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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies using pancreas perfusion techniques point to a physiological inhibition of glucagon release by insulin which should be mediated by A cell-residing insulin receptors. In this study, we have characterized the insulin receptors expressed in a hamster glucagonoma A cell line (INR1G9 cells) which is an accepted tool for A cell studies. In receptor binding assays 125I-insulin was displaced with a Kd of 3 nmol/l. Binding was also dependent upon time, temperature and cell number. Insulin concentration-dependently inhibited glucagon secretion (1 mumol: 59%, 100 nmol/l: 71%, 10 nmol/l: 86% of controls). In transient transfection experiments insulin inhibited proglucagon gene transcription (controls: 100%, 100 nmol/l: 54%, 10 nmol/l: 57%, 1 nmol/l: 72%, 100 pmol/l: 96%). Treatment of INR1G9 cells with insulin for 20 h induced a strong downregulation of insulin receptors (controls: 100%, 100 nmol/l: 30%, 10 nmol/l: 70%, 1 nmol/l: 73%, 100 pmol/l: 75%) and of insulin receptor mRNA levels (controls: 100%, 100 nmol/l: 42%, 10 nmol/l: 82%, 1 nmol/l: 84%, 100 pmol/l: 90%). When INR1G9 cells were transiently transfected with a hybrid gene containing the promotor/enhancer region of the human insulin receptor promotor (1,462 bp) linked to the transcriptional reporter gene chloramphenicol acetyltransferase and were treated with insulin it was demonstrated that insulin did not affect the insulin receptor gene transcription. In conclusion, INR1G9 cells express specific receptors for insulin. Insulin inhibits glucagon secretion and proglucagon gene expression via an inhibition of proglucagon gene transcription. Ligand-induced downregulation of the insulin receptor is not mediated by changes of insulin receptor gene transcription and is most likely regulated by posttranscriptional mechanisms, e.g. destabilization of insulin receptor mRNA.
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PMID:Molecular and functional characterization of insulin receptors present on hamster glucagonoma cells. 752 Apr 1

In the present study we have examined the levels and phosphorylation state of the insulin receptor and insulin receptor substrate 1 (IRS-1) as well as the association between IRS-1 and phosphatidylinositol 3-kinase (PI 3-kinase) in the liver and muscle of rats treated with glucagon. There was a decrease in the insulin-stimulated receptor and IRS-1 phosphorylation levels which was paralleled by a reduced association between IRS-1 and PI 3-kinase in vivo in the liver and muscle of glucagon-treated rats. These observations suggest that glucagon, probably acting through cAMP, may impair insulin signaling in the three early steps in insulin action after binding.
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PMID:Effect of glucagon on insulin receptor substrate-1 (IRS-1) phosphorylation and association with phosphatidylinositol 3-kinase (PI 3-kinase). 754

We have investigated the mitogenic effect of three mutant forms of human insulin on insulin-producing beta cells of the developing pancreas. We examined transgenic embryonic and adult mice expressing (i) human [AspB10]-proinsulin/insulin ([AspB10]ProIN/IN), produced by replacement of histidine by aspartic acid at position 10 of the B chain and characterized by an increased affinity for the insulin receptor; (ii) human [LeuA3]insulin, produced by the substitution of leucine for valine in position 3 of the A chain, which exhibits decreased receptor binding affinity; and (iii) human [LeuA3, AspB10]insulin "double" mutation. During development, beta cells of AspB10 embryos were twice as abundant and had a 3 times higher rate of proliferation compared with beta cells of littermate controls. The mitogenic effect of [AspB10]ProIN/IN was specific for embryonic beta cells because the rate of proliferation of beta cells of adults and of glucagon (alpha) cells and adrenal chromaffin cells of embryos was similar in AspB10 mice and controls. In contrast to AspB10 embryos, the number of beta cells in the LeuA3 and "double" mutant lines was similar to the number in controls. These findings indicate that the [AspB10]ProIN/IN analog increased the rate of fetal beta-cell proliferation. The mechanism or mechanisms that mediate this mitogenic effect remain to be determined.
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PMID:A transgene coding for a human insulin analog has a mitogenic effect on murine embryonic beta cells. 760 77

