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)

As part of an ongoing search for diabetes susceptibility loci, we tested linkage with non-insulin-dependent diabetes mellitus (NIDDM) for 19 candidate loci or regions chosen for their potential to affect directly or indirectly the action of insulin. Loci were associated with insulin resistance, known effects on lipid metabolism, or effects on glucose metabolism or insulin action. Loci included the insulin-responsive (GLUT4) glucose transporter, hexokinase 2, glucagon, growth hormone, insulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase, hepatic and muscle forms of pyruvate kinase, hepatic phosphofructokinase, the apolipoprotein B and the apolipoprotein A2 cluster, lipoprotein lipase, hepatic triglyceride lipase, the very-low-density-lipoprotein receptor, and the Pima insulin resistance locus on chromosome 4. For several candidates, no specific informative marker was available; consequently, we tested the surrounding region with highly informative markers. These regions included the diabetes-associated ras-like gene, rad, and the cholesterol ester-transfer gene, both mapped to chromosome 16. Additionally, we tested for linkage with markers at the tumor necrosis factor-alpha gene and the Friedreich's ataxia region. All regions were tested for linkage with microsatellite polymorphisms in > 450 individuals from a minimum of 16 Caucasian families under parametric (LINKAGE 5.1) and nonparametric (affected pedigree member) models.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Linkage analysis of 19 candidate regions for insulin resistance in familial NIDDM. 758 21

Human GLUT4 protein expression in muscle and adipose tissues of transgenic mice decreases plasma insulin and glucose levels and improves glucose tolerance compared with nontransgenic controls (Liu, M.-L., Gibbs, E. M., McCoid, S. C., Milici, A. J., Stukenbrok, H. A., McPherson, R. K., Treadway, J. L., and Pessin, J. E. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 11346-11350). We examined the basis of improved glycemic control in hGLUT4 transgenic mice by determining glucose homeostasis and metabolic profiles in vivo. Glucose turnover experiments indicated a 1.4-fold greater systemic glucose clearance in hGLUT4 mice relative to controls (p < 0.05), whereas hepatic glucose production was similar despite 26% lower (p < 0.05) glucose levels. Glucose infusion rate during an euglycemic-hyperinsulinemic clamp was 2-fold greater (p < 0.05) in hGLUT4 mice versus controls, and skeletal muscle and heart glycogen content were increased 3-5-fold (p < 0.05). The increased peripheral glucose clearance in hGLUT4 mice was associated with increased (25-32%) basal and insulin-stimulated glucose transport rate in soleus muscle (p < 0.01), and increased muscle plasma membrane-associated GLUT4 protein. Fed hGLUT4 mice displayed 20-30% lower plasma glucose and insulin levels (p < 0.05) and 43% elevated glucagon levels (p < 0.001) compared with controls. Triglycerides, free fatty acids, and beta-hydroxy-butyrate were elevated 43-63% (p < 0.05) in hGLUT4 mice due to hypoinsulinemia-induced lipolysis. Free fatty acids and beta-hydroxybutyrate levels in hGLUT4 mice increased further upon fasting, and skeletal muscle glycogen levels decreased markedly compared with controls. The data demonstrate that high level expression of hGLUT4 increases systemic glucose clearance and muscle glucose utilization in vivo and also results in marked compensatory lipolysis and muscle glycogenolysis during a fast.
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PMID:Enhanced peripheral glucose utilization in transgenic mice expressing the human GLUT4 gene. 796 94

We evaluated the hormonal and metabolic responses of denervated pancreas allografts in nine volunteers 3 to 12 months after the transplant (initial) and again 1 year later (follow-up). Eight of the patients received simultaneous pancreas-kidney transplants. The glucose clamp technique was used to create a square wave of hyperglycemia 5.5 mmol/L above the basal glucose level for 2 hours. A biphasic insulin response was evident in each subject, both initially and at follow-up. The initial plasma insulin response was fourfold higher in patients with pancreas-kidney transplants than in normal volunteers. However, the plasma insulin response of the patients with pancreas-kidney transplants at the follow-up study was more similar to that of the normal controls. The plasma glucagon levels were elevated in follow-up clamp studies. Hepatic glucose production and glucose disposal were similar in both studies. At the follow-up examination only, GLUT4, the major insulin-sensitive glucose transporter, was measured in muscle homogenates by immunoblotting. GLUT4 levels in the patients with pancreas-kidney transplants were only 55% as abundant as in normal volunteers. This may be due, in part, to immunosuppressive therapy or to persistent, albeit reduced, levels of hyperinsulinemia even 2 years after transplantation. We concluded that, despite systemic drainage of the pancreas and immunosuppressive therapy, pancreatic insulin secretion, peripheral insulin levels, and muscle insulin responsiveness are restored toward normal levels approximately 2 years after the transplant.
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PMID:Sequential evaluation of islet cell responses to glucose in the transplanted pancreas in humans. 841 90

