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

Glucose exerts inverse effects upon the secretory function of islet alpha- and beta-cells, suppressing glucagon release and increasing insulin release. This diverse action may result from differences in glucose transport and metabolism between the two cell types. The present study compares glucose transport in rat alpha- and beta-cells. beta-Cells transcribed GLUT2 and, to a lesser extent, GLUT 1; alpha-cells contained GLUT1 but no GLUT2 mRNA. No other GLUT-like sequences were found among cDNAs from alpha- or beta-cells. Both cell types expressed 43-kDa GLUT1 protein which was enhanced by culture. The 62-kDa beta-cell GLUT2 protein was converted to a 58-kDa protein after trypsin treatment of the cells without detectable consequences upon glucose transport kinetics. In beta-cells, the rates of glucose transport were 10-fold higher than in alpha-cells. In both cell types, glucose uptake exceeded the rates of glucose utilization by a factor of 10 or more. Glycolytic flux, measured as D-[5(3)H]glucose utilization, was comparable in alpha- and beta-cells between 1 and 10 mmol/liter substrate. In conclusion, differences in glucose transporter gene expression between alpha- and beta-cells can be correlated with differences in glucose transport kinetics but not with different glucose utilization rates.
 ...
PMID:Differences in glucose transporter gene expression between rat pancreatic alpha- and beta-cells are correlated to differences in glucose transport but not in glucose utilization. 772 7

Our previous studies have shown that increased expression of GLUT1/erythrocyte and GLUT3/brain type glucose transporter genes in human tumors is associated with cellular transformation. We have now determined the levels of messenger RNAs (mRNAs) encoding these two glucose transporter isoforms as well as that of GLUT2/liver isoform in insulin-, glucagon-, and gastrin-secreting islet cell tumors. Northern blot analysis and reverse transcriptase-polymerase chain reaction revealed the presence of GLUT1 and GLUT3 mRNA in all human islet cell tumors and normal islets examined. In contrast, GLUT2 mRNA, which is present at high levels in normal islets, was not detected in insulinomas or other types of islet cell tumors. These results imply that GLUT1 and GLUT3 are primarily responsible for glucose uptake by these tumors.
 ...
PMID:Abnormal facilitative glucose transporter gene expression in human islet cell tumors. 842 Nov 7

Liver insulin resistance and glucagon-stimulated hepatic glucose production are characteristics of the diabetic state. To determine the potential role of glucose toxicity in these abnormalities, we examined whether phlorizin treatment of streptozotocin-diabetic rats resulted in altered expression of genes involved in key steps of hepatic glucose metabolism. By inhibiting renal tubular glucose reabsorption, phlorizin infusion to diabetic rats induced normoglycaemia, did not significantly alter low circulating insulinaemia, but caused a marked decrease in hyperglucagonaemia. Glucokinase and L-type pyruvate kinase mRNA levels were reduced respectively by 90% and 70% in fed diabetic rats, in close correlation with changes in enzyme activities. Eighteen days of phlorizin infusion partially restored glucokinase mRNA and activity (40% of control levels), but had no effect on L-type pyruvate kinase mRNA and activity. In contrast to the glycolytic enzymes, mRNA and activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase were increased (10- and 2.2-fold, respectively) in fed diabetic rats. Phlorizin administration decreased phosphoenolpyruvate carboxykinase mRNA to values not different from those in control rats, while phosphoenolpyruvate carboxykinase activity remained 50% higher than that in control rats. The 50% rise in liver glucose transporter (GLUT 2) mRNA and protein, produced by diabetes, was also corrected by phlorizin treatment. In conclusion, we propose that phlorizin treatment of diabetic rats may induce a partial shift of the predominating gluconeogenesis, associated with hepatic glucose overproduction, into glycolysis, by correction of impaired pre-translational regulatory mechanisms. This could be essentially mediated through improved pancreatic alpha-cell function and subsequent lowering of hyperglucagonaemia. These observations suggest that glucagon-stimulated hepatic glucose production may result, in part, from glucose toxicity.
 ...
PMID:Phlorizin treatment of diabetic rats partially reverses the abnormal expression of genes involved in hepatic glucose metabolism. 847 72

