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)

A sporadic case of multiple endocrine neoplasia type I with coexisting insulinoma and hyperparathyroidism was investigated in vivo and in vitro. The insulinoma was localized by somatostatin receptor scintigraphy and these receptors were functionally active. Octreotide administration decreased the basal insulin and glucagon secretion by 90 and 46%, respectively. Immunocytochemistry of the insulinoma tissue was positive for insulin, chromogranin A and neuropeptide Y. The insulinoma cells were also isolated and cultured in vitro. Incubation experiments revealed that a low glucose concentration (1 mmol/l) was sufficient to increase cytosolic free calcium and to produce a maximal glucose-induced insulin release. Northern blot analysis of RNA obtained from the tumor showed a high abundance of the low Km glucose transporter GLUT1 but no transcript for the high Km glucose transporter GLUT2. The abnormal distribution of glucose transporters probably relates to the abnormal glucose sensing of insulinoma cells, and explains their sustained insulin secretion at low glucose concentrations. Whether these abnormalities share a pathogenetic link with the presence of functionally active somatostatin receptors remains to be elucidated.
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PMID:Insulinoma associated with a case of multiple endocrine neoplasia type I: Functional somatostatin receptors and abnormal glucose-induced insulin secretion. 925 24

Weaning onto chow diets causes the highest incidence of diabetes in the BB rat. Changes in gut development and absorption of nutrients in the diabetes prone rat and the subsequent effect on pancreatic function may play a role in the ultimate development of the disease. BB diabetes prone (dp) and BB normal (n) dams were fed chow diets. Pups were killed at various ages ranging from 7 to 30 days. BBdp rats had higher small intestine and colon weights expressed per body weight at all ages (p < 0.0001). RNA content (mg/g) in the jejunum, ileum and colon was higher in the BBdp rats beginning at the critical period at 21 days and maintained at 24 days and 30 days (p < 0.0001). Proglucagon message decreased with age in both BBdp and BBn animals (p < 0.0001). Levels of proglucagon mRNA were higher in BBdp compared to BBn animals only in the ileum at 10 days (p < 0.01). Adjusting for total ileal and colonic RNA content resulted in BBdp animals having higher total colonic proglucagon mRNA at 21, 24 and 30 days (p < 0.0001). Plasma GLP-1(7-36) amide was more than doubled in BBdp compared to BBn animals (p < 0.0005) at 30 days. Expressing sodium-dependent D-glucose co-transporter (SGLT-1), GLUT2 and GLUT5 mRNA per total jejunal RNA shows increased transporter mRNA in BBdp compared to BBn rats at weaning (21 days) (p < 0.05). Radical differences exist between BBdp and BBn animals at 'critical periods' in both proglucagon and glucose transporter gene expression. These differences may help explain altered growth and diseases incidence between these two strains.
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PMID:Ontogenic changes in proglucagon mRNA in BB diabetes prone and normal rats weaned onto a chow diet. 926 80

Previous work demonstrated that a high fiber diet upregulates proglucagon mRNA and secretion of glucagon-like peptide-1 [GLP-1(7-37)] and insulin compared with an elemental fiber-free diet. This study examined whether similar intakes of fibers differing in physiochemical and fermentative properties alter the expression of intestinal hormones and intestinal absorptive properties. Sprague-Dawley rats were fed either a 50 g/kg cellulose or rhubarb fiber diet for 14 d. Ileal proglucagon mRNA levels were significantly higher in rats fed rhubarb fiber than in those fed cellulose fiber (9.3 +/- 0.9 vs. 6.2 +/- 1.0 densitometer units). Proglucagon mRNA in the colon did not differ between diet treatments. Plasma c-peptide concentrations were significantly higher 30 min after an oral glucose tolerance test in the rhubarb vs. cellulose group (1627 +/- 67 vs. 1290 +/- 71 pmol/L). Passive permeability, measured by the uptake of L-glucose, was significantly higher in the jejunum of rats fed cellulose compared with those fed rhubarb fiber. Adjusting total glucose uptake for passive permeability and unstirred water layer resistance resulted in a higher Km being calculated for the jejunum and ileum of the cellulose fiber group. Jejunal and ileal carrier-mediated uptakes (Vmax) were not altered by diet and reflected the lack of difference between groups in sodium-dependent glucose cotransporter (SGLT-1) and sodium-independent glucose transporter (GLUT2) mRNA levels. Replacing cellulose fiber with rhubarb fiber in a diet upregulated ileal proglucagon mRNA and resulted in a reduced passive permeability but did not affect glucose transport of the small intestine. This work establishes the importance of dietary fiber fermentability in modulating intestinal proglucagon expression and possibly glucose homeostasis.
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PMID:A physiological level of rhubarb fiber increases proglucagon gene expression and modulates intestinal glucose uptake in rats. 931 46