The immune and endocrine mediators that are released during sepsis (e.g., tumor necrosis factor [TNF] alpha, interleukin [IL]-1, IL-6, transforming growth factor [TGF] beta, prostaglandin [PG] E2, catecholamines, vasopressin, glucagon, insulin, and glucocorticoids) can produce inappropriate detrimental cellular responses contributing to exacerbation of septic injury. Examples of such sepsis-related inappropriate responses are: exaggerated hepatic acute-phase protein (APP) expression and release skeletal muscle insulin resistance, and suppressed T-lymphocyte proliferation. The studies discussed in this article present evidence that the generation of the sepsis-related hepatic, skeletal muscle, and T-lymphocyte responses emanate from alterations in intracellular Ca2+ (Ca2+i) homeostasis. In hepatocytes, there is indication of a sepsis-mediated increase in Ca2+ influx from the extracellular milieu leading to a sustained increase in the apparent resting cell Ca2+i concentration ([Ca2+]i) and its depressed elevation on stimulation with Ca2+-mobilizing hormones such as catecholamines and vasopressin. These Ca(2+)- related changes can affect not only the signaling pathways in which Ca2+i itself serves as a signaling component, but also the signaling systems turned on by other sepsis-induced agonists which may not be dependent on Ca2+ signaling. TGF-beta, IL-1, TNF alpha, and IL-6 activate a primarily protein kinase C (PKC)-dependent intracellular signal system for the elicitation of a normal hepatic APP response (APPR). The increased apparent basal [Ca2+]i in sepsis can hypersensitize PKC activation and thus lead to an exaggerated APPR. In the skeletal muscle, an evident increase in Ca2+ membrane flux during sepsis pointed to an increase in the basal [Ca2+]i resulting from a plausible cytokine-mediated overactivation of the voltage-sensitive Ca2+ channels. The increased basal [Ca2+]i can negatively modulate the insulin-mediated stimulation of GLUT4-dependent glucose transport despite the possibility that Ca2+i might not participate as a component in the insulin-receptor-regulated signaling pathway. Increased [Ca2+]i in skeletal myocytes can either directly promote the phosphorylation of GLUT4 or prevent its dephosphorylation, both of which effectively block insulin stimulation of glucose uptake, thereby contributing to insulin resistance. In T lymphocytes, septic injury appears to induce an attenuation in the mitogen and, thus, presumably a T-cell antigen receptor (TCR)-mediated elevation in [Ca2+]i without affecting the basal [Ca2+]i. This decrease in TCR-related Ca2+i mobilization evidently contributes to the suppression of T lymphocyte proliferation during sepsis, probably via an in vivo action of prostaglandin (PG) E2 on the T cells during sepsis. The blockade of PGE2 production after indomethacin administration to septic animals prevents alterations in both T-cell Ca2+i mobilization and proliferation. PGE2 probably acts through its second messenger, cyclic adenosine 3'5'-monophosphate, which can antagonize Ca2+i signaling in T cells.
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PMID:Alterations in calcium signaling and cellular responses in septic injury. 868 77

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.
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PMID:Immunohistochemical localization of facilitated-diffusion glucose transporters in rat pancreatic islets. 900 33

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.
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PMID:Regulation of glucose transporters and hexose uptake in 3T3-L1 adipocytes: glucagon-like peptide-1 and insulin interactions. 946 Jun 45

Glucagon-like peptide-1 (G LP-1) is an incretin with glucose-dependent insulinotropic and insulin-independent antidiabetic properties that exerts insulin-like effects on glucose metabolism in rat liver, skeletal muscle, and fat. This study aimed to search for the effect of a prolonged treatment, 3 ds, with GLP-1 on glucotransporter GLUT2 expression in liver, and on that of GLUT4 in skeletal muscle and fat, in rats. Normal rats and streptozotocin-induced type 1 and type 2 diabetic models were used; diabetic rats were also treated with insulin for comparison. In normal rats, GLP-1 treatment reduced in the three tissues the corresponding glucotransporter protein level, without modifying their mRNA. In the type 2 diabetic model, GLP-1, like insulin, stimulated in liver and fat only the glucotransporter translational process, while in the muscle an effect at the GLUT4 transcriptional level was also observed. In the type 1 diabetic model, GLP-1 apparently exerted in the liver only a posttranslational effect on GLUT2 expression; in muscle and fat, while insulin was shown to have an action on GLUT4 at both transcriptional and translational levels, the effect of GLP-1 was restricted to glucotransporter translation. In normal and diabetic rats, exogenous GLP-1 controlled the glucotransporter expression in extrapancreatic tissues participating in the overall glucose homeostasis-liver, muscle, and fat-where the effect of the peptide seems to be exerted only at the translational and/or posttranslational level; in muscle and fat, the presence of insulin seems to be required for GLP-1 to activate the transcriptional process. The stimulating action of GLP-1 on GLUT2 and GLUT4 expression, mRNA or protein, could be a mechanism by which, at least in part, the peptide exerts its lowering effect on blood glucose.
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PMID:Effect of GLP-1 treatment on GLUT2 and GLUT4 expression in type 1 and type 2 rat diabetic models. 1172 Feb 53

