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Mitochondrial Dysfunction in Chronic Disease
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Christopher Newell, Heather Leduc-Pessah, Aneal Khan, Jane Shearer
Hexokinase is an enzyme responsible for glycolysis initiation. As an anti-apoptotic mediator, VDAC1 enables hexokinase to bind to the OMM and access ATP for the generation of a concentration gradient that drives glycolysis (15). This mechanism is up-regulated in many malignant cancer cell lines, thus enabling sustained cell growth—the basis of the Warburg effect. Under conditions facilitating apoptosis, VDAC1 is hypothesized to interact with the monomeric cytosolic protein BAX and the OMM localized protein BAK (141). The BH3:groove model suggests that upstream regulation by BH3 and Bcl-2 proteins initiates a signalling cascade, which enables BAX to migrate to the OMM (141). Following migration of BAX to the OMM, BAX or BAK are able to self- or hetero-oligomerize, which results in mitochondrial permeabilization through formation of large oligomeric pore complexes (28). Interestingly, it is also proposed that the same protein grooves responsible for BAX and BAK apoptotic signalling may also be the site of pro-survival proteins which inhibit the oligomerization process from occurring (28). The formation of these mitochondrial pores enables cytochrome c to be released into the cytosol as a pro-apoptotic signalling molecule. Once released, cytochrome c cleaves and activates caspase 9, which perpetuates the apoptosis cascade and results in cell death (55).
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
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
Phosphorylation of glucose to glucose 6 phosphate by the low-Km, hexokinase II is an important step in the regulation of glucose metabolism. Despite the existence of hexokinase II polymorphisms, the majority of evidence favours the finding of reduced activity in NIDDM as being secondary to the insulin resistance.2 Transgenic mice overexpressing human hexokinase II had relatively normal OGTTs, intravenous insulin tolerance, and insulin levels.369
Metabolic and Metabolomic Effects of Metformin in Murine Model of Pulmonary Adenoma Formation
Published in Nutrition and Cancer, 2023
Andrew C. Elton, Vannesa Cedarstrom, Arman Quraishi, Beverly Wuertz, Kevin Murray, Todd W. Markowski, Donna Seabloom, Frank G. Ondrey
Another anticancer mechanism metformin exhibits is an anti-Warburg effect (59). The Warburg Effect states that cancer cells preferentially use anaerobic glycolysis for energy (16, 60). It is thought that metformin also prevents cancer through an anti-Warburg effect involving hexokinase expression and activity (61). Hexokinases perform a necessary phosphorylation of glucose prior to entry into glycolysis, and thus inhibition limits glycolysis (16). A study on oral squamous cell cancer cells found that metformin also reduced cancer cell lactate production (62). We found significant alterations in lactic acid levels between our treated and control cohorts, which may, in part, represent an anti-Warburg effect contributing to the reduced lung adenoma counts seen previously. However, further studies would be needed to evaluate metabolomic changes localized to the cancerous tissue to establish this conclusion.
Prothrombotic state and calcium deficiency in early pregnancy are risk factors for gestational diabetes mellitus: a retrospective cohort study
Published in Gynecological Endocrinology, 2022
Qingyun Liu, Shanshan Wei, Feng Wang
Women with pre-pregnancy diabetes were excluded from the cohort. During the first trimester, women with fasting plasma glucose ≥7.0 mmol/L were diagnosed with pre-pregnancy diabetes. To determine the GDM outcome, 75-g OGTT was performed at 24–28 weeks of gestation. 75-g glucose load was administered in the morning after an overnight fast. Venous blood was taken by trained nurses at fasting, 1-h and 2-h post-load. The sample was centrifuged within one hour to separate the plasma. The Hexokinase method was used to measure plasma glucose levels [19]. Diagnosis of GDM was made by clinicians according to recommendations from the former Ministry of Health of China, which was based on the IADPSG guidelines [20,21]. Pregnant women whose blood glucose met one of the following conditions will be diagnosed with GDM: fasting glucose ≥ 5.1 mmol/L, 1-h glucose ≥ 10.0 mmol/L, or 2-h glucose ≥ 8.5 mmol/L.
Targeting glucose metabolism to develop anticancer treatments and therapeutic patents
Published in Expert Opinion on Therapeutic Patents, 2022
Yan Zhou, Yizhen Guo, Kin Yip Tam
Hexokinase catalyzes the phosphorylation of glucose into glucose-6-phosphate (G6P) by transferring a phosphate group from ATP to glucose, which is the first committed and rate-limiting step of glycolysis [10]. Among its four isoforms, Hexokinase 2 (HK2) is the uppermost isoform in insulin-sensitive tissues, such as heart, skeletal muscle, and adipose tissues in mammal [11]. It has also been found to be upregulated in multiple types of solid tumors, exhibiting enhanced aerobic glycolysis [10,11]. In addition to its basic role in glycolysis, HK2 also affects many important cellular processes including cellular growth and survival by direct molecular-molecular or functional interactions with the Akt/mTOR pathways [12]. Excitingly, the differences in expression level of HK2 between cancer cells and normal cells may indicate huge potential for inhibiting HK2 as therapeutic strategies to preferentially kill cancer cells.