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)

DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in approximately 80% of French families with this form of diabetes. We previously identified a nonsense mutation in exon 7 in one of these families and showed that it was the likely cause of glucose intolerance in this dominantly inherited disorder. Here we report the isolation and partial sequence of the human glucokinase gene and the identification of two missense mutations in exon 7, Thr-228----Met and Gly-261----Arg, that cosegregate with early-onset non-insulin-dependent diabetes mellitus. To assess the molecular mechanism by which mutations at these two sites may affect glucokinase activity, the crystal structure of the related yeast hexokinase B was used as a simple model for human beta-cell glucokinase. Computer-assisted modeling suggests that mutation of Thr-228 affects affinity for ATP and mutation of Gly-261 may alter glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism.
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PMID:Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. 150 86

Abnormal glucose and lipid metabolism in striated muscles and arterial wall has been demonstrated in 3 species: the pig, the dog, and human Type 2 diabetic patients, sharing the common feature of peripheral hyperinsulinaemia. In this study eighteen consecutive patients undergoing coronary bypass surgery and eight control patients were examined. Prior to surgery an oral glucose tolerance test showed that eleven out of eighteen patients had impaired glucose tolerance and significantly elevated fasting immune reactive insulin (IRI) and C-peptide concentrations. There was a statistically significant correlation between the 2 hour blood glucose value and the fasting plasma insulin level (R = 0.55, p less than 0.05). During the operation, aortic and muscle biopsies were taken. The eighteen patients undergoing coronary bypass surgery showed disturbances in glucose metabolism, i.e. decreased activity of glycolytic enzymes (hexokinase 0.30 +/- 0.06 versus 0.40 +/- 0.06 U/g, p less than 0.001, and phosphofructokinase 0.48 +/- 0.09 versus 0.61 +/- 0.07 U/g, p less than 0.01). Malic enzyme activity was increased in all patients (0.17 +/- 0.03 versus 0.06 +/- 0.02 U/g, p less than 0.001). Glucose-6-phosphate dehydrogenase was increased in the eleven patients with impaired glucose tolerance (0.55 +/- 0.10 versus 0.30 +/- 0.07, p less than 0.01) parallel to a significant increase in triglyceride content in the aortic wall (16.1 +/- 4.8 versus 3.7 +/- 3.2 mumol/g, p less than 0.01) as well as in the striated muscles (374 +/- 44 versus 48 +/- 6 mumol/g, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intracellular metabolism in biopsies from the aorta in patients undergoing coronary bypass surgery. 295 78

Carbohydrate intolerance was investigated in 8 alcoholics with liver cirrhosis and in controls. Indices of carbohydrate metabolism, glucose and insulin levels after glucose loading, were compared with glucose phosphorylating (glucokinase, hexokinase) and releasing (glucose-6-phosphatase) enzymes. Comparison was also made with pericellular collagen in liver biopsies and with insulin sensitivity assessed by the euglycemic clamp technique and with conventional liver function tests including oral antipyrine test. Glucokinase activity was low or absent, hexokinase activity increased and the GK/HK ratio reduced. Glucose-6-phosphatase activity was lowered and insulin sensitivity decreased. Pericellular collagen was increased (P less than 0.001) and related to the fasting glucose (r0.593) and insulin levels (r0.526). Blood glucose was related to antipyrine metabolism (r-0.727) but not to the other liver tests. Glucose intolerance in cirrhosis seems to be associated with reduced glucose phosphorylating and liberating enzyme activities. Hyperinsulinaemia, developing secondarily, may then lead to insulin resistance.
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PMID:Carbohydrate intolerance associated with reduced hepatic glucose phosphorylating and releasing enzyme activities and peripheral insulin resistance in alcoholics with liver cirrhosis. 299 23