The subcellular localization of five isoforms of facilitated-diffusion glucose transporters (GLUTs), from GLUT1 to GLUT5, in rat pancreatic islets was studied by immunohistochemistry using rabbit polyclonal antisera against mouse or rat GLUT peptides. Animals were perfusion-fixed with phosphate-buffered 4% paraformaldehyde and the pancreases were removed. Some specimens were embedded in paraffin, serially sectioned, and immunostained for glucagon, insulin, somatostatin, and the GLUTs for light microscopic observation. Others were prepared for immunoelectron microscopy by the post-embedding method. By these methods, GLUT2 immunostaining was observed on the lateral membranes of pancreatic beta-cells, whereas GLUT3 immunoreaction was predominantly localized in the cytoplasm of beta-cells and was not found in alpha-cells. In contrast, GLUT5 immunostaining was preferentially localized in the cytoplasm of alpha-cells compared to that of beta-cells. However, GLUT1 and GLUT4 were either barely or not at all detectable in any cells. These results suggest that rat islets take up glucose by at least three different processes and that blood glucose levels could be modulated differentially by: a high Km glucose transporter, GLUT2, in beta-cells; by a low Km glucose transporter, GLUT3, in beta-cells; and by a low Km glucose transporter, GLUT5, in alpha-cells.
 ...
PMID:Immunohistochemical localization of facilitated-diffusion glucose transporters in rat pancreatic islets. 900 33

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.
 ...
PMID:Insulinoma associated with a case of multiple endocrine neoplasia type I: Functional somatostatin receptors and abnormal glucose-induced insulin secretion. 925 24

Syngeneic islets were transplanted into the liver of streptozotocin (STZ)-induced diabetic LEW.1W rats, and the expression of the glucose transporter isoform GLUT 2, an essential component of the glucose-sensing mechanism of the pancreatic beta-cell, was determined in the grafted islet tissue. Graft-bearing liver was obtained 12, 36, and 60 weeks after transplantation, and tissue sections were immunoperoxidase stained for GLUT 2 and major islet peptides. Islet cell aggregates of different sizes were found in the portal tract and in juxtaposition to the hepatocytes. At all time points, beta-cells in the grafts displayed GLUT 2 expression comparable to that of islets in nondiabetic rats. Islet cells containing immunoreactive insulin and islet amyloid polypeptide were plentiful, while those staining positive for glucagon and somatostatin were scarce in these grafts. The results show that beta-cells in islets engrafted in the liver, although initially exposed to chronic hyperglycemia, have the capability of stably expressing GLUT 2 over long-term periods.
 ...
PMID:Glucose transporter isoform (GLUT) 2 expression in beta-cells of long-term syngeneic islet grafts. 945 76

Glucagon-like peptide-1 (7-36 amide) (GLP-1) is known to increase insulin release when given as a bolus in the fasted and fed state. GLP-1 also increases glucose uptake and lipid synthesis in cultured adipocytes. In this study we investigated the effects of GLP-1 on glucose uptake and on the levels of expression of the facilitative glucose transporters, GLUT1 and GLUT4, in fully differentiated 3T3-L1 adipocytes. Cells were incubated with GLP-1 (10 nM) with or without insulin (10 and 100 nM) for 24 h. Under these conditions, GLP-1 alone caused an increase in basal and acute insulin-stimulated glucose uptake along with an increase in GLUT1 and GLUT4 protein levels. However, there was no change in the expression of GLUT1 and GLUT4 mRNAs. In the absence of GLP-1, prolonged exposure to insulin caused a marked reduction in the levels of GLUT4 mRNA and protein, and an inhibition of glucose uptake after an acute exposure to insulin. This insulin-induced down-regulation of GLUT4 was prevented when GLP-1 was present during the 24-h treatment. In contrast, the acute insulin-stimulated glucose uptake could not be restored by GLP-1. GLP-1 is therefore the first gut hormone shown to be capable of modulating glucose transporter levels in cultured adipocytes.
 ...
PMID:Regulation of glucose transporters and hexose uptake in 3T3-L1 adipocytes: glucagon-like peptide-1 and insulin interactions. 946 Jun 45

GLUT2-null mice are hyperglycemic, hypoinsulinemic, hyperglucagonemic, and glycosuric and die within the first 3 weeks of life. Their endocrine pancreas shows a loss of first phase glucose-stimulated insulin secretion (GSIS) and inverse alpha to beta cell ratio. Here we show that reexpression by transgenesis of either GLUT1 or GLUT2 in the pancreatic beta cells of these mice allowed mouse survival and breeding. The rescued mice had normal-fed glycemia but fasted hypoglycemia, glycosuria, and an elevated glucagon to insulin ratio. Glucose tolerance was, however, normal. In vivo, insulin secretion assessed following hyperglycemic clamps was normal. In vitro, islet perifusion studies revealed that first phase of insulin secretion was restored as well by GLUT1 or GLUT2, and this was accompanied by normalization of the glucose utilization rate. The ratio of pancreatic insulin to glucagon and volume densities of alpha to beta cells were, however, not corrected. These data demonstrate that 1) reexpression of GLUT1 or GLUT2 in beta cells is sufficient to rescue GLUT2-null mice from lethality, 2) GLUT1 as well as GLUT2 can restore normal GSIS, 3) restoration of GSIS does not correct the abnormal composition of the endocrine pancreas. Thus, normal GSIS does not depend on transporter affinity but on the rate of uptake at stimulatory glucose concentrations.
 ...
PMID:Transgenic reexpression of GLUT1 or GLUT2 in pancreatic beta cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion. 1082 33