IDX-1 (islet/duodenum homeobox-1) is a transcription factor expressed in the duodenum and pancreatic beta and delta cells. It is required for embryonic development of the pancreas and transactivates the Glut2, glucokinase, insulin, and somatostatin genes. Here we show that exposure of isolated rat pancreatic islets to palmitic acid induced a approximately 70% decrease in IDX-1 mRNA and protein expression as well as 40 and 65% decreases in the binding activity of IDX-1 for its cognate cis-regulatory elements of the Glut2 and insulin promoters, respectively. The inhibitory effect of palmitic acid required its mitochondrial oxidation since it was prevented by the carnitine palmitoyltransferase I inhibitor bromopalmitic acid. The palmitic acid effect on IDX-1 was correlated with decreases in GLUT2 and glucokinase expression of 40 and 25%, respectively, at both the mRNA and protein levels. Insulin and somatostatin mRNA expression was also decreased by 40 and 60%, whereas glucagon mRNA expression was not modified. After 48 h of exposure to fatty acids, total islet insulin, somatostatin, and glucagon contents were decreased by 85, 55, and 65%, respectively. At the same time, total hormone release was strongly stimulated (13-fold) for glucagon, whereas its was only marginally increased for insulin and somatostatin (1.5- and 1.7-fold, respectively). These results indicate that elevated fatty acid levels 1) negatively regulate Idx-1 expression; 2) decrease the expression of genes transactivated by IDX-1 such as those for GLUT2, glucokinase, insulin, and somatostatin; and 3) lead to an important increase in glucagon synthesis and secretion. Fatty acids thus have pleiotropic effects on pancreatic islet gene expression, and the negative control of Idx-1 expression may be an initial event in the development of these multiple defects.
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PMID:Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. 937 11

Luminal and systemic short chain fatty acids (SCFA) stimulate mucosal proliferation but the mechanism(s) is unclear. This study examined acute effects of systemic SCFAs on gastrointestinal structure and function and signals potentially mediating SCFA-induced mucosal proliferation. Male Sprague-Dawley rats (246+/-2 g) received nutrients as either standard total parenteral nutrition (TPN) or an isoenergetic, isonitrogenous formulation containing SCFAs (TPN + SCFA). Animals were randomized to one of five treatments: standard TPN for 72 hr, TPN + SCFA for 72 hr, or standard TPN followed by TPN + SCFA for the final 6, 12, and 24 hr. SCFAs reduced (P < 0.003) ileal protein within 6 hr. Jejunal GLUT2 expression was increased (P=0.0001) in all SCFA groups and ileal GLUT2 protein in the 6-, 12-, and 24-hr SCFA groups (P < 0.05). SCFAs increased (P < 0.003) ileal proglucagon abundance following 6, 12, and 24 hr, and plasma GLP-2 concentration following 12 hr (P < 0.03). Jejunal c-myc expression was increased (P < 0.001) following 6, 12, and 24 hr of SCFAs. SCFAs increased ileal c-myc, c-jun, and c-fos expression following 24 hr (P < 0.02), 12 hr (P < 0.05) and 6, 12, and 24 hr (P=0.0001), respectively. In conclusion, systemic SCFAs increase plasma GLP-2 and ileal proglucagon mRNA, GLUT2 expression and protein, and c-myc, c-jun, and c-fos expression.
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PMID:Systemic short-chain fatty acids rapidly alter gastrointestinal structure, function, and expression of early response genes. 969 Mar 91