The microsomal triglyceride transfer protein (MTP) is a heterodimeric lipid transfer protein that is required for the assembly and secretion of apoB-containing lipoproteins. In this study, four factors that modulate lipid and lipoprotein metabolism were tested for their ability to regulate MTP levels in HepG2 cells. Of the factors tested, only insulin (> or = 10(-9) M), and high concentrations of glucose (> 30 mM) were found to decrease MTP large subunit mRNA levels. Oleate and glucagon had no effect on MTP mRNA levels. The insulin effect was dose- and time-dependent and was mediated through the insulin receptor. In addition, insulin also decreased protein disulfide isomerase (the small subunit of MTP) mRNA levels, although to a lesser extent. Due to the slow turnover rate of MTP (t1/2 = 4.4 days), short-term insulin treatment (24 h) did not change MTP activity levels, indicating that the regulation of MTP mRNA levels by insulin is unrelated to insulin's acute inhibition of apoB secretion in HepG2 cells. In summary, MTP mRNA levels are acutely regulated by insulin in HepG2 cells; however, sustained changes in MTP mRNA levels would be required to affect MTP protein levels.
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PMID:Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: insulin negatively regulates MTP gene expression. 765 55

Activation of the mitogen-activated protein kinase (MAP kinase) isoforms ERK1 and ERK2 was investigated in rat adipocytes. Kinase activities were measured by using myelin basic protein as substrate after the isoforms were resolved by Mono Q chromatography or by immunoprecipitation with specific antibodies. Insulin increased the activity of both isoforms by 3- to 4-fold. The beta-adrenergic agonist isoproterenol was without effect in the absence of insulin but markedly reduced the increases in ERK1 and ERK2 activities produced by the hormone. MAP kinase activation was also attenuated by forskolin and glucagon, which increase intracellular cAMP, and by dibutyryl-cAMP, 8-bromo-cAMP, and 8-(4-chlorophenylthio)-cAMP. Thus, increasing cAMP is associated with decreased activation of MAP kinase by insulin. Forskolin also inhibited activation of MAP kinase by several agents (epidermal growth factor, phorbol 12-myristate 13-acetate, and okadaic acid) that act independently of insulin receptors. Moreover, forskolin did not inhibit insulin-stimulated tyrosine phosphorylation of the insulin receptor substrate IRS-1. Therefore, the inhibitory effect on MAP kinase did not result from compromised functioning of the insulin receptor. The inhibitory effect was not confined to adipocytes, as forskolin and dibutyryl-cAMP inhibited the increase in MAP kinase activity by phorbol 12-myristate 13-acetate in wild-type CHO cells. In contrast, these agents did not inhibit MAP kinase activity in mutant CHO cells (line 10248) that express a cAMP-dependent protein kinase resistant to activation by cAMP. Our results suggest that activation of cAMP-dependent protein kinase represents a general counter-regulatory mechanism for opposing MAP kinase activation.
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PMID:Increasing cAMP attenuates activation of mitogen-activated protein kinase. 769 90

In pancreatic alpha cells, the existence and function of the insulin receptor has not yet been fully established. In this study, to confirm the expression of functional insulin receptors in pancreatic alpha cells, we performed: 1) insulin receptor binding assay, 2) Northern blot analysis and RT-PCR (reverse transcription-polymerase chain reaction) amplification of insulin receptor mRNA, 3) immunocytochemical staining, 4) biosynthetic labelling of insulin receptor protein using [35S]methionine, 5) analysis of insulin-stimulated autophosphorylation of the insulin receptor in glucagon secreting cell lines, In-R1-G9 and alpha TC clone 6 cells. Glucagon secretion decreased with the addition of insulin in both cells. The receptor binding studies using [125I-Tyr-A14] insulin revealed that both cells possessed a significant number of insulin receptors (In-R1-G9:K1 = 2.1 x 10(9) mol/l-1, K2 = 6.2 x 10(7) mol/l-1, R1 = 0.27 x 10(4), R2 = 1.86 x 10(4) sites/cell; alpha TC clone 6: K1 = 2.1 x 10(9) mol/l-1, K2 = 7.3 x 10(7) mol/l-1, R1 = 0.27 x 10(4), R2 = 1.95 x 10(4) sites/cell). Northern blot analysis as well as RT-PCR amplification showed the mRNA specific for insulin receptor in both cells. By immunocytochemical staining using anti-insulin receptor alpha-subunit antibody, positive immunostaining for insulin receptor was observed in both cells. [35S]Methionine labelling of both cells followed by immunoprecipitation using anti-insulin receptor antibody showed the correct size of the insulin receptor protein. The insulin receptor expressed in these cells underwent autophosphorylation by insulin stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of insulin receptor on clonal pancreatic alpha cells and its possible role for insulin-stimulated negative regulation of glucagon secretion. 779 82

