IMPAIRED REGULATION OF HEPATIC FRUCTOSE-1,6-BISPHOSPHATASE IN THE NEW-ZEALAND OBESE MOUSE MODEL OF NIDDM

The New Zealand obese mouse, a model of NIDDM, is characterized by hyp erglycemia, hyperinsulinemia, and hepatic and peripheral insulin resis tance. The aim of this study was to investigate the biochemical basis of hepatic insulin resistance in NZO mice. Glycolytic and gluconeogeni c enzyme activities were measured in fed and overnight fasted 19- to 2 0-wk-old NZO and control New Zealand chocolate mice. The NZO mice were twice as heavy as the NZC mice. The activity of the glycolytic enzyme s glucokinase and pyruvate kinase was higher, whereas that of the gluc oneogenic enzymes PEPCK and glucose-6-phosphatase was lower in fed and fasted NZO mice. These enzyme changes are consistent with a normal re sponse to the hyperinsulinemia in NZO mice. In contrast, the activity of the third regulated gluconeogenic enzyme, fructose-1,6-bisphosphate . The levels of this metabolite were measured and found to be increase d in both the fed and fasted states in the NZO mouse, suggesting that the activity of the bifunctional enzyme that regulates the level of in hibitor (6- hosphofructo-2-kinase/fructose-2,6-bisphosphatase) is norm ally regulated in the NZO mouse. We conclude that most insulin-respons ive gluconeogenic and glycolytic enzymes are normally regulated in the NZO mouse, but an abnormality in the regulation of fructose-1,6-bisph osphatase may contribute to the increased hepatic glucose production i n these mice.