Glucose production by liver is a major physiological function, which is required to prevent development of hypoglycemia in the postprandial and fasted states. The mechanism of glucose release from hepatocytes has not been studied in detail but was assumed instead to depend on facilitated diffusion through the glucose transporter GLUT2. Here, we demonstrate that in the absence of GLUT2 no other transporter isoforms were overexpressed in liver and only marginally significant facilitated diffusion across the hepatocyte plasma membrane was detectable. However, the rate of hepatic glucose output was normal. This was evidenced by (i) the hyperglycemic response to i.p. glucagon injection; (ii) the in vivo measurement of glucose turnover rate; and (iii) the rate of release of neosynthesized glucose from isolated hepatocytes. These observations therefore indicated the existence of an alternative pathway for hepatic glucose output. Using a [14C]-pyruvate pulse-labeling protocol to quantitate neosynthesis and release of [14C]glucose, we demonstrated that this pathway was sensitive to low temperature (12 degreesC). It was not inhibited by cytochalasin B nor by the intracellular traffic inhibitors brefeldin A and monensin but was blocked by progesterone, an inhibitor of cholesterol and caveolae traffic from the endoplasmic reticulum to the plasma membrane. Our observations thus demonstrate that hepatic glucose release does not require the presence of GLUT2 nor of any plasma membrane glucose facilitative diffusion mechanism. This implies the existence of an as yet unsuspected pathway for glucose release that may be based on a membrane traffic mechanism.
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PMID:Normal hepatic glucose production in the absence of GLUT2 reveals an alternative pathway for glucose release from hepatocytes. 977 Apr 84

Glucose, that Claude Bernard has demonstrated in 1850 to be synthesized and secreted by the liver, is an important regulator of gene transcription in all types of organisms. In vertebrates, it especially regulates transcription of metabolic genes in the liver and fat tissue, activating genes encoding enzymes and regulators of the glycolytic and lipogenic pathways. Working with the L-type pyruvate kinase gene we have found that in hepatocytes glucose-dependent gene regulation requires: Presence of the GLUT2 glucose transporter, necessary to allow for an effective depletion in glucose 6-phosphate (G-6P) under gluconeogenic conditions. Phosphorylation of glucose to G-6P assured either by insulin-dependent glucokinase or by another hexokinase isoform. Most likely, entry of G-6P in the pentose phosphate pathway. Modulation of a kinase/phosphatase cascade, in particular inhibition of the 5'AMP-activated protein kinase. Signalling through a glucose response complex assembled onto a glucose-response element (GIRE) located in regulatory regions of glucose-responsive genes. The activators USF belong to the complex, and are required for a normal gene activation by glucose, as evidenced from the phenotype of knock-out mice deficient in USF. The study of USF-defective knock-out mice suggest that USF could be involved in nutritional activation of a whole class of genes regulated by glucose, and not by insulin itself. In particular, lipogenic genes and the ob gene, encoding the leptin satiety hormone, are abnormally responsive to diet in USF-/- mice. The transactivation potential of USF would be modulated by a glucose sensor system implying the COUP-TFII transcription inhibitor. The main role of insulin in the glucose response of genes like the L-PK gene is to induce the glucokinase gene. Glucagon, through cyclic AMP, inhibits L-PK gene transcription mainly through activation of PKA. The PKA catalytic subunit could act by phosphorylating member(s) of the glucose-response complex, or of contiguous transcription factor, e.g. HNF4. In conclusion, through a pluridisciplinary approach ranging from Claude Bernard-derived biology to modern molecular biology, important progress have been made during the last years on the mechanisms of the regulation of gene transcription by glucose in vertebrates.
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PMID:[From the glycogenic function of the liver to gene regulation by glucose]. 987 95

