Glucose and gluconeogenic substrates promote the activation of hepatic glycogen synthase in vivo and in vitro; activation occurs as inactive glycogen synthase D is dephosphorylated to active glycogen synthase I by glycogen synthase phosphatase. Impairments of glycogen accumulation and glycogen synthase activation in diabetes have been attributed to decreased glycogen synthase phosphatase activity. To determine the role of glycogen synthase phosphatases associated with cytosol and smooth endoplasmic reticulum in the impairment of glycogen synthase activation, livers of normal and streptozotocin-diabetic fed rats were sampled by freeze-clamping before and after perfusion with a mixture of 25 mM glucose, 10 mM glutamine, 4 mM lactate, and 1 mM pyruvate. Perfusion induced activation of glycogen synthase in normal rats, but activation was reduced in the diabetic rats in proportion to the severity of insulin deficiency (r = 0.72, P < 0.0001). There was also a close correlation between insulin levels and glycogen synthase phosphatase activities of both cytosol (r = 0.76, P < 0.0001) and SER (r = 0.71, P < 0.0001) fractions. In contrast, glycogen phosphorylase phosphatase activity and inactivation of glycogen phosphorylase during perfusion were normal in the diabetic livers. This is the first demonstration that glycogen synthase phosphatase activities in both soluble and SER fractions of liver cells are closely related to circulating insulin levels, and that the impairment of glycogen synthesis in diabetes may result from deficient glycogen synthase phosphatase activity in both cell compartments.

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