Influence of long-term diabetes on liver glycogen metabolism in the rat

Abstract

Diabetes acutely impairs the ability of the liver to synthesize glycogen. However, the effect of chronic diabetes on the glycogenic function of the liver is not known. We measured hepatic glycogen contents in streptozotocin (STZ)-diabetic rats 3 weeks or 9 months after the induction of diabetes, in the fed state and following a 24-hour fast. In the fed state, liver glycogen levels were markedly decreased in short-term diabetic animals (5.8 ± 2.0 v 33.9 ± 2.3 mg/g, P < .001), but not in long-term diabetic rats (18.3 ± 4.4 v 20.7 ± 1.3 mg/g, P=NS) as compared with age-matched nondiabetic animals, despite comparable hyperglycemia (portal plasma glucose levels of 424 ± 21 and 449 ± 24 mg 100 mL , short- and long-term diabetics, respectively). In the fasted state, on the other hand, liver glycogen was depleted in acute diabetes (4.5 ± 2.2 mg/g v 1.9 ± 0.5 of control rats), but significantly increased in chronic diabetes (10.1 ± 3.1 v 0.2 ± 0.03 mg/g, P < .001). The latter finding was confirmed by electron-microscopical examination of liver cells. Furthermore, the percentage of hepatic glycogen synthase in the active form (synthase a) was lower than normal in short-term diabetic rats and in old nondiabetic rats. In long-term diabetic animals, on the other hand, synthase a was significantly higher than in old controls ( P < .01). To further characterize the response of hepatic glycogenesis to chronic diabetes, insulin and glucagon concentrations were measured in portal vein plasma at sacrifice, and uridine diphosphoglucose (UDPG), glucose-6-phosphate (G-6-P), cyclic adenosinemonophosphate (cAMP), fructose-2,6-bisphosphate (F-2,6-P 2), lactate, and pyruvate were assayed in liver extracts from all experimental groups. In the analysis of these data, account was taken of the independent effects of ageing per se on the metabolic parameters. Long-term diabetes was thus found to be specifically associated with a decreased insulin/glucagon molar ratio, a reduction in F-2,6-P 2, and an increase in lactate concentrations, both in the fasted and fed state. These metabolic changes suggest that enhanced gluconeogenesis may participate in the repletion of liver glycogen stores in long-term diabetes.