In order to assess different methods for early detection of unsuspected diabetes, urine and venous blood samples were collected at random from 1082 patients visiting a primary health care centre in southern Sweden. Blood glucose was analysed by the hexokinase method along with the Dextrostix-Eyetone reflectance meter. Urine glucose was determined by Clinistix, Diastix, Neostix, Rediatest, Clinitest and quantitatively by the hexokinase method. Patients fulfilling the criteria of a positive screen were subjected to a diagnostic investigation with an oral glucose tolerance test. Out of 89 positive screenees, 37 patients were classified as diabetics, showing a prevalence of diabetes in the study population of 3.4% according to the WHO criteria. Impaired glucose tolerance was found in 14 patients. In a control group of 56 patients, randomly selected among negative screenees, no cases of diabetes were found. Random blood glucose measurement by the hexokinase method, using 7 mmol/l as a screening level, had a significantly higher sensitivity (95%) than all urine glucose methods (59-30%) with comparable specificity (97-99%). Use of the Dextrostix-Eyetone reflectance meter resulted in a decrease in sensitivity to 75% without any change in specificity or predictability, compared with the hexokinase method. Urine testing for glucose was found to be a suboptimal method for early case finding of diabetes among patients receiving primary health care.
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PMID:Assessment of laboratory methods for detection of unsuspected diabetes in primary health care. 372 33

Malnourished surgical patients have metabolic and functional abnormalities of skeletal muscle and it has been suggested that these are due to reduced activities of glycolytic enzymes associated with abnormalities of muscle fibres. We have measured the activities of four key enzymes of glucose utilization and the size and distribution of muscle fibre types in vastus lateralis biopsies from 14 undernourished patients awaiting surgery (mean weight loss 24 +/- 10 per cent). These results were compared with those from 14 normally nourished controls, comparable in age, sex, race and habitual activity. Fructose bisphosphatase activity was reduced in undernourished patients by 44 per cent (P less than 0.01), phosphofructokinase by 40 per cent (P = 0.005) and hexokinase by 37 per cent (P less than 0.001). Both fibre types were smaller in patients than controls (area I, 41.4 micron2 X 10(-2) +/- 0.4 vs. 73.3 micron2 X 10(-2) +/- 0.6, less than 0.001; area II, 27.7 micron2 X 10(-2) +/- 0.4 vs. 72.5 micron2 X 10(-2) +/- 0.5, P less than 0.001), and there was a smaller proportional number of type II fibres in patients (35 per cent vs. 65 per cent, P less than 0.01). This loss of type II fibre numbers and preferential type II atrophy may account for the enzyme depression associated with it and could produce the syndrome of impaired glucose tolerance, muscle weakness and fatigue seen in undernourished patients. In a subgroup of 11 patients, biopsy was repeated after 14 days of intravenous nutrition. Only phosphofructokinase activity rose significantly (19.62 +/- 1.85 to 30.74 +/- 2.99 mumol min-1 g-1, P less than 0.01) and both type II fibre size (40.6 +/- 18.5 to 47.4 micron2 +/- 20.3 X 10(-2), P less than 0.05) and number (42 per cent +/- 6 to 56 per cent +/- 5, P less than 0.05) also rose. Intravenous nutrition may therefore increase maximum glycolytic rate and improve muscle function in undernourished surgical patients.
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PMID:Abnormalities of muscle metabolism and histology in malnourished patients awaiting surgery: effects of a course of intravenous nutrition. 632 97

The effect of biotin administration on the glucose tolerance of streptozotocin (STZ)-induced diabetic Wistar rats was investigated. STZ-induced diabetes was induced by intraperitoneal injection of streptozotocin (45 mg/kg body weight as a single dose). The impaired glucose tolerance in response to an oral glucose load (1.8g per kg body weight) in STZ-induced diabetic rats (STZ-rat) was partially improved by intraperitoneal administration of biotin for 15 days (100 micrograms/rat/day). However, a recovery in the STZ-rat's insulin secretion was not found after biotin administration. To help clarify the mechanism underlying the improvement in glucose tolerance seen with biotin treatment, glucokinase and hexokinase activities were determined in the liver and pancreas. In STZ-rats that had received biotin (STZ-biotin rats), glucokinase activity was higher by 3.4-fold in liver and by 2.4-fold in pancreas than in the STZ-rats. The biotin level of STZ-rats was significantly lower in the liver and pancreas than that of the control rats (no STZ administration); but in STZ-biotin rats, the level in these organs recovered to the control level. These results demonstrate that injected biotin can improve glucose handling without increasing insulin secretion in STZ-rats.
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PMID:Biotin administration improves the impaired glucose tolerance of streptozotocin-induced diabetic Wistar rats. 926 17