It is well known that pinealectomy induces in rats a diminished glucose tolerance, insulin resistance, a reduction in GLUT4 content in adipose and muscular tissues, a decrease in hepatic and muscular glycogenesis, impairment of glucagon action and an increase in blood pyruvate concentration. In addition, it has been shown that melatonin suppresses insulin secretion in several experimental conditions. The objective of the present study was to investigate the daily rhythm of glucose-induced insulin secretion and glucose oxidation by isolated pancreatic islets and to investigate the effect of chronic absence of melatonin (30 days of pinealectomy) on this rhythmic process. The data obtained confirmed the presence of a strong 24-hr rhythm of insulin secretion by isolated pancreatic islets. In addition, it was demonstrated that the glucose-metabolizing ability of the B-cell follows a daily rhythm phase locked to insulin secretion rhythm. Most interesting, however, was the demonstration that the daily rhythmic processes of insulin secretion and B-cell -[U-14C]-glucose oxidation by isolated pancreatic islets is completely modified by the chronic absence of the pineal gland. Thus, pinealectomy induced in all groups an increase in 24-hr mean glucose-stimulated insulin secretion and [U-14C]-glucose oxidation, in addition to some alterations in the rhythmic amplitude and a remarkable phase-advancing of the daily curves for 8.3 mm glucose (a condition similar to that observed in fed animals and where the B-cells are supposedly more active). These observations strongly suggest that the presence of the pineal gland may be necessary for the proper synchronization of these metabolic rhythms with other circadian rhythms like activity-rest and feeding.
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PMID:Daily rhythm of glucose-induced insulin secretion by isolated islets from intact and pinealectomized rat. 1222 Mar 33