Liver cirrhosis is characterized by an increased incidence of glucose intolerance, diabetes and insulin resistance. We report a cirrhotic man (41 years old) who developed glucose intolerance and diabetes with insulin resistance over a period of six years. This patient suffered from severe portal hypertension with oesophageal varices and a enormously increased spleen volume. The subject underwent prophylactic endoscopic sclerotherapy of oesophageal varices. Splenectomy was performed because of severe piastrinopenia with recurrent nose bleeding. During laparotomy, multiple liver biopsies confirmed diagnosis of liver cirrhosis. Intra-operatory exploration revealed a splenic vein thrombosis. For this reason the planned spleno-renal shunting was not performed and the patient was only submitted to splenectomy. Liver function improved in the month following splenectomy and concomitant decrease of insulin resistance was observed (with a reduction in daily insulin dosage from 126 to 10 I.U.). We propose the following explanations of this event: 1) A decrease of portal and pancreatic vein pressure may have induced a proportional decrease (as already reported) of glucagon secretion. 2) The ameliorated liver function may have induced an improvement of liver glucose, insulin and glucagon metabolism. 3) A reduction of insulin circulating level (proved by a decrease of C Peptide value) may have lessened the insulin receptor down-regulation.
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PMID:[Decrease of insulin resistance after splenectomy in a diabetic patient with liver cirrhosis and portal hypertension. Physiopathologic evaluation]. 784 51

Using enzymatic assay and radioimmunoassay, we studied the functional status of pancreatic islet in 50 patients with acute leukemia. Oral glucose tolerance test and insulin and C peptide release were made in 40 patients before and after treatment. 14 patients who revealed diabetic curve and delayed insulin and C peptide release before treatment showed normal values in 6 after therapy. Five patients with impaired glucose tolerance and decreased insulin and C peptide release before treatment showed normalization of these parameters following therapy. Five patients with normal pretreatment values disclosed abnormal post-treatment results. The remaining 16 patients displayed normal results both before and after therapy. Anti-insulin antibodies were negative, and glucagon level was normal in all the 50 patients. The red cell insulin receptor binding rate analysed in 47 patients was significantly higher than in controls (P < 0.001). We considered that the disturbed glucose metabolism in acute leukemia was not uncommon mainly due to the dysfunction of pancreatic islet beta cells as a result of islet damage by leukemic cells, the effect of corticosteroid and chemotherapy and the preexisting diabetes. Impaired glucose metabolism had no influence on therapeutic effect.
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PMID:Functional status of pancreatic islet in acute leukemia. 786 89

Non-insulin-dependent diabetes mellitus is a complex metabolic disorder that involves numerous biochemical abnormalities, a heterogenous clinical picture, and a polygenic hereditary component. The pathophysiologic state involves increased basal hepatic glucose production, decreased insulin-mediated glucose utilization in target tissues, and altered pancreatic function with decreased beta cell function and enhanced glucagon secretion. Prospective studies indicate that insulin resistance and hyperinsulinemia exist in the prediabetic state at a time when glucose tolerance is normal. When hyperglycemia supervenes, both insulin secretion and insulin-mediated glucose utilization are further compromised, mediated in part by sustained hyperglycemia itself. Insulin resistance may occur at any level in the biologic action of insulin, from initial binding to cell surface receptors to the phosphorylation cascade that is initiated by autophosphorylation of the insulin receptor. Receptors isolated from patients with non-insulin-dependent diabetes mellitus have compromised autophosphorylation-kinase activity when isolated from adipocytes, liver, erythrocytes, and skeletal muscle. The magnitude of the decrease in insulin receptor kinase activity is correlated with the degree of fasting hyperglycemia. However, the defect in insulin receptor kinase activity is normalized after weight reduction or other measures that reduce hyperglycemia, indicating the secondary nature of the defect. Clarification of the mechanisms underlying insulin resistance in non-insulin-dependent diabetes mellitus will lead to new treatment modalities for this disease.
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PMID:Insulin resistance and non-insulin-dependent diabetes mellitus: cellular and molecular mechanisms. 790 Jun 97

The aim of the study was to estimate the effect of hypothermia on (125J)-iodoinsulin binding to liver plasma membranes. Rat liver membranes were prepared from control, normothermic rats (Tr = 35.6 +/- 0.3 degrees C) and hypothermic rats (Tr = 26.5 +/- 0.9 degrees C) and purified according to Havrankowa. In addition, serum insulin and glucagon levels by means of RIA and glucose concentration using the glucose oxidase method were measured. Scatchard analysis was used to determine the kinetic parameters of the hormone receptor interaction. The data showed no significant differences in the affinity of the binding sites but indicated a decrease in receptor concentrations in liver plasma membranes from hypothermic rats. In contrast to changes in serum insulin level which was decreased by about 50% in hypothermic rats blood glucose concentrations did not significantly differ between the hypothermic and normothermic ones. Our results show that in hypothermic rats the hormonal adaptation operates on the level of the number of liver receptors whereas the insulin receptor affinity remains unaffected.
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PMID:Effect of hypothermia on the insulin--receptor interaction in liver plasma membranes. 812 87


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