IMPAIRED GLUCOSE-TOLERANCE AND INCREASED WEIGHT-GAIN IN TRANSGENIC RATS OVEREXPRESSING A NON-INSULIN-RESPONSIVE PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE

The effects of an overexpressed, non-insulin-responsive gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (GTP) (PEPCK; EC 4.1.1.32), on glucose homeostasis were investigated. Transgenic rats harboring a metallothionein-driven PEPCK gene (lacking the entire PEPCK upstream- regulatory region) expressed transgene PEPCK mRNA in the key gluconeog enic tissues, liver and kidney. Female transgenic rats, studied at 10 weeks of age, showed mild fasting hyperglycemia (6.9 +/- 0.2 vs. 5.9 /- 0.1 mM P = 0.002 n = 6), hyperinsulinemia (92.2 +/- 4.0 vs. 54.0 +/ - 6.6 pM, P = 0.001, n = 6), impaired glucose tolerance and increased weight gain (178.3 +/- 3.2 vs. 153.4 +/- 2.5 g, P = 0.001, n = 16 and n = 13 transgenic and control rats, respectively). Despite hyperinsuli nemia at this age, kidneys of transgenic rats maintained a significant 20% elevation of total PEPCK enzyme activity, while total liver PEPCK activity was not reduced. This study suggests that an insulin-resista nt step in the gluconeogenic pathway can lead to glucose intolerance a nd an increase in weight. These rats offer the unique opportunity to s tudy the metabolic consequences of chronic, mild excess glucose supply , as seen in non-insulin-dependent diabetes.