Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.1.1 (hexokinase)
5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spontaneously hypertensive rats (SHR) demonstrate elevated blood pressure, cardiac hypertrophy, glucose intolerance, and insulin resistance compared with age-matched Wistar-Kyoto rats (WKY). We investigated concurrent effects of captopril on blood pressure, cardiac mass, myocardial enzyme activities, glucose tolerance, and insulin action in young male SHR. At 10 weeks of age, SHR were randomized into two groups, one receiving distilled water, the other a captopril solution (50 mg/kg body weight/day). We also examined age-matched WKY receiving distilled water. Blood pressure was measured by tail-cuff during the 4-week treatment period and oral glucose tolerance was tested at the end of treatment. Hearts were weighed and ventricular tissue was assayed for activities of 3-hydroxyacyl-CoA dehydrogenase, citrate synthase, and hexokinase. Growth rates were similar between captopril-treated and control SHR, but less than those of WKY. Captopril reduced blood pressure (134 +/- 8 v 177 +/- 8 mm Hg, P < .05) and left ventricular mass (-18%, P < .05) in SHR. Cardiac enzyme activities also changed with captopril treatment, reflecting an increased capacity for beta-oxidation of fatty acids and reduced potential for glucose phosphorylation in the left ventricle of SHR. Serum concentrations of glucose, insulin, and free fatty acids after a brief fast and in response to oral glucose were not different after captopril treatment, suggesting no improvement in insulin action or glucose tolerance. In summary, treatment of young male SHR with captopril reduces blood pressure and cardiac mass, and promotes a small but significant increase in cardiac capacity for oxidation of fatty acids and reduction of glucose phosphorylation. In contrast, metabolic effects of captopril on oral glucose tolerance and insulin action were not evident.
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PMID:Metabolic, hemodynamic, and cardiac effects of captopril in young, spontaneously hypertensive rats. 1037 67

Growth hormone (GH) deficiency in adults is characterized by central obesity, dyslipidemia, coagulopathy and glucose intolerance, all features of the "metabolic syndrome", explaining the increased cardiovascular morbidity and mortality associated with GH deficiency in adults. Employing the 2-step euglycemic-hyperinsulinemic clamp, we have demonstrated severe insulin resistance in GH-deficient adults, with a reduction in insulin-mediated glucose utilization of -50%. Basal glucose turnover and partitioning of whole body glucose utilization into glycolytic flux (GF) and glycogen synthesis/glucose storage (GS) pathways are normal, but insulin activation of these 2 pathways is reduced, predominantly in the GS pathway. Activation of muscle glycogen synthase by insulin is markedly decreased, as is glycogen content of muscle. Insulin-induced muscle hexokinase activity appears also to be attenuated in GH-deficient adults with raised intramuscular cellular glucose and normal-reduced concentrations of glucose-6-phosphate. Beta-cell function is not excessive in GH-deficient adults and is inappropriately low for the insulin resistance. Following treatment of GH-deficient adults with recombinant GH (rhGH), the insulin resistance is either unchanged or more pronounced by 3, 6 or 24 months of treatment, despite the significant reduction in general and central obesity. The GF and GS pathways and muscle glycogen synthase and hexokinase activities remain severely impaired. Abnormalities in free fatty acid (FFA) metabolism are present in rhGH-treated GH-deficient adults and correlate significantly with the degree of insulin resistance as do the concentrations of rhGH-induced insulin-like growth factor (IGF)-I, the post-basal insulinemia and the duration of the GHD, but is independent of obesity. In conclusion, long-term rhGH treatment in GH-deficient adults results in persistent insulin resistance and abnormalities in the GF and GS pathways due to reduced glycogen synthase and hexokinase activities, in the presence of an ongoing reduction of central obesity. We postulate that the insulin resistance is due to chronic rhGH-induced alterations in FFA metabolism, non-physiological levels of IGF-I and chronic basal hyperinsulinemia.
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PMID:Insulin sensitivity in growth hormone (GH)-deficient adults and effect of GH replacement therapy. 1044 67

In Western countries 25-35% of the population have insulin resistance syndrome characteristics. The defects most likely to explain the insulin resistance of the insulin resistance syndrome include: 1) the glucose transport system of skeletal muscle (GLUT-4) and its different signalling proteins and enzymes; 2) glucose phosphorylation by hexokinase; 3) glycogen synthase activity and 4) competition between glucose and fatty acid oxidation (glucose-fatty acid cycle). High carbohydrate/low fat diets deteriorate insulin sensitivity on the short term. However, on the long term, high fat/low carbohydrate diets have a lower satiating power, induce low leptin levels and eventually lead to higher energy consumption, obesity and more insulin resistance. Moderately high-carbohydrate (45-55% of the daily calories)/low-fat diets seem to be a good choice with regard to the prevention of diabetes and cardiovascular risk factors as far as the carbohydrates are rich in fibers. Long-term interventions with regular exercise programs show a 1/3 decrease in the appearance of overt diabetes in glucose intolerant subjects. Furthermore, diet and exercise interventions "normalise" the mortality rate of patients with impared glucose tolerance. Therefore, moderately high carbohydrate/low fat diets are most likely to prevent obesity and type 2 diabetes. Triglycerides should be monitored and, in some cases, a part of the carbohydrates could be replaced by fat rich in monounsaturated fatty acids. However, total caloric intake is of utmost importance, as weight gain is the major determinant for the onset of insulin resistance and glucose intolerance. Regular (when possible daily) exercise, decreases cardiovascular risk. With regard to insulin resistance, resistance training seems to offer some advantages over aerobic endurance activities.
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PMID:Interaction of physical activity and diet: implications for insulin-glucose dynamics. 1061 74

