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Regulation of hepatic glucose output some current concepts

, : Regulation of hepatic glucose output some current concepts. Journal of the Japan Diabetes Society 24(11): 1051-1063

The minute to minute hepatic output of glucose in health and disease is regulated largely by the balance between the effects of glucagon and insulin, although actions of the catecholamines make an additional important contribution. Virtually every condition involving physiological or pathological hyperglycemia, including juvenile and maturity onset diabetes, is associated with a high glucagon to insulin activity ratio. Glucagon activates glycogen breakdown to glucose, inhibits resynthesis of glycogen and promotes gluconeogenesis from lactate, amino acids and glycerol. These actions begin with binding of the hormone to the receptor on the plasma membrane of the liver cell. This interaction activates adenylate cyclase in a complex process involving physical rearrangements of at least 3 membrane proteins and is facilitated by guanine nucleotides. Activation raises the intracellular level of cAMP. This nucleotide binds to the inhibitory subunit of the protein kinase holoenzyme and releases an active catalytic subunit. The latter phosphorylates and raises the activity of enzymes which increase the rate of glycogenolysis and inhibit glycogen synthesis. Epinephrine also activates glucose production, but this hormone action may be mediated by the alpha 1 receptor system which brings about release of mitochondrial Ca as an intracellular signal transducer rather than cAMP. In the dog phosphorylase kinase and a newly discovered Ca plus calmodulin dependent protein kinase are activated by the rise in intracellular Ca and bring about increased phosphorylase and decreased glycogen synthase activities, respectively. Insulin opposes the effects of glucagon and epinephrine by at least 2 actions. First, it lowers cAMP levels by activating the low Km phosphodiesterase which destroys cAMP, and second, it inhibits the catecholamine effect on intracellular Ca. Prolonged elevation of the glucagon/insulin activity ratio, as in untreated diabetes, leads to progressive activation of gluconeogenesis which eventually becomes the main source of blood glucose. Chronic stimulation induces increased synthesis and activation of key enzymes of the gluconeogenic pathway. Activation of this pathway depends largely on interruption of 2 back reactions which reduce substrate flow to glucose. First, pyruvate kinase is inhibited by cAMP mediated phosphorylation and also by the fall in the level of an allosteric activator of the enzyme, F1, 6P2 [fructose 1,6-biphosphate]. Second, the level of the latter compound is regulated by a newly discovered sugar phosphate, F2, 6P2 [fructose-2,6-biphosphate], the level of which is raised by glucose and is reduced by glucagon and presumably by diabetes. F2, 6P2 strongly activates phosphofructokinase and inhibits fructosebisphosphatase. These actions raise the level of F1, 6P2 and have the overall effect of promoting glycolysis and inhibiting gluconeogenesis.

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