This chapter describes a physiological and profound effect of amylin to inhibit meal-related glucagon secretion. Glucagon is processed from a large precursor, proglucagon, in a tissue-specific manner in pancreatic alpha-cells. In addition to amino acid nutrient stimuli, glucagon is also secreted in response to stressful stimuli, such as hypoglycemia and hypovolemia. Glucagon primarily acts on liver to initiate glycogenolysis and gluconeogenesis, resulting in a rapid increase in endogenous production of glucose. With longer stimulation, glucagon action at the liver results in a glucose-sparing activation of free fatty acid oxidation and production of ketones. During hypoglycemia, glucagon secretion is clearly a protective feed-back, defending the organism against damaging effects of low glucose in brain and nerves (neuroglycopenia). Amino acid-stimulated glucagon secretion during meals has a different purpose: amino acids stimulate insulin secretion, which mobilizes amino acid transporters and effects their storage in peripheral tissues. At the same time, insulin obligatorily recruits GLUT4 glucose transporters in muscle and fat. The hypoglycemic potential of such GLUT4 mobilization is averted only by the simultaneous liberation of endogenous glucose in response to feedforward (anticipatory) glucagon secretion. The effect of amylin and its agonists to inhibit amino acid-stimulated glucagon secretion is both potent (EC50 = 18 pM) and profound (approximately 70% inhibition). This glucagonostatic action appears to be extrinsic to the pancreatic islet, occurring in intact animals and in patients, but not in isolated islets or isolated perfused pancreas preparations. On the other hand, the effect of hypoglycemia to stimulate glucagon secretion, which is intrinsic to the islet and occurs in isolated preparations, is not affected by amylin or its agonists. The physiological interpretation of these actions fits with the general concept, illustrated in Fig. 1, that amylin and insulin secreted in response to meals shut down endogenous production as a source of glucose, in favor of that derived from the meal. Amylin and insulin secreted in response to nutrients already absorbed act as a feedback switch for glucose sourcing. The insulinotropic (incretin) gut peptides, GLP-1 and GIP, secreted in response to yet-to-be-absorbed intraluminal nutrients, amplify beta-cell secretion and thereby activate the glucose sourcing switch in a feedforward manner. Hypoglycemia-stimulated glucagon secretion and nutrient (amino acid)-stimulated glucagon secretion are two clearly different processes, differently affected by amylin. The balance of glucose fluxes is disturbed in diabetic states, partly as a result of inappropriate glucagon secretion. Although glucose production due to glucagon secreted in response to hypoglycemia is normal or even reduced in diabetic patients, the secretion of glucagon (and production of endogenous glucose) in response to protein meals is typically exaggerated. Absence of appropriate beta-cell suppression of alpha-cell secretion has been invoked as a mechanism that explains exaggerated glucagon responses, especially prevalent in patients with deficient beta-cell secretion (type 1 diabetes and insulinopenic type 2 diabetes). A proposed benefit of insulin replacement therapy is the reduction of absolute or relative hyperglucagonemia. High glucagon is said to be necessary for ketosis in severe forms of diabetes. A further benefit of reversing hyperglucagonemia is reduction of the excessive endogenous glucose production that contributes to fasting and postprandial hyperglycemia in diabetes. The idea that amylin is a part of the beta-cell drive that normally limits glucagon secretion after meals fits with the observation that glucagon secretion is exaggerated in amylin-deficient states (diabetes characterized by beta-cell failure). This proposal is further supported by the observation that postprandial glucagon suppression is restored following amylin replacement therapy in such states. These observations argue for a therapeutic case for amylin replacement in patients in whom excess glucagon action contributes to fasting and postprandial hyperglycemia and ketosis. The selectivity of amylin's glucagonostatic effect (wherein it is restricted to meal-related glucagon secretion, while preserving glucagon secretion and glucagon action during hypoglycemia) may confer additional benefits; the patient population amenable to amylin replacement therapy is likely to also be receiving insulin replacement therapy, and is thereby susceptible to insulin-induced hypoglycemia. Most explorations of the biology of amylin have used the endogenous hormone in the cognate species (typically rat amylin in rat studies). Clinical studies have typically employed the amylinomimetic agent pramlintide. Studies of amylinomimetic effects on glucagon secretion include effects of rat amylin in anesthetized non-diabetic rats (Jodka et al., 2000; Parkes et al., 1999; Young et al., 1995), effects of rat amylin in isolated perfused rat pancreas (Silvestre et al., 1999), effects of pramlintide in anesthetized non-diabetic rats (Gedulin et al., 1997b,c,d, 1998), effects of pramlintide in patients with type l diabetes (Fineman et al., 1997a,b,c,d, 1998a; Holst, 1997; Nyholm et al., 1996, 1997a,b,c; Orskov et al., 1999; Thompson and Kolterman, 1997), and effects in patients with type 2 diabetes (Fineman et al., 1998b). In addition, effects of amylin antagonists have been observed in isolated preparations (Silvestre et al., 1996), and effects of antagonists or neutralizing antibody have been determined in whole-animal preparations (Gedulin et al., 1997a,e,f).
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PMID:Inhibition of glucagon secretion. 1649 45

GLP-1 has anorectic properties and regulates fuel homeostasis through both its insulinotropic and insulinotrophic actions and effects in extrapancreatic tissue. This study is aimed at characterizing the response to GLP-1 of adipocytes from obese patients, in terms of D-glucose transport and lipid metabolism, in comparison with data from normal subjects. Adipocytes were obtained by enzymatic digestion from the abdominal fat tissue of 25 morbidly obese patients and 8 normal subjects undergoing bariatric or inguinal hernia surgery, respectively. Basal GLUT4 expression, D-glucose transport, glycerol release and lipogenesis were measured in cells treated, when required, with 10(-12)-10(-9) M GLP-1, insulin, glucagon and the GLP-1 structurally related peptides, exendin-4 and exendin-9. In obese patients, versus normal subjects, a trend towards lower values was found in GLUT4 protein or mRNA, although the differences were not statistically significant; insulin-stimulated glucose uptake was higher and cells did not respond to GLP-1, while both exendins (10(-10) and 10(-9) M) exerted an inhibitory action; basal lipolysis was higher and so was the effect of GLP-1 and glucagon, whereas insulin abolished the lipolytic action of all peptides; both basal lipogenesis and the response to insulin were higher while GLP-1 and exendin-4 were ineffective. These results document the analogies and dissimilarities between the response to GLP-1, exendin-4 and exendin-9, as well as to insulin and glucagon, relative to glucose transport and lipid metabolism of fat tissue from obese patients versus normal subjects, the reduced lipogenic effect and enhanced lipolytic action of GLP-1 being, perhaps, adequate for its therapeutic use in obesity.
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PMID:Effect of GLP-1 on D-glucose transport, lipolysis and lipogenesis in adipocytes of obese subjects. 1668 26


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