Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have indicated that insulin secretion in response to glucose diminishes with age but insulin synthesis and gene transcription do not. To determine whether expression of genes other than those that encode insulin are subject to age-related changes that could alter pancreatic islet function, mRNAs for insulins I and II, amylin, glucose transporter 2 (GluT2), glucagon, and glucokinase were quantified in 2-, 6-, 12-, and 24-month-old Fischer 344 rats using species-specific ribonuclease (RNase) protection assays. There was only a modest (1.2- to 1.3-fold) increase in insulin I and insulin II mRNAs between ages 2 and 12 months. There were no statistically significant changes in levels of glucokinase mRNA with age. In contrast, the abundances of amylin, GluT2, and glucagon mRNAs all doubled during the same period. Variance in values from 24-month-old rats was too great to allow conclusions, except that the ratio of insulin II mRNA to insulin I mRNA increased with age. This change was not related to islet mass or total insulin mRNA abundance because it persisted at age 24 months, when total mRNA abundance had decreased. These results indicate that aging is associated with significant alterations in the relative proportion of expression of pancreatic islet cell genes implicated in insulin secretion and in intraislet glucose metabolism.
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PMID:Age-related changes in pancreatic islet cell gene expression. 788 76

A characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) is the lack of an acute insulin response to intravenous glucose with maintenance of the response to other secretagogues. It has been hypothesized that impaired glucose sensing stems from defective beta-cell glucokinase. It remains unclear whether decreased pancreatic glucokinase activity will produce defects of insulin secretion similar to those observed in NIDDM. In this study, the effects of glucosamine on glucokinase activity and on islet function were assessed in vitro and in vivo. Glucosamine (5 mmol/l) reduced glucokinase activity in islet homogenate and diminished the insulin response to glucose (200 mg/dl) by isolated islets, whereas the response to arginine (20 mmol/l at 100 mg/dl glucose) was unaffected. In conscious normal rats, glucosamine lowered plasma insulin, followed by an increase in blood glucose. Administration of glucosamine 10 min before an infusion of glucose (10 mg.min-1. 15 min) reduced the insulin response. The primary effect was an attenuation of the first-phase insulin response relative to the decreased basal insulin levels. Arginine (10 mg.min-1.15 min) induced biphasic insulin release in both groups. Although glucosamine slightly reduced the absolute insulin response, it was normal relative to preinfusion levels. In all experiments, glucagon secretion was unaffected by glucosamine. The results indicate that glucosamine inhibits beta-cell glucokinase activity in vitro. In addition, glucosamine impairs glucose- but not arginine-induced insulin secretion. We conclude that glucosamine, probably via a reduction of glucokinase activity, impairs insulin secretion in a manner comparable to that seen in NIDDM.
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PMID:Glucosamine inhibits glucokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats. 792 84

Insulin and glucagon release and insulin sensitivity were investigated in patients with glucokinase deficiency. Five subjects with a missense mutation (Glu256Lys) were studied. They were compared with six healthy subjects with low insulin response but normal glucose tolerance. Insulin and glucagon levels were measured at blood glucose 7.1 +/- 0.1 mmol/l and at 10.9 +/- 0.2 mmol/l with or without arginine (5 g i.v.). Insulin sensitivity was assessed as the ratio between infused glucose and the insulin level (M:I) during hyperglycemic clamps. Glu256Lys subjects were nonobese and had fasting blood glucose 6.7 +/- 0.1 mmol/l (P < 0.001 vs. control group). Insulin release was reduced in response to 11 mmol/l glucose (61% of control group, P < 0.05) as well as to arginine in the presence of 11 mmol/l glucose (54% of control group, P < 0.01). Also, the slope of potentiation, i.e., the enhancement of arginine-induced release as a function of prevailing glucose concentration, was reduced (delta insulin/delta glucose, 47% of control group, P < 0.05). As for glucagon release, the response to arginine was not inhibited normally by glucose, resulting in threefold higher levels at 11 mmol/l glucose versus control subjects. Insulin sensitivity, assessed as M:I, was significantly (P < 0.05) reduced (55% of control group). Glucokinase deficiency thus affects not only insulin responses to glucose per se but also glucose potentiation of responses to non-nutrient secretagogues. Abnormalities in glucagon release and insulin sensitivity coexist with attenuated insulin responses in glucokinase-deficient subjects.
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PMID:Glucose potentiation of arginine-induced insulin secretion is impaired in subjects with a glucokinase Glu256Lys mutation. 795 90

