal HGP was significantly higher In OL ETF than in LETO rats at 8 and 28 weeks (8 weeks, 12.7 +/- 1.7 v 9.4 /- 1.8 mg.kg(-1).min(-1), P < .05; 28 weeks, 10.9 +/- 1.6 v 7.1 +/- 1. 3 mg.kg(-1).min(-1), P < .01). At 14 weeks, basal Hop was not signific antly different between OLETF and LETO rats. However, at all study poi nts, HGU during a portal glucose infusion was significantly lower in O LETF than in LETO rats (8 weeks, 0.9 +/- 0.2 v 2.3 +/- 0.5, P < .01; 1 4 weeks, 0.8 +/- 0.3 v 1.4 +/- 0.3, P < .05; 28 weeks, 0.7 +/- 0.2 v 1 .4 i 0.3 mg.kg(-1).min(-1), P < .01). Fasting plasma free fatty acid ( FFA) levels were not significantly different between OLETF and LETO, e xcept at 8 weeks. Suppression of plasma FFA levels by endogenous insul in during a portal glucose infusion was impaired in OLETF rats compare d with LETO rats. In summary, this study demonstrates that derangement of hepatic glucose handling, such as increased basal Hop and decrease d HGU, is observed in obese NIDDM model OLETF rats at the prediabetic phase when hyperglycemia is still not apparent. Furthermore, these der angements may be accompanied by impaired lipid metabolism. Copyright ( C) 1998 by W.B. Saunders Company.