Teleost fish are generally considered to be glucose intolerant. This mini-review examines some of the background and the possible mechanistic bases for this statement. Glucose intolerance is a clinical mammalian term meaning that a glucose load results in persistent hyperglycemia. Teleost fish show persistent hyperglycemia that is generally coincident with transient hyperinsulinemia. The fact that teleost generally have high plasma insulin compared with mammals implies insulin-deficiency is not a suitable explanation for this persistent hyperglycemia. Instead, peripheral utilization of glucose is probably the principle cause of hyperglycemia. Recent evidence for muscle insulin receptors, glucose transporters and hexokinase/glucokinase is reviewed and future experimental directions are suggested. If by altering peripheral glucose utilization fish could become more glucose tolerant, costs to the aquaculture industry may be substantially reduced.
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PMID:Glucose intolerance in teleost fish: fact or fiction? 1139 56

Low birth weight (LBW) is an important risk factor for type 2 diabetes. We have developed a mouse model of LBW resulting from undernutrition during pregnancy. Restriction of maternal food intake from day 12.5 to 18.5 of pregnancy results in a 23% decrease in birth weight (P < 0.001), with normalization after birth. However, offspring of undernutrition pregnancies develop progressive, severe glucose intolerance by 6 months. To identify early defects that are responsible for this phenotype, we analyzed mice of undernutrition pregnancies at age 2 months, before the onset of glucose intolerance. Fed insulin levels were 1.7-fold higher in mice of undernutrition pregnancies (P = 0.01 vs. controls). However, insulin sensitivity was normal in mice of undernutrition pregnancies, with normal insulin tolerance, insulin-stimulated glucose disposal, and isolated muscle and adipose glucose uptake. Although insulin clearance was mildly impaired in mice of undernutrition pregnancies, the major metabolic phenotype in young mice of undernutrition pregnancies was dysregulation of insulin secretion. Despite normal beta-cell mass, islets from normoglycemic mice of undernutrition pregnancies showed basal hypersecretion of insulin, complete lack of responsiveness to glucose, and a 2.5-fold increase in hexokinase activity. Taken together, these data suggest that, at least in mice, primary beta-cell dysfunction may play a significant role in the pathogenesis of LBW-associated type 2 diabetes.
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PMID:Beta-cell secretory dysfunction in the pathogenesis of low birth weight-associated diabetes: a murine model. 1573 46

Compelling evidence from epidemiologic studies indicates that elevated circulating insulin-like growth factor (IGF)-I, insulin resistance, and associated complications, such as elevated fasting plasma insulin, glucose and free fatty acids, glucose intolerance, increased body mass index, and visceral adiposity, are linked with increased risk of colorectal cancer. However, the role of insulin and markers of glucose control in the development of adenomas, precursors to colorectal cancer, has not been fully explored. We evaluated the relationship between plasma insulin, glucose, IGF-I, IGF-II, IGF-binding protein-3 (IGFBP-3), apoptosis, and colorectal adenomas in a case-control study. Participants were drawn from consenting patients undergoing colonoscopy at the University of North Carolina hospitals (Chapel Hill, NC). Participants were classified as cases or controls based on whether they had one or more colorectal adenomatous polyps. Fasting plasma insulin, IGF-I, IGF-II, and IGFBP-3 levels were assessed by ELISA. Glucose was measured by glucose hexokinase assay. Apoptosis was assessed by morphology on H&E-stained sections. Dietary and lifestyle information were obtained by telephone interview. Logistic regression was used to examine the association between adenoma status and insulin-IGF markers. Adenoma cases (n = 239) and adenoma-free controls (n = 517) provided rectal biopsies and/or blood samples and interview data. Consistent with prior findings, cases were more likely to be males, older, have higher waist-to-hip ratio, lower calcium intake, lower apoptosis, and less likely to report nonsteroidal anti-inflammatory drug use. Those in the highest quartile of insulin (adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.2) and glucose (adjusted odds ratio, 1.8; 95% confidence interval, 0.9-3.6) were more likely to have an adenoma compared with the lowest quartile. Similarly, subjects in the highest two quartiles of insulin were more likely to be in the lowest two quartiles of apoptosis. Overall, there were no significant differences between mean circulating levels of glucose, IGF-I, IGF-II, and IGFBP-3 among cases and controls and no association between these variables and apoptosis. The results provide novel evidence that elevated insulin and glucose are associated with increased adenoma risk and decreased apoptosis in normal rectal mucosa. These findings suggest that insulin may act early in the adenoma-carcinoma sequence to promote the development of colorectal adenoma by decreasing apoptosis in the normal mucosa.
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PMID:Insulin resistance, apoptosis, and colorectal adenoma risk. 1617 12

