Hepatic Enzyme Activities of Glycolysis and Gluconeogenesis in Diabetes of Man and Laboratory Animals

Willms, B.; Ben-Ami, P.; Söling, H.D.

doi:10.1055/s-0028-1095102

Cited by 55 publications

(26 citation statements)

References 6 publications

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“…Enzyme activity increased fourfold over the next 2 d on a high-carbohydrate diet (33). Two reports have indicated that glucokinase activity was reduced by about 50% in newly diagnosed insulin-dependent diabetics (37,38). The present study shows that human hepatocytes in primary culture respond to the addition of insulin by induction of glucokinase mRNA.…”

Section: Discussionsupporting

confidence: 67%

Glucokinase and cytosolic phosphoenolpyruvate carboxykinase (GTP) in the human liver. Regulation of gene expression in cultured hepatocytes.

Iynedjian¹,

Marie²,

Gjinovci³

et al. 1995

J. Clin. Invest.

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Glucokinase and phosphoenolpyruvate carboxykinase are key enzymes of glucose metabolism in the rat liver. The former is considered to be instrumental in regulating glucose hepatic release/uptake according to the glycaemia level, and cytosolic phosphoenolpyruvate carboxykinase is a major flux-generating enzyme for gluconeogenesis. The level of expression of both enzymes and the regulation of their mRNAs in the human liver cell were investigated. Surgical biopsies of liver from patients undergoing partial hepatectomies and parenchymal hepatocytes derived from the biopsies were used to assay glucokinase, hexokinase and phosphoenolpyruvate carboxykinase activities. Hepatocytes were placed in culture and the actions of insulin, glucagon and cAMP on glucokinase and phosphoenolpyruvate carboxykinase mRNAs were studied. The main results are: (a) glucokinase accounts for 95% of the glucose phosphorylation activity of human hepatocytes, although this fact is masked in assays of total liver tissue; (b) glucokinase activity is set at a lower level in human hepatocytes than in rat hepatocytes, and vice-versa for the gluconeogenic enzyme phosphoenolpyruvate carboxykinase; and (c) as previously shown in rat liver, glucokinase and phosphoenolpyruvate carboxykinase mRNAs are regulated in a reciprocal fashion in human hepatocytes, insulin inducing the first enzyme and repressing the latter, whereas glucagon has opposite effects. These data have interesting implications with respect to metabolic regulation and intracellular hormone signaling in the human liver. (J. Clin. Invest. 1995Invest. . 95:1966Invest. -1973

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Section: Discussionsupporting

confidence: 67%

Glucokinase and cytosolic phosphoenolpyruvate carboxykinase (GTP) in the human liver. Regulation of gene expression in cultured hepatocytes.

Iynedjian¹,

Marie²,

Gjinovci³

et al. 1995

J. Clin. Invest.

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“…The relationship between human GK and insulin was first evident from the study of hepatic activity in diabetic patients, in which GK can be depressed 50 % when compared with a healthy volunteer (63) . Further data confirm this, as the hyperinsulinaemia observed at certain stages of the diabetic condition is also able to actually increase GK activity in human subjects (108) . The confirmation of an insulin-sensitive GK in the human liver came from the studies by Iynedjian et al (109) using hepatocytes isolated from fasted human subjects, where GK activity and expression are strongly up-regulated, with a peak of induction 8 h after stimulation by insulin.…”

Section: Rattus Norvegicussupporting

confidence: 59%

Nutritional regulation of glucokinase: a cross-species story

Panserat

Rideau²,

Polakof

2014

Nutr. Res. Rev.

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The glucokinase (GK) enzyme (EC 2.7.1.1.) is essential for the use of dietary glucose because it is the first enzyme to phosphorylate glucose in excess in different key tissues such as the pancreas and liver. The objective of the present review is not to fully describe the biochemical characteristics and the genetics of this enzyme but to detail its nutritional regulation in different vertebrates from fish to human. Indeed, the present review will describe the existence of the GK enzyme in different animal species that have naturally different levels of carbohydrate in their diets. Thus, some studies have been performed to analyse the nutritional regulation of the GK enzyme in humans and rodents (having high levels of dietary carbohydrates in their diets), in the chicken (moderate level of carbohydrates in its diet) and rainbow trout (no carbohydrate intake in its diet). All these data illustrate the nutritional importance of the GK enzyme irrespective of feeding habits, even in animals known to poorly use dietary carbohydrates (carnivorous species).

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“…The assessment of the hepatic GK status in T2DM in man is based on two publications. The available data indicate that hepatic GK in individuals with IFG, IGT, or mild diabetes mellitus is normal or actually increased (Wilms et al 1970) whereas it is drastically reduced in liver tissue of morbidly obese with diabetes mellitus (Caro et al 1995). These latter results resemble the finding in diabetic fatty rats (Torres et al 2009).…”

Section: Glucokinase Disease and The Status Of Gk In Type I And Ii Dimentioning

confidence: 68%

Research and Development of Glucokinase Activators for Diabetes Therapy: Theoretical and Practical Aspects

Matschinsky

Zelent

Doliba

et al. 2011

Diabetes - Perspectives in Drug Therapy

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Glucokinase Glucokinase (GK GK ; EC 2.7.1.1.) phosphorylates and regulates glucose metabolism in insulin-producing pancreatic beta-cells, hepatocytes, and certain cells of the endocrine and nervous systems allowing it to play a central role in glucose homeostasis glucose homeostasis . Most importantly, it serves as glucose sensor glucose sensor in pancreatic beta-cells mediating glucose-stimulated insulin biosynthesis and release and it governs the capacity of the liver to convert glucose to glycogen. Activating and inactivating mutations of the glucokinase gene cause autosomal dominant hyperinsulinemic hypoglycemia and hypoinsulinemic hyperglycemia in humans, respectively, illustrating the preeminent role of glucokinase in the regulation of blood glucose and also identifying the enzyme as a potential target for developing antidiabetic drugs antidiabetic drugs . Small molecules called glucokinase activators (GKAs) glucokinase activators (GKAs) which bind to an allosteric activator allosteric activator site of the enzyme have indeed been discovered and hold great promise as new antidiabetic agents. GKAs increase the enzyme's affinity for glucose and also its maximal catalytic rate. Consequently, they stimulate insulin biosynthesis and secretion, enhance hepatic glucose uptake, and augment glucose metabolism and related processes in other glucokinase-expressing cells. Manifestations of these effects, most prominently a lowering of blood glucose, are observed in normal laboratory animals and man but also in animal models of diabetes and patients with type 2 diabetes mellitus (T2DM T2DM ) type 2 diabetes mellitus (T2DM) . These compelling concepts and results sustain a strong R&D effort by many pharmaceutical companies to generate GKAs with characteristics allowing for a novel drug treatment of T2DM.

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Hepatic Enzyme Activities of Glycolysis and Gluconeogenesis in Diabetes of Man and Laboratory Animals

Cited by 55 publications

References 6 publications

Glucokinase and cytosolic phosphoenolpyruvate carboxykinase (GTP) in the human liver. Regulation of gene expression in cultured hepatocytes.

Glucokinase and cytosolic phosphoenolpyruvate carboxykinase (GTP) in the human liver. Regulation of gene expression in cultured hepatocytes.

Nutritional regulation of glucokinase: a cross-species story

Research and Development of Glucokinase Activators for Diabetes Therapy: Theoretical and Practical Aspects

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