Recent studies indicate that renal gluconeogenesis is substantially stimulated in patients with type 2 diabetes, but the mechanism that is responsible for such stimulation remains unknown. Therefore, this study tested the hypothesis that renal gluconeogenesis is intrinsically elevated in the Zucker diabetic fatty rat, which is considered to be an excellent model of type 2 diabetes. For this, isolated renal proximal tubules from diabetic rats and from their lean nondiabetic littermates were incubated in the presence of physiologic gluconeogenic precursors. Although there was no increase in substrate removal and despite a reduced cellular ATP level, a marked stimulation of gluconeogenesis was observed in diabetic relative to nondiabetic rats, with near-physiologic concentrations of lactate (38%), glutamine (51%) and glycerol (66%). This stimulation was caused by a change in the fate of the substrate carbon skeletons resulting from an increase in the activities and mRNA levels of the key gluconeogenic enzymes that are common to lactate, glutamine, and glycerol metabolism, i.e., mainly of phosphoenolpyruvate carboxykinase and, to a lesser extent, of glucose-6-phosphatase and fructose-1,6-bisphosphatase. Experimental evidence suggests that glucocorticoids and cAMP were two factors that were 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 upregulated 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 by and crucially contribute to the hyperglycemia of type 2 diabetes.
In order to obtain information (1) on the quantitative contribution of various circulating substrates to renal metabolism and (2) on the relative importance of net luminal and basolateral transport for substrate uptake, we have precisely quantified the renal blood flow, the urinary flow, and the rates of substrate handling by the kidney of anesthetized fed and 72-hour-starved rats. For this, the concentration of twelve metabolites were simultaneously measured in arterial and venous whole blood and plasma as well as in urine of each rat thanks to the use of microassays based on enzymatic cycling. In fed rats, the main potential energy sources were glucose and lactate followed by fatty acids, ketone bodies, citrate and glycerol. Starvation caused a large increase in renal uptake and metabolism of fatty acids, ketone bodies, glutamine and glycerol, and a large inhibition of lactate utilization. The net peritubular uptake of acetoacetate, citrate, glycerol and free fatty acids demonstrated in both nutritional states was increased by starvation only for glycerol and free fatty acids; net peritubular efflux of both β-hydroxybutyrate and ammonium ions was stimulated whereas that of glutamine was converted into net peritubular uptake by starvation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.