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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Control of blood sugar involves the complex interaction of the pancreatic glucose-sensing beta-cells with the liver, which serves as the primary site of glucose disposal after a meal. Glucokinase occupies an important role in controlling glucose phosphorylation and metabolism both in the liver and in pancreatic islets. In the beta-cells, glucokinase functions as pacemaker of glycolysis at physiological glucose levels. It determines the unique characteristics of islet hexose usage, that is, the rate, affinity, cooperativity, and anomeric discrimination of glucose metabolism. Because glycolysis controls hexose-induced insulin release, glucokinase is considered the best-qualified candidate for the elusive glucose sensor of beta-cells. A deficiency of glucokinase would disturb glucose homeostasis. Decreased islet glucokinase would diminish islet glycolysis and would result in a higher set point of beta-cells for glucose-induced insulin release. Decreased liver glucokinase would cause less efficient hepatic glucose disposal. Human maturity-onset diabetes (type II diabetes) has these characteristics. It is thus conceivable that certain forms of type II diabetes are due to a glucokinase deficiency.
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PMID:New perspectives on pancreatic islet glucokinase. 636 28

Starvation refeeding experiments were conducted in rats to test the hypothesis that adaptation of glucokinase (the high Km component of glucose phosphorylation) could be the major determinant of glucose metabolism of pancreatic islet cells and of glucose-stimulated insulin release. It was found that glucokinase of islet homogenates, glucose use by intact isolated islets, and glucose-induced insulin release as studied in a perifusion system were decreased after 24 h of fasting, whereas P-fructokinase and 3-P-glyceraldehyde DH were unaltered. After extended fasting (e.g., 120 h) all three enzymes were decreased but glucose use did not change any further. Refeeding normalized all parameters. These and previous results support the concept that glucokinase serves as the adaptive beta-cell glucoreceptor relating blood glucose to insulin release.
Diabetes 1981 Nov
PMID:Adaptation of glycolytic enzymes: glucose use and insulin release in rat pancreatic islets during fasting and refeeding. 645 66

The effects of a high fat diet (30% (w/w) corn oil) on chronic streptozotocin-diabetic rats were investigated at the whole body level and at the enzyme level. The diet caused significant decreases in the extent of polydipsia (66% decrease), polyphagia (49%), polyuria (67%) and glycosuria (70%). The activities of selected hepatic enzymes from the glycolytic, gluconeogenic, ureogenic and lipogenic clusters were determined. The fat diet caused significant decreases (range: 47 to 54%) in the activity of the ureogenic enzymes carbamyl phosphate synthetase, ornithine transcarbamylase and arginase; had no effect on the glycolytic enzymes glucokinase, hexokinase and pyruvate kinase; partially decreased the diabetes-induced elevated activities of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (63% decrease), serine dehydratase (90%), alanine aminotransferase (31%) and aspartate aminotransferase (65%), and partially reversed the activity of one lipogenic enzyme, ATP citrate lyase.
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PMID:The effects of a high fat diet on chronic streptozotocin-diabetic rats. 692 68

To study the pathways involved and the effect of insulin on the autoregulation of hepatic glucose balance, isolated hepatocytes from normal, diabetic and treated diabetic rats were incubated with varying concentrations of glucose (100-400 mg/dl) with and without pyruvate (10 mM). New glucose production or utilization was calculated from the change in media glucose concentrations before and after incubation, new glycogenolysis by the change in tissue glycogen levels before and after incubation, net glycolysis by following the incorporation of glucose-C14 into lactate C14 and gluconeogenesis by the difference in glucose production in the presence and absence of pyruvate. Hepatocytes from control and insulin-treated animals manifested autoregulation of glucose balance. Glucose modulated the glycogen and glycolytic pathways but did not affect gluconeogenesis. In hepatocytes from diabetic rats, there was no autoregulation, tissue glycogen was unmeasurable both before and after incubation, glycolysis was markedly curtailed and gluconeogenesis was increased. It may be concluded that (1) glucose autoregulates its own production or utilization by modulating the glycogen and glycolytic pathways, (2) autoregulation is lost in severe diabetes leading to fasting hyperglycemia, and (3) insulin has a permissive effect on the autoregulation of glucose balance by maintaining the rate-limiting enzymes, glycogen synthase and glucokinase, so that glucose can exert its effect on these pathways.
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PMID:Autoregulation by glucose of hepatic glucose balance: permissive effect of insulin. 701 73

Rat liver glucokinase synthesis and degradation was estimated in fasted/fed and diabetic/diabetic-insulin-treated rats by the radioimmunological technique. Starvation and Streptozotocin-diabetes led to basal rates of synthesis and, consequently, to low levels in enzyme activity. In addition, a decrease in the apparent half-life from about 19 h in the fed or diabetic-insulin substituted to about 11 h in the starved or diabetic rat, respectively, was observed. Injection of Bt2cAMP into glucose-fed animals reduced glucokinase synthesis to basal levels within 90 min, without affecting enzyme activity. It is concluded that in metabolic states associated with elevated levels in tissue cAMP glucokinase synthesis is reduced to basal values and, in addition, its rate of degradation is significantly enhanced.
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PMID:Accelerated turnover of hepatic glucokinase in starved and streptozotocin-diabetic rat. 717 97