We examined changes in high- and low-Km glucose phosphorylating activity in pancreatic islet extracts from the prediabetic Zucker diabetic fatty (ZDF) rat between 5-6 weeks and 12 weeks of age (after the onset of diabetes). Comparisons were made between the activity observed in the ZDF rat and that seen in the ZDF lean control (ZLC) rat and the obese nondiabetic Zucker fatty (ZF) rat. At 5-6 weeks of age, insulin resistant ZDF and ZF rats were hyperinsulinemic, compared with the ZLC rat, but had normal plasma glucose levels. Kinetic parameters (Vmax and Km for glucose) of hexokinase (HK) and Km of glucokinase (GCK) did not differ between groups. Islet GCK activity for ZDF and ZF rats was 1.7-fold greater than in ZLC rats (P < 0.02 and P < 0.001, respectively). By 12 weeks of age, hypersecretion of insulin at 5.0 mmol/l glucose was observed in perifused islets from both obese groups relative to the ZLC rat. Islets from ZDF rats failed to increase insulin secretion in response to increased glucose concentration. Group differences in the kinetic parameters for GCK or in the Km values for HK were not significant. Islet HK activity for ZDF and ZF rats was 1.9-fold (P < 0.05) and 1.7-fold (P < 0.05) greater, respectively, than for ZLC rats. Compared with the 5- to 6-week-old animals, HK activity increased 3.1-fold (P < 0.001), 2.5-fold (P < 0.002), and 2.0-fold (P < 0.05) for ZDF, ZF, and ZLC rats, respectively. Differences in GCK activity between 5- to 6- and 12-week-old rats were not significant for any of the groups. We conclude: 1) increased islet glucose phosphorylating activity is present in insulin resistant and hyperinsulinemic ZF and ZDF rats, relative to the ZLC rat; 2) at 12 weeks of age, hyperinsulinemic ZDF and ZF rats demonstrated significant increases in HK activity, compared with lean controls; and 3) deficiency in GCK activity does not explain failure of diabetic ZDF islets to respond to glucose, since differences between diabetic ZDF and nondiabetic ZF rats were not statistically significant. Increases in pancreatic islet phosphorylating activity seem to be important in maintaining basal hyperinsulinemia in insulin-resistant animals, but do not appear to play a role in the progression to glucose intolerance and diabetes.
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PMID:Changes in pancreatic islet glucokinase and hexokinase activities with increasing age, obesity, and the onset of diabetes. 928 43

The activities of hexokinase isoenzymes I-IV (EC 2.7.1.1) and of N-acetylglucosamine kinase (EC 2.7.1.59) were determined in normal human liver and in alcoholic liver disease and primary biliary cirrhosis after FPLC fractionation of high-speed supernatants on Mono-Q with a linear NaCl gradient. In control human liver the hexokinase activities were: I, 3.6; II, 0.7; III, 3.5, IV, 4.8 (mUnits/mg supernatant protein). The activity of N-acetylglucosamine kinase was 8 mU/mg of protein. In alcoholic liver disease and primary biliary cirrhosis, the activity of hexokinase IV (glucokinase) was suppressed to less than 10% of control activity and the activity of hexokinase I was increased 3-fold. The activity of hexokinase II was increased approximately 7-fold in alcoholic liver disease. The activities of hexokinase III and N-acetylglucosamine kinase were unchanged in cirrhosis. Hexokinase III showed 50% substrate inhibition at 100 mM glucose as compared with 0.5mM glucose. The high activity of hexokinase III in human liver (approximately 50% of the low-Km activity and 70% of glucokinase activity) results in a significant underestimation of glucokinase activity as determined by the conventional spectrometric assay while the activity of N-acetylglucosamine kinase may contribute to an overestimation of glucokinase activity in the radiochemical assay. Furthermore glucokinase is dramatically suppressed in liver disease, which although partly compensated for by the increase in hexokinase I (and II), accounts in part for the well-known glucose intolerance of liver cirrhosis.
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PMID:Hexokinase isoenzymes in normal and cirrhotic human liver: suppression of glucokinase in cirrhosis. 946 41