The mouse ob gene encodes leptin, an adipocyte hormone that regulates body weight and energy expenditure. Leptin has potent metabolic effects on fat and glucose metabolism. A mutation of the ob gene results in mice with severe hereditary obesity and diabetes that can be corrected by treatment with the hormone. In lean mice, leptin acutely increases glucose metabolism in an insulin-independent manner, which could account, at least in part, for some of the antidiabetic effect of the hormone. To investigate further the acute effect of leptin on glucose metabolism in insulin-resistant obese diabetic mice, leptin (40 ng x g(-1) x h(-1)) was administered intravenously for 6 h in C57Bl/6J ob/ob mice. Leptin increased glucose turnover and stimulated glucose uptake in brown adipose tissue (BAT), brain, and heart with no increase in heart rate. A slight increase in all splanchnic tissues was also noticed. Conversely, no increase in skeletal muscle or white adipose tissue (WAT) glucose uptake was observed. Plasma insulin concentration increased moderately but neither glucose, glucagon, thyroid hormones, growth hormone, nor IGF-1 levels were different from phosphate-buffered saline-infused C57Bl/6J ob/ob mice. In addition, leptin stimulated hepatic glucose production, which was associated with increased glucose-6-phosphatase activity. Conversely, PEPCK activity was rather diminished. Interestingly, hepatic insulin receptor substrate (IRS)1-associated phosphatidylinositol 3-kinase activity was slightly elevated, but neither the content of glucose transporter GLUT2 nor the phosphorylation state of the insulin receptor and IRS-1 were changed by acute leptin treatment. Hepatic lipid metabolism was not stimulated during the acute leptin infusion, since the content of triglycerides, glycerol, and citrate was unchanged. These findings suggest that in ob/ob mice, the antidiabetic antiobesity effect of leptin could be the result of a profound alteration of glucose metabolism in liver, BAT, heart, and consequently, glucose turnover. Insulin resistance of skeletal muscle and WAT, while not affected by acute leptin treatment, could also be corrected in the long term and account for some of leptin's antidiabetic effects.
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PMID:Acute intravenous leptin infusion increases glucose turnover but not skeletal muscle glucose uptake in ob/ob mice. 1034 14

Glucagon-like peptide-1 (GLP-1) enhances insulin biosynthesis and secretion as well as transcription of the insulin, GLUT2 and glucokinase genes. The latter are also regulated by the PDX-1 homeoprotein. We investigated the possibility that GLP-1 may be having its long-term pleiotropic effects through a hitherto unknown regulation of PDX-1. We found that PDX-1 mRNA level was significantly increased (p<0.01) after 2 hours and insulin mRNA level was subsequently increased (p<0.01) after 3 hours of treatment with GLP-1 (10 nM) in RIN 1046-38 insulinoma cells. Under these experimental conditions, there was also a 1.6-fold increase in the expression of PDX-1 protein in whole cell and nuclear extracts. Overexpression of PDX-1 in these cells confirmed the finding of the wild type cells such that GLP-1 induced a 2-fold increase in whole cell extracts and a 3-fold increase in nuclear extracts of PDX-1 protein levels. The results of electrophoretic mobility shift experiments showed that PDX-1 protein binding to the Al element of the rat insulin II promoter was also increased 2 h post treatment with GLP-1. In summary, we have uncovered a previously unknown aspect to the regulation of PDX-1 in beta cells. This has important implications in the physiology of adult beta cells and the treatment of type 2 diabetes mellitus with GLP-1 or its analogs.
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PMID:Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells. 1049 50

The homeodomain (HD) protein Nkx6.1 is the most beta-cell-specific transcription factor known in the pancreas and its function is critical for the formation of the insulin-producing beta-cells. However, the target genes, DNA-binding site, and transcriptional properties of Nkx6.1 are unknown. Using in vitro binding site selection we have identified the DNA sequence of the Nkx6.1 binding site to be TTAATTG/A. A reporter plasmid containing four copies of this sequence is activated by an Nkx6.1HD/VP16 fusion construct. Full-length Nkx6.1 fails to activate this reporter plasmid in spite of robust interaction with the binding site in vitro. Stable expression of Nkx6.1 in the glucagon-producing alpha-cell-like MSL-G-AN cells induces expression of the endogenous insulin gene in a subset of the cell population. The expression of other known beta-cell-specific factors such as Pax4, Pax6, Pdx1, GLUT2 and GLP1-R is unchanged by the introduction of Nkx6.1.
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PMID:Cloning and DNA-binding properties of the rat pancreatic beta-cell-specific factor Nkx6.1. 1056 13


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