EurekaMag.com logo
+ Translate

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.

(PDF 0-2 workdays service)

Accession: 006288396

Submit PDF Full Text: Here


Submit PDF Full Text

No spam - Every submission is manually reviewed

Due to poor quality, we do not accept files from Researchgate

Submitted PDF Full Texts will always be free for everyone
(We only charge for PDFs that we need to acquire)

Select a PDF file:
Close
Close

Related references

Jenkins, A.B.; Furler, S.M.; Chisholm, D.J.; Kraegen, E.W., 1986: Regulation of hepatic glucose output during exercise by circulating glucose and insulin in humans. We have tested the hypothesis that hepatic glucose output (Ra) during exercise in humans is subject to feedback control by circulating glucose within a control range that is determined by the circulating insulin concentration. Three exercise proto...

Steele, Robert, 1959: Influences of glucose loading and of injected insulin on hepatic glucose output Current trends in research and clinical management of diabetes. Ann New York Acad Sci 82(2): 420-430

Mueller M.J.; Moering J.; Seitz H.J., 1988: Regulation of hepatic glucose output by glucose in vivo. The effect of infusing glucose at a rate estimated to equal hepatic glucose production (2 mg/kg BW .times. min) was investigated in postabsorptive unrestrained miniature pigs. Glucose turnover was estimated by the use of 3-H-glucose before and dur...

Wittmann, I.; Mazák, I.; Wagner, L.; Nagy, J., 1997: Possible role of free radicals generated by pseudohypoxia in the regulation of hepatic glucose output. An in vitro model using rat liver microsomal glucose 6-phosphatase. Hepatic glucose output is decreased by hyperglycaemia through an unknown mechanism. We hypothesize that free radicals generated by hyperglycaemic pseudohypoxia might cause glucose output to decrease by inhibiting glucose 6-phosphatase - a key enzy...

Hoshi, T.; Anzai, J.; Osa, T., 1995: Controlled deposition of glucose oxidase on platinum electrode based on an avidin/biotin system for the regulation of output current of glucose sensors. A facile method for the regulation of enzyme loading on an electrode surface has been studied using avidin and biotinylated glucose oxidase (GOx). It was demonstrated that an alternate and repeated deposition of avidin and biotinylated GOx gives a...

Mine, T.; Kimura, S.; Koide, Y.; Ohsawa, H.; Ogata, E., 1985: Influence of extracellular phosphate concentrations on the regulation of hepatic glucose output. Experiments were carried out to investigate the role of extracellular phosphate in the hormonal regulation of glycogenolysis in perfused fed-rat liver. Omission of phosphate from the perfusate did not affect the ATP, ADP and AMP contents of the ti...

Lu, S.C., 1999: Regulation of hepatic glutathione synthesis: current concepts and controversies. Glutathione (GSH) is an important intracellular peptide with multiple functions ranging from antioxidant defense to modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major...

Jenkins, A.B.; Furler, S.M.; Bruce, D.G.; Chisholm, D.J., 1988: Regulation of hepatic glucose output during moderate exercise in non-insulin-dependent diabetes. In normal subjects during moderate exercise there is a strong negative correlation between plasma glucose and hepatic glucose output (HGO) suggesting a negative feedback regulation of HGO by plasma glucose. Little information is available about HG...

Ozanne, S.E.; Smith, G.D.; Tikerpae, J.; Hales, C.N., 1996: Altered regulation of hepatic glucose output in the male offspring of protein-malnourished rat dams. Offspring of protein-malnourished rat dams have permanent alterations in hepatic enzyme activities associated with glucose homeostasis. Hormonal control of hepatic glucose output (HGO) was studied in male offspring of dams fed either a 20% (contro...

Rebrin, K.; Steil, G.M.; Getty, L.; Bergman, R.N., 1995: Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin. Overproduction of glucose by the liver in the face of insulin resistance is a primary cause of hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM). However, mechanisms involved in control of hepatic glucose output (HGO) remain less th...