Voltage-dependent anion channels (VDACs), also known as mitochondrial porins, are the main pathway for metabolites across the mitochondrial outer membrane and may serve as binding sites for kinases, including hexokinase. We determined that mitochondria-bound hexokinase activity is significantly reduced in oxidative muscles (heart and soleus) in vdac1(-/-) mice. The activity data were supported by western blot analysis using HK2 specific antibody. To gain more insight into the physiologic mean of the results with the activity data, VDAC deficient mice were subjected to glucose tolerance testing and exercise-induced stress, each of which involves tissue glucose uptake via different mechanisms. vdac1(-/-) mice exhibit impaired glucose tolerance whereas vdac3(-/-) mice have normal glucose tolerance and exercise capacity. Mice lacking both VDAC1 and VDAC3 (vdac1(-/-)/vdac3(-/-)) have reduced exercise capacity together with impaired glucose tolerance. Therefore, we demonstrated a link between VDAC1 mediated mitochondria-bound hexokinase activity and the capacity for glucose clearance.
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PMID:VDAC1 serves as a mitochondrial binding site for hexokinase in oxidative muscles. 1720 67

Beta-cell mass, hexokinase/glucokinase (HK/GK) activity, glucose metabolism and insulin secretion were studied in the islets of rats with fructose-induced insulin resistance (IR). Normal male Wistar rats were fed a standard commercial diet and water without (control, C) or with 10% fructose-rich diet (FRD) for 3 weeks. Blood glucose (strips), triglyceride (commercial kit), and insulin (RIA) levels were measured at the time of death. Glucose-induced insulin release, glucose metabolism ((14)CO(2) and (3)H(2)O production from D-[U-(14)C]- and D-[5-(3)H]-glucose) and HK/GK activity (G-6-P production), transcription (RT-PCR), protein expression (Western blot), and cellular compartmentalization were measured in isolated islets (collagenase digestion). FRD rats presented normoglycemia but impaired glucose tolerance, hypertriglyceridemia, hyperinsulinemia, and increased HOMA-IR index. In these rats, beta-cell mass decreased significantly by 33%, with a 44% increase in the percentage of apoptotic cells. Glucose-induced insulin release and islet glucose metabolism were higher in FRD rats. While GK activity (total and cytosolic fraction) and protein expression were significantly higher in FRD islets, HK showed no change in any of these parameters. Our results demonstrate that the changes induced by dietary-induced IR upon beta-cell function and mass are strongly conditional on the nutrient model used. In our model (intact animals with impaired glucose tolerance), GK activity increases through mechanisms previously shown only in vitro or under highly hyperglycemic conditions. Such an increase plays a pivotal role in the adaptive increased release of insulin in response to IR, even in the presence of marked beta-cell mass reduction.
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PMID:Islet adaptive changes to fructose-induced insulin resistance: beta-cell mass, glucokinase, glucose metabolism, and insulin secretion. 1903 94

Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness.
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PMID:Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease. 2274 35

In a recent genome-wide association study, hexokinase domain-containing protein 1, or HKDC1, was found to be associated with gestational glucose levels during 2-hour glucose tolerance tests at 28 weeks of pregnancy. Because our understanding of the mediators of gestational glucose homeostasis is incomplete, we have generated the first transgenic mouse model to begin to understand the role of HKDC1 in whole-body glucose homeostasis. Interestingly, deletion of both HKDC1 alleles results in in utero embryonic lethality. Thus, in this study, we report the in vivo role of HKDC1 in whole-body glucose homeostasis using a heterozygous-deleted HKDC1 mouse model (HKDC1(+/-)) as compared with matched wild-type mice. First, we observed no weight, fasting or random glucose, or fasting insulin abnormalities with aging in male and female HKDC1(+/-) mice. However, during glucose tolerance tests, glucose levels were impaired in both female and male HKDC1(+/-) mice at 15, 30, and 120 minutes at a later age (28 wk of age). These glucose tolerance differences also existed in the female HKDC1(+/-) mice at earlier ages but only during pregnancy. And finally, the impaired glucose tolerance in HKDC1(+/-) mice was likely due to diminished whole-body glucose use, as indicated by the decreased hepatic energy storage and reduced peripheral tissue uptake of glucose in HKDC1(+/-) mice. Collectively, these data highlight that HKDC1 is needed to maintain whole-body glucose homeostasis during pregnancy but also with aging, possibly through its role in glucose use.
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PMID:HKDC1 Is a Novel Hexokinase Involved in Whole-Body Glucose Use. 2745 89


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