Hepatic glucokinase is induced by insulin and repressed by glucagon. The effects of epidermal growth factor (EGF) on glucokinase expression were investigated in rat hepatocytes. EGF does not affect the decline in glucokinase activity in hepatocytes cultured for 48h in the absence of insulin, but it counteracts the increase in activity induced by insulin. This effect of EGF is greater in cells cultured at low cell density than in confluent cultures. EGF suppressed the insulin-induced increase in glucokinase mRNA levels by 50% indicating that its effect is at least in part at a pretranslational level. However, it potentiated the stimulatory effect of insulin on glucose-6-phosphate dehydrogenase activity and mRNA, indicating that the effect on glucokinase expression is due to a specific post-receptor mechanism. The effect of EGF on glucokinase mRNA expression is mimicked by phospholipase D but not by phosphatidylinositol-specific phospholipase C or by phorbol ester, an activator of protein kinase C, suggesting that it is unlikely to be mediated by activation of protein kinase C.
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PMID:Epidermal growth factor counteracts insulin-induced expression of glucokinase in hepatocytes. 800 30

A transgene consisting of an upstream glucokinase (GK) promoter fragment linked to coding sequences of the human growth hormone gene was expressed in certain neuroendocrine cells of the pancreas, pituitary, brain, gut, thyroid, and lungs of mice. In pancreas, the transgene was expressed in a nonuniform manner among beta cells and in a variable but substantial fraction of the other islet cell types. In pituitary, it was expressed in corticotropes, and in brain, it was expressed in cells of the medial hypothalamus. Within the gut transgene expression was detected in a subset of enteroendocrine cells of the stomach and duodenal epithelium, some of which also exhibited glucagon-like polypeptide-1 immunoreactivity. In thyroid, transgene expression was observed in C cells of neonatal animals, whereas in the lung, it was expressed among rare endocrine cells of the bronchopulmonary mucosa. RNA polymerase chain reaction analysis of human growth hormone mRNA corroborated the tissue-specific transgene expression pattern. Prompted by the finding of transgene expression in specific neuroendocrine cells, we sought to determine whether GK mRNA and GK itself was also expressed in the brain and gut, tissues not previously associated with the expression of this enzyme. Using rat tissues, GK mRNA was detected by RNA polymerase chain reaction in both the brain and intestine and was localized to specific cells in the hypothalamus and enteric mucosa by in situ hybridization. A high Km glucose phosphorylating activity was detected from isolated rat jejunal enterocytes that displayed a chromatographic elution profile identical to hepatic GK. GK immunoreactivity was detected in cells of the medial hypothalamus with many of the same cells also displaying GLUT2 immunoreactivity. Together, these studies provide evidence for upstream GK promoter activity, GK mRNA, and GK itself in certain neuroendocrine cells outside the pancreatic islet and lead us to suggest that GK may play a broader role in glucose sensing by neuroendocrine cells than was thought previously.
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PMID:Analysis of upstream glucokinase promoter activity in transgenic mice and identification of glucokinase in rare neuroendocrine cells in the brain and gut. 810 9

