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Hormones of the Pancreas
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The enhanced uptake of glucose by liver cells is due to the increased activity of glucokinase. Glucokinase phosphorylates glucose after it diffuses intracellularly, and the phosphorylated glucose is held in the liver cell. Glycogen synthesis is enhanced due to the increased activity of glycogen synthase, which polymerizes glucose to form glycogen.
Genetics of Endocrine Disorders and Diabetes Mellitus
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Bess Adkins Marshall, Abby Solomon Hollander
Glucokinase (type IV hexokinase) catalyzes the first step of glucose metabolism, phosphorylation to glucose-6-phosphate, in the β cell and the liver. The enzyme belongs to a family of hexokinases (type I–IV) but has a higher Km for glucose (5 mM vs. 20–130 μM) and is not inhibited by glucose-6-phosphate, as are the other three hexokinases. The glucokinase gene is on chromosome 7 and contains two different first exons and promoters. One of these is utilized exclusively in β-cell glucokinase and the other in hepatocyte glucokinase (see Magnuson98 for review). It has been proposed that glucokinase, perhaps in combination with the high-Km glucose transporter (GLUT2), acts as the “glucose sensor” in the pancreas.99
Endocrinology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Mehul Dattani, Catherine Peters
Correct diagnosis is important. Patients with mutations in the glucokinase gene rarely require treatment and are not at increased risk of diabetic complications. Those with mutations in HNF1a and HNF4a may respond to sulphonylurea treatment.
Anti-diabetic and hypolipidemic effects of Cinnamon cassia bark extracts: an in vitro, in vivo, and in silico approach
Published in Archives of Physiology and Biochemistry, 2023
K. Vijayakumar, B. Prasanna, R. L. Rengarajan, A. Rathinam, S. Velayuthaprabhu, A. Vijaya Anand
Carbohydrate metabolising enzymes play an important role in the regulation of glucose level (O’Doherty et al.1999). In the present study, the glucokinase level is decreased in STZ-induced diabetic rats; this may be due to the decreasing concentration of insulin after the treatment of C. cassia, the level of glucokinase is increased. This increasing concentration of glucokinase initiates the glycolysis process, and this process reduces the glucose concentration in the blood. Glucose-6-phosphatase is another enzyme involved in the gluconeogenesis and glycogenolysis process (Maiti et al.2004). In the present study, the level of glucose-6-phosphatase is increased, and this may be due to the damage of the liver by the toxin. After the treatment of C. cassia, the level of this enzyme is decreased, this may be due to the liver cell regeneration effect or the increasing concentration of insulin.
Type 1 diabetes: key drug targets and how they could influence future therapeutics
Published in Expert Opinion on Therapeutic Targets, 2023
Yoon Kook Kim, Kashif M. Munir, Stephen N. Davis
Glucokinase serves as a glucose sensor in pancreatic islet cells promoting glucose-stimulated insulin secretion. Activation of glucokinase in the liver promotes hepatic glucose uptake and glycogen synthesis and storage[67], and mutations in glucokinase have shown to lead to dysglycemia [68]. TTP399 is an oral, small molecule, liver selective glucokinase activator. A two-part study, randomly assigning 20 patients with T1DM in Part 1 and 85 patients in Part 2 to TTP399 800 mg vs placebo, demonstrated reduction of HbA1c over 12 weeks of −0.7% in Part 1 and −0.21% in Part 2 [69]. Despite improvements in HbA1c, TTP399 treated patients also showed a 40% reduction in hypoglycemia without increase in episodes of diabetic ketoacidosis. This is because in the liver, glucokinase is notably regulated by its interaction with the glucokinase regulatory protein, which ensures its activation only in the setting of hyperglycemia. Dorzagliatin is a dual-acting (pancreatic and hepatic) glucokinase activator in late phase trials for the treatment of type 2 diabetes [70,71]. Preliminary data show this class as a potential therapy for individuals with type 1 and type 2 diabetes. TTP399 was recently granted breakthrough therapy designation by the Food and Drug Administration (FDA) in the United States as an adjunctive therapy for patients with T1DM. With further studies, glucokinase activation may play a larger role in safe pharmacologic treatment of T1DM.
Using adjuvant pharmacotherapy in the treatment of type 1 diabetes
Published in Expert Opinion on Pharmacotherapy, 2021
Glucokinase is the rate-limiting enzyme in β-cell glycolysis and thus an important determinant of insulin secretion [54]. Nonselective glucokinase activators have been tested in T2D patients, the rationale being that activation of β-cell glucose metabolism would augment insulin secretion and thereby improve glycemia [54]. However, such studies met with limited success as the insulinotropic effects of the activators were not sustained and because of concerns for hepatic steatosis [55]. Recently, a hepatoselective glucokinase activator was tested in T1D patients in a phase 1b study [56]. In this 12-week study, HbA1c was significantly lowered (by 0.7%) and the frequency of severe or symptomatic hypoglycemia decreased by 40% relative to placebo without increased risk of ketosis. Larger studies are required to further evaluate glucokinase activators as adjunctive therapy for the treatment of T1D.