Genetics of diabetic pregnancy
Moshe Hod, Lois G. Jovanovic, Gian Carlo Di Renzo, Alberto de Leiva, Oded Langer in Textbook of Diabetes and Pregnancy, 2018
Glucokinase (GCK) is an enzyme present in the β-cells of the pancreas that helps the cells, through phosphorylating glucose to glucose-6-phosphate, accurately detect circulating glucose and adjust insulin secretion accordingly. A loss of function mutation in the GCK gene impacts the ability to detect glucose at lower levels, thereby causing a rise in the homeostatic set point of blood glucose in that individual. Glucokinase monogenic diabetes (GCK-MODY) has been estimated to have a prevalence of 1.1 in 1000 primarily European population and that the prevalence in women with GDM is at least 0.9%.27 Fifty percent of the fetuses of women with GCK mutations will inherit the mutation. It is expected that an unaffected fetus of a mother with a GCK mutation would produce excess insulin in response to the increased circulating maternal blood glucose, causing an increase in birth weight compared to a fetus with the GCK mutation. In fact, a 700 g birth weight difference was seen between infants that did not carry the mutation and those that inherited the mutation from their mother.28,29 There are currently no standardized guidelines as to how to manage women with GCK mutations during pregnancy to minimize the risk of maternal and fetal complications.
Introduction
Emmanuel Opara in NUTRITION and DIABETES, 2005
Since activation of the initial stages of GSIS or increased ΔΨ leads immediately to increased insulin secretion, it is not surprising that these stages are targets for therapeutic intervention. For example, glucokinase plays a key role in initial GSIS stages by catalyzing the phosphorylation of glucose in β-cells. A new class of antidiabetic agents, mixed-type glucokinase activators that increased both the affinity for glucose and the Vmax, was shown to stimulate GSIS [13, 68]. A reduction in UCP2 activity was also suggested as a mechanism for significant improvement in insulin secretion [69]. However, such therapeutic strategies should be used with caution, since, according to our proposal, an increase in insulin secretion achieved by these approaches could also considerably increase ROS production, leading to oxidative stress.
Genetics of Endocrine Disorders and Diabetes Mellitus
George H. Gass, Harold M. Kaplan in Handbook of Endocrinology, 2020
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
Understanding circadian dynamics: current progress and future directions for chronobiology in drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Meltem Weger, Benjamin D. Weger, Frédéric Gachon
Glucokinase activator (GKA) represent a drug class that may require a timed dosing regimen informed by fasting-feeding cycles. GKAs are designed to treat diabetes by lowering blood glucose levels through the activation of glucokinase (GCK). However, there have been setbacks in their development as phase 2 clinical trials revealed considerable side effects such as hypoglycemia and hepatic steatosis [95]. As glucokinase plays a major role in glucose metabolism and shows circadian oscillation that follows daily cycles of fasting and feeding [31,97], a preclinical study investigated the effects of timing administration of a GKA based on fasting or feeding periods in obese Zucker rats [98]. They found that GKA treatment during feeding periods improved glucose disposal, hepatic insulin sensitivity, and lipid metabolism, in the absence of hepatic steatosis and inflammation. In contrast, GKA treatment during fasting periods had detrimental metabolic effects. In conclusion, the time-dependent effects of drugs including acetaminophen and GKA are caused by cell autonomous liver clocks which in turn are entrained by the fasting-feeding cycle. This dependency opens the possibility for treatment schedules that optimize the timing of food intake and the time of day for drug administration to maximize the drug’s benefits and minimize side effects.
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.
Related Knowledge Centers
- Enzyme
- Glucose
- Pancreas
- Metabolism
- Liver
- Phosphorylation
- Carbohydrate
- Glucose 6-Phosphate
- Cell
- Fasting