Pancreatic carcinoma is characterized by poor prognosis and lack of response to conventional therapy for reasons that are not clear. Because of the structural relationship between the exocrine and endocrine pancreas and high concentrations of islet hormones bathing pancreatic tissue, we hypothesized that pancreatic cancer cell proliferation and glucose utilization are regulated by pancreatic islet hormones, particularly insulin. Based on this, the effect of islet hormones on pancreatic cancer cells in vitro was investigated. Five pancreatic cancer cell lines, CD11, CD18, HPAF, PANC-1, and MiaPaCa2 were used to investigate the effect of islet hormones on cell proliferation, glucose utilization, and GLUT-1 expression. Insulin, but not somatostatin and glucagon, induced pancreatic cancer cell growth in a concentration- and time-dependent manner. At concentrations within the range of those in the intrapancreatic vasculature, insulin (10(-10)-10(-8) mol/L) markedly increased [3H]-thymidine incorporation. Insulin significantly enhanced glucose utilization of pancreatic cancer cells before it enhanced cell proliferation. The MAPK kinase inhibitor PD 098059 abolished insulin-stimulated DNA synthesis and partially reduced insulin-stimulated glucose uptake. In contrast, the PI3 kinase inhibitor wortmannin substantially inhibited insulin-induced glucose uptake and partially blocked thymidine incorporation. Furthermore, after 24-hour treatment with insulin, GLUT-I expression in pancreatic cancer cells was markedly increased, indicating that insulin enhances glucose utilization partly through increasing glucose transport. These findings suggest that insulin stimulates proliferation and glucose utilization in pancreatic cancer cells by two distinct pathways. Insulin augments DNA synthesis mainly by MAP kinase activation and glucose uptake mainly by PI3 kinase activation and enhancement of GLUT-I expression. High intrapancreatic concentrations of insulin are likely to play an important role in stimulating pancreatic cancer growth indirectly by increasing substrate availability as well as by direct action as a trophic factor.
 ...
PMID:Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression. 1103 77

There is a progressive impairment in beta-cell function with age. As a result, 19 percent of the U.S. population over the age of 65 is diagnosed with type 2 diabetes mellitus (DM). Glucagon-like peptide-1 (GLP-1) is a potent insulin secretagogue that has multiple synergetic effects on the glucose-dependent insulin secretion pathways of the beta-cell. This peptide and its longer-acting analog exendin-4 are currently under review as treatments for type 2 DM. In our work on the rodent model of glucose intolerance in aging, we found that GLP-1 is capable of rescuing the age-related decline in beta-cell function. We have shown that this is due to the ability of GLP-1 to 1) recruit beta-cells into a secretory mode; 2) upregulate the genes of the beta-cell glucose-sensing machinery; and 3) cause beta-cell differentiation and neogenesis. Our investigations into the mechanisms of action of GLP-1 began by using the reverse hemolytic plaque assay to quantify insulin secretion from individual cells of the RIN 1046-38 insulinoma cell line in response to acute treatment with the peptide. GLP-1 increases both the number of cells secreting insulin and the amount secreted per cell. This response to GLP-1 is retained even in the beta cell of the old (i.e., 22-month), glucose-intolerant Wistar rat, which exhibits a normal, first-phase insulin response to glucose following an acute bolus of GLP-1. Preincubation with GLP-1 (24 hours) potentiates glucose- and GLP-1-dependent insulin secretion and increases insulin content in the insulinoma cells. Treatment of old Wistar rats for 48 hours with GLP-1 leads to normalization of the insulin response and an increase in islet insulin content and mRNA levels of GLUT 2 and glucokinase. PDX-1, a transcriptional factor activator of these three genes, also is upregulated in the insulinoma cell line in aged rats and diabetic mice following treatment with GLP-1. Administration of GLP-1 to old rats leads to pancreatic cell proliferation, insulin-positive clusters, and an increase in beta-cell mass. This evidence led us to believe that GLP-1 is an endocrinotrophic factor. We used an acinar cell line to show that GLP-1 can directly cause the conversion of a putative pro-endocrine cell into an endocrine one. Thus, the actions of GLP-1 on the beta-cell are complex, with possible benefits to the diabetic patient that extend beyond a simple glucose-dependent increase in insulin secretion. The major limitation to GLP-1 as a clinical treatment is its short biological half-life. We have shown that the peptide exendin-4, originating in the saliva of the Gila monster, exhibits the same insulinotropic and endocrinotrophic properties as GLP-1 but is more potent and longer acting in rodents and humans.
 ...
PMID:Glucagon-like peptide-1. 1123 22


1 2 3 Next >>