Glucokinase

Glucokinase EC 2. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates, glucokinase.

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The secretion of glucagon by pancreatic alpha cells is regulated by a number of external and intrinsic factors. While the electrophysiological processes linking a lowering of glucose concentrations to an increased glucagon release are well characterized, the evidence for the identity and function of the glucose sensor is still incomplete. In the present study we aimed to address two unsolved problems: 1 do individual alpha cells have the intrinsic capability to regulate glucagon secretion by glucose, and 2 is glucokinase the alpha cell glucose sensor in this scenario.

Glucokinase

Federal government websites often end in. The site is secure. Glucose transport is by facilitated diffusion and is not rate limiting. Once inside, glucose is phosphorylated to glucosephosphate by GCK in a reaction that is dependent on glucose throughout the physiological range of concentrations, is irreversible, and not product inhibited. High glycerol phosphate shuttle, pyruvate dehydrogenase, and pyruvate carboxylase activities, combined with low pentose-P shunt, lactate dehydrogenase, plasma membrane monocarboxylate transport, and glycogen synthase activities constrain glucosephosphate to being metabolized through glycolysis. Under these conditions, glycolysis produces mostly pyruvate and little lactate. Pyruvate either enters the citric acid cycle through pyruvate dehydrogenase or is carboxylated by pyruvate carboxylase. Reducing equivalents from glycolysis enter oxidative phosphorylation through both the glycerol phosphate shuttle and citric acid cycle. Specific roles of different cell types are determined by the diverse molecular mechanisms used to couple energy state to cell specific responses. Having a common glucose sensor couples complementary regulatory mechanisms into a tightly regulated and stable glucose homeostatic network. Our hypothesis is that glucokinase GCK is the primary glucose sensor in mammals and the sensor responsible for regulation of glucose homeostasis as schematically represented in Figure 1.

The siRNA treatment resulted in reduction of glucokinase expression to Low monocarboxylate transport both minimizes pyruvate loss through transport to the extracellular medium and prevents increased blood lactate glucokinase, as during exercise, glucokinase, from interfering with glucose sensing Otonkoski et al.

Official websites use. Share sensitive information only on official, secure websites. The GCK gene provides instructions for making a protein called glucokinase. This protein plays an important role in the breakdown of sugars particularly glucose in the body. Glucokinase is primarily found in the liver and in beta cells in the pancreas. Beta cells produce and release secrete the hormone insulin, which helps regulate blood glucose levels by controlling how much glucose is passed from the bloodstream into cells to be used as energy. Glucokinase acts as a sensor, recognizing when the level of glucose in the blood rises and helping stimulate the release of insulin from beta cells to control it.

Glucose metabolism in humans is tightly controlled by the activity of glucokinase GCK. GCK is predominantly produced in the pancreas, where it catalyzes the rate-limiting step of insulin secretion, and in the liver, where it participates in glycogen synthesis. A multitude of disease-causing mutations within the gck gene have been identified. Activating mutations manifest themselves in the clinic as congenital hyperinsulinism, while loss-of-function mutations produce several diabetic conditions. Indeed, pharmaceutical companies have shown great interest in developing GCK-associated treatments for diabetic patients. Due to its essential role in maintaining whole-body glucose homeostasis, GCK activity is extensively regulated at multiple levels. GCK possesses a unique ability to self-regulate its own activity via slow conformational dynamics, which allows for a cooperative response to glucose. GCK is also subject to a number of protein-protein interactions and post-translational modification events that produce a broad range of physiological consequences. While significant advances in our understanding of these individual regulatory mechanisms have been recently achieved, how these strategies are integrated and coordinated within the cell is less clear. This review serves to synthesize the relevant findings and offer insights into the connections between molecular and cellular control of GCK.

Glucokinase

Federal government websites often end in. The site is secure. Glucose metabolism in humans is tightly controlled by the activity of glucokinase GCK. GCK is predominantly produced in the pancreas, where it catalyzes the rate-limiting step of insulin secretion, and in hepatocytes, where it participates in glycogen synthesis. A multitude of disease-causing mutations within the gck gene have been identified. Activating mutations manifest themselves in the clinic as congenital hyperinsulinism, while loss-of-function mutations produce several diabetic conditions. Indeed, pharmaceutical companies have shown great interest in developing GCK-associated treatments for diabetic patients. Due to its essential role in maintaining whole-body glucose homeostasis, GCK activity is extensively regulated at multiple levels.

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Much, but not all, of the glucokinase found in the cytoplasm of beta cells is associated with insulin secretory granules and with mitochondria. Concordant glucose induction of glucokinase, glucose usage and glucose stimulated insulin release in pancreatic islets maintained in organ culture. Insulin signaling in alpha cells modulates glucagon secretion in vivo. Drug Discovery. The siRNA treatment resulted in reduction of glucokinase expression to Immunofluorescence Verification of the biosensor by immunofluorescence Isolated primary rat alpha cells were prepared and transduced as described below. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. GKA binding is glucose dependent and the degree of dependence varies with chemical structure. Diabetes 66 , — Dorzagliatin monotherapy in Chinese patients with type 2 diabetes: a dose-ranging, randomized, double-blind, placebo-controlled, phase 2 study. Sensing of glucose in the brain. When maximally active, GK and glycogen synthase appears to be located in the same peripheral areas of hepatocyte cytoplasm in which glycogen synthesis occurs. The supporting metabolism glycogen synthesis, glycolysis, fatty acid oxidation, etc. The resulting PCR-products were subcloned and sequenced. This mechanism seems to be especially relevant for the paradoxical hypersecretion of glucagon in type 2 diabetes

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To answer the question whether lowering of glucose alone is sufficient to directly stimulate glucagon release and whether glucokinase is acting as the alpha cell glucose sensor, we studied glucose-regulated glucagon release in purified alpha cells to avoid any confounding para- or juxtacrine signals. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. We hypothesize that GCK is the primary glucose sensor utilized for maintaining glucose homeostasis, i. Inhibition of glucose phosphorylation by mannoheptulose. Sweet et al. The kinetic relationship with the other substrate, MgATP, can be described by classical Michaelis-Menten kinetics, with an affinity at about 0. All play crucial roles in responding to rising or falling levels of blood glucose. Oxidative phosphorylation: regulation and role in cellular and tissue metabolism. No use, distribution or reproduction is permitted which does not comply with these terms. Glucose-sensing neurons of the hypothalamus. Isolated primary rat alpha cells were prepared and transduced as described below. Individuals carrying genetic mutations in GCK that result in altered kinetic constants present with symptoms consistent with predictions based on the measured changes Osbak et al.