We have investigated the mechanism of the rebound of glycogen stores in the liver of 72-h fasted rats. The liver of 72- and 96-h fasted rats contains significant amounts of glycogen (about 5 mg/g, wet weight) as compared to the liver of 24- and 48-h fasted rats, which contains less than 2 mg of glycogen/g of liver, wet weight. Rebound of glycogen does not involve glycogen synthase activation or glycogen phosphorylase inhibition. It could be dependent on the concentration of the precursor substrate of glycogenesis, i.e. glucose 6-phosphate (Glc-6-P), which is higher by about 45% in the liver of 72- and 96-h fasted rats than in the liver of 48-h fasted rats. The 72-h increase of Glc-6-P compared with the 48-h values could not be explained either by late modifications of the total activities of glucokinase, hexokinases, Glc-6-P dehydrogenase, and glucose-6-phosphatase (Glc-6-Pase) or by changes in plasma glucose and insulin/glucagon ratio. In agreement with the fact that total glucose output tends to decrease upon prolonged fasting, the increase of Glc-6-P concentration in the liver of 72-h fasted rats suggests the involvement of a metabolite inhibition of Glc-6-Pase. The increase of the alpha-ketoglutarate concentration in the 72- and 96-h fasted liver with regard to the 48-h fasted liver (about three times) might account for such an inhibition since we show here that Glc-6-Pase is inhibited in vitro in the presence of relevant concentrations of alpha-ketoglutarate, Glc-6-P, and Mg2+ ions.
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PMID:Investigation of the mechanism of glycogen rebound in the liver of 72-hour fasted rats. 820 76

The release of glucokinase from digitonin-permeabilized hepatocytes shows different characteristics with respect to ionic strength and [MgCl2] from the release of other cytoplasmic enzymes. Release of glucokinase is most rapid at low ionic strength (300 mM sucrose, 3 mM Hepes) and is inhibited by increasing concentration of KCl [concn. giving half-maximal inhibition (I50) 25 mM] or Mg2+ (I50 0.5 mM). Release of phosphoglucoisomerase, phosphoglucomutase and glucose-6-phosphate dehydrogenase is independent of ionic strength, but shows a small inhibition by MgCl2 (20%, versus > 80% for glucokinase). Lactate dehydrogenase release increases with increasing ionic strength [concn. giving half-maximal activation (A50) 10 mM KCl] or [MgCl2]. The rate and extent of glucokinase release during permeabilization in 300 mM sucrose, 5 mM MgCl2 or in medium with ionic composition resembling cytoplasm (150 mM K+, 50 mM Cl-, 1 mM Mg2+) depends on the substrate concentrations with which the hepatocytes have been preincubated. In hepatocytes pre-cultured with 5 mM glucose the release of glucokinase was much slower than that of other cytoplasmic enzymes measured. However, preincubation with glucose (10-30 mM) or fructose (50 microM-1 mM) markedly increased glucokinase release. This suggests that, in cells maintained in 5 mM glucose, glucokinase is present predominantly in a bound state and this binding is dependent on the presence of Mg2+. The enzyme can be released or translocated from its bound state by an increase in [glucose] (A50 15 mM) or by fructose (A50 50 microM). The effects of glucose and fructose were rapid (t1/2 5 min) and reversible, and were potentiated by insulin and counteracted by glucagon. They were inhibited by cyanide, but not by cytochalasin D, phalloidin or colchicine. Mannose had a glucose-like effect (A50 approximately 15 mM), whereas galactose, 3-O-methyl-D-glucose and 2-deoxyglucose were ineffective. When hepatocytes were incubated with [2-3H, U-14C]glucose, the incorporation of 3H/14C label into glycogen correlated with the extent of glucokinase release. Since 2-3H is lost during conversion of glucose 6-phosphate into fructose 6-phosphate, substrate-induced translocation of glucokinase from a Mg(2+)-dependent binding site to an alternative site might favour the partitioning of glucose 6-phosphate towards glycogen, as opposed to phosphoglucoisomerase.
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PMID:Intracellular binding of glucokinase in hepatocytes and translocation by glucose, fructose and insulin. 828 78

Glucose can modulate the transcription of many genes, particularly those encoding enzymes of liver metabolism. The transcriptional effect of glucose can be indirect, being mediated in vivo by hormonal variations, especially increase in insulin and decrease in glucagon secretion. Whereas the transcription of the glucokinase gene, for example, is stimulated by insulin without the aid of glucose, the transcriptional activation of most glycolytic and lipogenic genes in hepatocytes requires the presence of both glucose and insulin. The role of insulin in the activation of these genes seems mainly to stimulate glucokinase synthesis, and thus to permit glucose phosphorylation. In some cells in which hexokinase activity is constitutive, the glucose-dependent activation of the same genes does not require insulin and, in addition, can be produced by the nonmetabolisable analog, 2-deoxyglucose. In hepatocytes, the insulin effect on the glucose-dependent activation of the L-pyruvate kinase gene can be reproduced by fructose at low concentrations. Fructose probably acts through the fructose 1-phosphate dependent deinhibition of glucokinase activity. A glucose/carbohydrate element has been identified on the L-type pyruvate kinase and spot 14 gene promoters. It is able to bind, in vitro, transcriptional factors of the MLTF/USF family and could act in cooperation with tissue-specific contiguous elements, such as the HNF4 binding site in the L-type pyruvate kinase gene.
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PMID:Transcriptional control of metabolic regulation genes by carbohydrates. 829 88

