Intrinsic gluconeogenesis is enhanced in kidney tubules of Zucker Diabetic Fatty rats

Abstract

Renal gluconeogenesis is stimulated in type 2 diabetic patients, but the mechanism of this stimulation remains unknown. Therefore, we have tested the hypothesis that renal gluconeogenesis is elevated in the Zucker Diabetic Fatty rat, an excellent model of type 2 diabetes. Isolated renal proximal tubules from diabetic rats and from their non-diabetic littermates were incubated with physiological gluconeogenic precursors. Despite a reduced cellular ATP level, we observed a marked stimulation of gluconeogenesis in diabetic relative to non-diabetic rats, with near-physiological concentrations of lactate (+ 38%), glutamine (+ 51%) and glycerol (+ 66%). This was caused by a change in the fate of the substrate carbon skeletons resulting from an increase in the activities and mRNAs levels of key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase. Experimental evidence suggests that glucocorticoids and cAMP were two factors responsible for the long-term stimulation of renal gluconeogenesis observed in the diabetic rats. These data provide the first demonstration in an animal model that renal gluconeogenesis is up-regulated by a long-term mechanism during type 2 diabetes. Together with the increased renal mass (+ 38%) observed, they lend support to the view so far based only on in vivo studies performed in humans that renal gluconeogenesis may be stimulated and crucially contribute to the hyperglycemia of type 2 diabetes.