Glucose homeostasis depends upon a balance between glucose production by the liver and glucose utilization by insulin-dependent tissues, such as muscle and fat. Insulin, secreted by the pancreatic B cell, inhibits hepatic glucose output and facilitates glucose utilization in the muscle and fat tissues. In the diabetic patients, there are three types of pathological defects; (1) inability of the B cell to secrete normal insulin in an accurate fashion, (2) increase in the hepatic glucose output, and (3) decrease in glucose metabolism at the muscle and fat tissues. Candidate genes which cause the first defect are the insulin gene, the glucokinase gene and the mitochondrial tRNA gene. The glucokinase gene causes the second defect, too. Those which cause the third defect are the insulin receptor gene and glycogen synthase gene. However, these genes in total account for 3% or less of type II diabetes. Further analyses of systems of both insulin secretion and insulin receptor-signaling at a molecular level will help elucidate the other diabetes candidate genes.
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PMID:[Diabetogenes; which cause type II diabetes mellitus]. 747 36

Maturity-onset diabetes of the young (MODY) is a model for genetic studies of non-insulin-dependent diabetes mellitus. We have identified 15 MODY families in which diabetes is not the result of mutations in the glucokinase gene. This cohort of families will be useful for identifying other diabetes-susceptibility genes. Nine other candidate genes potentially implicated in insulin secretion or insulin action have been tested for linkage with MODY in these families, including glucokinase regulatory protein, hexokinase II, insulin receptor substrate 1, fatty acid-binding protein 2, glucagon-like peptide-1 receptor, apolipoprotein C-II, glycogen synthase, adenosine deaminase (a marker for the MODY gene on chromosome 20), and phosphoenolpyruvate carboxykinase. None of these loci showed evidence for linkage with MODY, implying that mutations in these genes do not make a major genetic contribution to the development of MODY. In addition to these linkage analyses, one or two affected subjects from each family were screened for the presence of the A to G mutation at nucleotide 3,243 of the mitochondrial tRNA(Leu(UUR)) gene. This mutation was not found in any of these subjects. Finally, we report the localization of the gene encoding the regulatory protein of glucokinase to chromosome 2, band p22.3 and the identification of a restriction fragment length polymorphism at this locus.
Diabetes 1994 Mar
PMID:Search for a third susceptibility gene for maturity-onset diabetes of the young. Studies with eleven candidate genes. 750 74

Phosphorylation of glucose to glucose 6-phosphate by glucokinase (GK; EC 2.7.1.2) serves as a glucose-sensing mechanism for regulating insulin secretion in beta cells. Recent findings of heterozygous GK gene mutations in patients with maturity-onset diabetes of the young (MODY), a form of type II (non-insulin-dependent) diabetes characterized by autosomal dominant inheritance, have raised the possibility that a decrease in beta-cell GK activity may impair the insulin secretory response of these cells to glucose. To generate an animal model for MODY we have expressed in transgenic mice a GK antisense RNA with a ribozyme element under control of the insulin promoter. Mice in two independent lineages had about 30% of the normal islet GK activity. Insulin release in response to glucose from in situ-perfused pancreas was impaired; however, the plasma glucose and insulin levels of the mice remained normal. These mice are likely to be predisposed to type II diabetes and may manifest increased susceptibility to genetic and environmental diabetogenic factors. They provide an animal model for studying the interaction of such factors with the reduced islet GK activity.
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PMID:Ribozyme-mediated attenuation of pancreatic beta-cell glucokinase expression in transgenic mice results in impaired glucose-induced insulin secretion. 751 Aug 84

Genetic linkage studies of families with early-onset type 2 diabetes have facilitated the identification of diabetes-susceptibility genes. In order to assess the feasibility of using linkage approaches to identify genes responsible for the development of type 2 diabetes in Japanese subjects, we examined our clinical records for multigenerational families suitable for genetic studies. We identified 16 families in which at least one subject was diagnosed with type 2 diabetes before 25 years of age. Seven of these families had a pattern of inheritance consistent with a diagnosis of maturity-onset diabetes of the young (MODY) and nine families showed a complex pattern of inheritance of type 2 diabetes with transmission of diabetes-susceptibility genes from both parents. The glucokinase and mitochondrial tRNA(Leu(UUR)) genes were screened for mutations in at least one affected subject from each family in order to assess the contribution of mutations in these genes to the development of the diabetes. No mutations were found, which suggests that the diabetes in these families resulted from mutations in other genes.
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PMID:Characterization of Japanese families with early-onset type 2 (non-insulin dependent) diabetes mellitus and screening for mutations in the glucokinase and mitochondrial tRNA(Leu(UUR)) genes. 754 40

The secretion of insulin is controlled by the rate of glucose metabolism in the pancreatic beta cells. As phosphorylation by glucokinase (GLK) appears to be the rate-limiting step for glucose catabolism in beta cells, this enzyme may be the glucose sensor. To test this possibility and to resolve the relative roles of liver and beta cell GLK in maintaining glucose levels, we have generated mice completely deficient in GLK and transgenic mice in which GLK is expressed only in beta cells. In mice with only one GLK allele, blood glucose levels are elevated and insulin secretion is reduced. GLK-deficient mice die perinatally with severe hyperglycemia. Expression of GLK in beta cells in the absence of expression in the liver is sufficient for survival. These mice demonstrate the critical need for beta cell GLK in maintaining normal glucose levels and provide a novel model for one form of noninsulin-dependent diabetes.
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PMID:Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis. 755 75


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