Abstract
Rates of cycling between glucose and glucose 6-phosphate and between glucose and pyruvate, and the effects of these cycles on glucose metabolism, were compared in hepatocytes isolated from fasted normal or streptozotocin-induced diabetic rats. In diabetic hepatocytes the rate of glucose phosphorylation was 30% lower than that in normal hepatocytes, and there was a doubling of the rate of glucose/glucose 6-phosphate cycling. In addition, the rate of glycolysis was 60% lower in diabetic hepatocytes. This inhibition of glycolysis and stimulation of glucose/glucose 6-phosphate cycling appeared to be a consequence of the elevated rates of endogenous fatty acid oxidation observed in diabetic hepatocytes. The proportion of glycolytically derived pyruvate that was recycled to glucose was more than doubled in hepatocytes from diabetic rats compared with normal animals. This increase also appeared to be linked to the high rates of endogenous fatty acid oxidation in diabetic cells. As a consequence of the increased rates of both these cycles, 85% of all glucose molecules taken up by diabetic hepatocytes were recycled to glucose, compared with only 50% in normal hepatocytes. Glucose cycling is therefore likely to make a substantial contribution to the hyperglycemia of diabetes.
Highlights
Insulin-dependent diabetes is characterized by elevated blood glucose levels, the result of perturbations of glucose uptake and metabolism in both the liver and extrahepatic tissues
glucose/glucose 6-phosphate (G/glucose 6-phosphate (G6P)) Cycling in Diabetes—An increase in the rate of cycling between glucose and G6P in the liver may contribute to the development of hyperglycemia in diabetes (3–7)
We have shown that G/G6P cycling is stimulated in hepatocytes from streptozotocin-treated rats
Summary
Insulin-dependent diabetes is characterized by elevated blood glucose levels, the result of perturbations of glucose uptake and metabolism in both the liver and extrahepatic tissues. In addition to an increase in gluconeogenic activity in liver, a suppression of hepatic glycolysis contributes to the elevation of blood glucose levels (1, 2). We have demonstrated a glucose/pyruvate (G/P) cycle in hepatocytes from normal rats, brought about through the concomitant operation of glycolysis and gluconeogenesis (8). Because the activity of this cycle increased with glucose concentration (8), it seemed possible that a G/P cycle might contribute to hepatic glucose output in diabetes. Amined this possibility in this study and have determined the contribution of the G/G6P cycle to hepatic glucose output in diabetes. Fatty acid oxidation stimulates both G/G6P and G/P cycling in hepatocytes from normal rats (9). As livers from diabetic rats exhibit elevated rates of endogenous fatty acid oxidation (10), we investigated whether an increase in glucose cycling may be associated with the high rates of fatty acid oxidation in hepatocytes from diabetic rats
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