Glucokinase first appears in the liver of the rat 2 weeks after birth and its activity rapidly increases after weaning on to a high-carbohydrate diet. The appearance of glucokinase is principally due to the increase of plasma insulin and to the decrease of plasma glucagon concentrations. Oral glucose administration to 1- or 10-day-old suckling rats induced an increase in plasma insulin and a fall in plasma glucagon and allowed a rapid accumulation of liver glucokinase mRNA, secondarily to a stimulation of gene transcription. When unrestrained late pregnant rats were infused with glucose during 36 h to induce an increase in fetal plasma insulin and a decrease in fetal plasma glucagon concentrations, glucokinase mRNA was detectable in fetal liver but the level was 100-fold lower than that observed in 1- or 10-day-old suckling rats. It is suggested that the hormonal environment did not allow glucokinase gene expression to be induced in fetal liver and that the absence of expression of glucokinase in suckling rat liver is due to the presence of low plasma insulin and high plasma glucagon levels. The chromatin structure of the glucokinase gene was examined during development by identification of DNase-I-hypersensitive sites from the region comprised between -8 kb upstream and +4 kb downstream of the cap site. Five hypersensitive sites were found: four liver-specific sites upstream of the cap site and one non-specific site in the first intron. These sites are already present in term fetus but the intensity of the two proximal sites located upstream of the cap site increase markedly after birth. This suggests that these sites could be implicated in the regulation of glucokinase gene expression by insulin and glucagon. Full DNase-I-hypersensitivity of these two proximal sites seems necessary for the mature response of glucokinase gene in response to changes in pancreatic hormones concentrations.
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PMID:Glucose administration induces the premature expression of liver glucokinase gene in newborn rats. Relation with DNase-I-hypersensitive sites. 835 93

The purpose of these studies was to quantify several mRNAs expressed specifically in pancreatic islet cells and known or postulated to be important for insulin release after acute well defined alterations in levels of plasma glucose. Glucose levels were maintained at 50, 120, or 180 mg/dl (2.8, 6.7, or 10 mM) for 3 h in conscious unrestrained rats. Hypoglycemia (for 3 h) caused significant decreases in pancreatic content of mRNAs for insulin 2 and GLUT-2 to 55 and 34% of control values, respectively. There were no significant changes in insulin 1, amylin, glucokinase, or glucagon mRNAs. Unprocessed insulin 1 and 2 mRNA precursors were decreased to 17 and 10% of levels in controls, consistent with effects of short-term hypoglycemia on new mRNA synthesis. Hyperglycemia (for 3 h) caused no increase in pancreatic content of any mRNA measured. To discriminate between effects of hypoglycemia and hyperinsulinemia in the hypoglycemic animals, rats were made hypoglycemic by infusion with etomoxir, a carnitine palmitoyltransferase I inhibitor that lowers glucose in the fasted (glycogen-depleted) state by inhibiting hepatic gluconeogenesis. A single dose of this agent caused a decrease in glucose from 120 mg/dl (6.7 mM) to 80 mg/dl (4.4 mM) and significantly decreased insulin mRNA and pre-mRNA. These results are consistent with the hypothesis that glucose modulates islet cell gene transcription directly. They indicate that the range of glucose concentrations that modulate gene transcription differs from the levels of glucose that alter both insulin biosynthetic and secretion rates.
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PMID:Hypoglycemia but not hyperglycemia induces rapid changes in pancreatic beta-cell gene transcription. 836 95


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