We have shown previously that the combination of a long-acting, non-sulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor (trandolapril) and the Ca2+ channel blocker verapamil improve insulin-stimulated glucose transport in skeletal muscle of the obese Zucker rat, a model of insulin resistance, hyperinsulinemia, and dyslipidemia. In the present study, we investigated the interactions of chronic treatment (28 days) with verapamil (20 mg/kg) and a short-acting, sulfhydryl-containing ACE inhibitor (captopril, 50 mg/kg) in combination on insulinemia, lipidemia, glucose tolerance, and insulin action on skeletal muscle glucose transport (2-deoxyglucose uptake in epitrochlearis) in lean and obese Zucker rats. In lean animals, verapamil alone and in combination with captopril actually increased (P < .05) plasma insulin, whereas in obese animals, verapamil alone worsened the hyperinsulinemia already present, and this effect was abolished by cotreatment with captopril. Captopril alone or in combination with verapamil reduced plasma free fatty acid (FFA) levels in obese rats, but not in lean rats. Captopril alone reduced the glucose-insulin index in obese animals given an oral glucose load, and this was associated with a significant increase in insulin-mediated muscle glucose transport. The greatest improvement in these responses was elicited in obese animals receiving combined captopril and verapamil treatment, and was associated with increases in muscle GLUT-4 glucose transporter protein and hexokinase and citrate synthase activities. In conclusion, these findings indicate that the short-acting, sulfhydryl-containing ACE inhibitor captopril can elicit beneficial metabolic effects on the hyperinsulinemia, dyslipidemia, glucose intolerance, and insulin resistance of muscle glucose transport of the obese Zucker rat. Moreover, there is a positive interactive effect on these pathophysiological parameters between captopril and verapamil in this animal model of insulin resistance.
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PMID:Interactions of captopril and verapamil on glucose tolerance and insulin action in an animal model of insulin resistance. 971 96

Exercise training or chronic treatment with angiotensin-converting enzyme (ACE) inhibitors can ameliorate glucose intolerance, insulin resistance of muscle glucose metabolism, and dyslipidemia associated with the obese Zucker rat. The purpose of the present study was to determine the interactions of exercise training and ACE inhibition (trandolapril) on these parameters in the obese Zucker rat. Animals were assigned to a sedentary control, a trandolapril-treated (1 mg. kg-1. day-1 for 6 wk), an exercise-trained (treadmill running for 6 wk), or a combined trandolapril-treated and exercise-trained group. Exercise training, alone or with trandolapril, significantly (P < 0. 05) increased peak O2 consumption by 31-34%. Similar decreases in fasting plasma insulin (34%) and free fatty acids (31%) occurred with exercise training alone or in combination with trandolapril. Compared with control, exercise training or trandolapril alone caused smaller areas under the curve (AUC) for glucose (12-14%) and insulin (28-33%) during an oral glucose tolerance test. The largest decreases in the glucose AUC (40%) and insulin AUC (53%) were observed in the combined group. Similarly, whereas exercise training or trandolapril alone improved maximally activated insulin-stimulated glucose transport in isolated epitrochlearis (26-34%) or soleus (39-41%) muscles, the greatest improvements in insulin action (67 and 107%, respectively) were seen in the combined group and were associated with similarly enhanced muscle GLUT-4 protein and total hexokinase levels. In conclusion, these results indicate combined exercise training and ACE inhibition improve oral glucose tolerance and insulin-stimulated muscle glucose transport to a greater extent than does either intervention alone.
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PMID:Interactions of exercise training and ACE inhibition on insulin action in obese Zucker rats. 1036 72


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