Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucagon-like peptide 1 stimulates insulin secretion and inhibits glucagon secretion, gastric emptying, and feeding, suggesting it may be biologically useful for the treatment of diabetes. A lizard glucagon-like peptide 1 (GLP-1)-related peptide, exendin 4, binds to the GLP-1 receptor and mimics the actions of GLP-1 in vivo. To determine the genetic relationship between exendin 4 and GLP-1, we analyzed the structure and expression of pancreatic and intestinal proglucagon mRNAs in the reptile Heloderma suspectum. Two different proglucagon cDNAs (lizard proglucagon I (LPI) and lizard proglucagon II (LPII)), with unique 3'-untranslated regions were identified. Two LPI mRNA transcripts, approximately 1.6 and 2.1 kilobases, encoded glucagon and GLP-1 but not GLP-2 and were restricted in expression to the pancreas. In contrast, a 1.1-kilobase LPII mRNA transcript, encoding glucagon, GLP-1, and GLP-2 utilized a different 3'-untranslated region and was expressed in both pancreas and intestine. Lizard proglucagon mRNA transcripts were not detectable by reverse transcription-polymerase chain reaction or Northern blotting in salivary gland. A single class of lizard salivary gland proexendin cDNAs encoded the sequence of exendin 4 and a 45-amino acid exendin NH2-terminal peptide. Exendin mRNA transcripts were expressed in the salivary gland, but not pancreas or intestine. These data demonstrate that GLP-1 and exendin 4 represent related yet distinct peptides encoded by different genes in the lizard.
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PMID:Tissue-specific expression of unique mRNAs that encode proglucagon-derived peptides or exendin 4 in the lizard. 902 Jan 21

As part of an ongoing search for susceptibility loci for NIDDM, we tested 19 genes whose products are implicated in insulin secretion or action for linkage with NIDDM. Loci included the G-protein-coupled inwardly rectifying potassium channels expressed in beta-cells (KCNJ3 and KCNJ7), glucagon (GCG), glucokinase regulatory protein (GCKR), glucagon-like peptide I receptor (GLP1R), LIM/homeodomain islet-1 (ISL1), caudal-type homeodomain 3 (CDX3), proprotein convertase 2 (PCSK2), cholecystokinin B receptor (CCKBR), hexokinase 1 (HK1), hexokinase 2 (HK2), mitochondrial FAD-glycerophosphate dehydrogenase (GPD2), liver and muscle forms of pyruvate kinase (PKL, PKM), fatty acid-binding protein 2 (FABP2), hepatic phosphofructokinase (PFKL), protein serine/threonine phosphatase 1 beta (PPP1CB), and low-density lipoprotein receptor (LDLR). Additionally, we tested the histidine-rich calcium locus (HRC) on chromosome 19q. All regions were tested for linkage with microsatellite markers in 751 individuals from 172 families with at least two patients with overt NIDDM (according to World Health Organization criteria) in the sibship, using nonparametric methods. These 172 families comprise 352 possible affected sib pairs with overt NIDDM or 621 possible affected sib pairs defined as having a fasting plasma glucose value of >6.1 mmol/l or a glucose value of >7.8 mmol/l 2 h after oral glucose load. No evidence for linkage was found with any of the 19 candidate genes and NIDDM in our population by nonparametric methods, suggesting that those genes are not major contributors to the pathogenesis of NIDDM. However, some evidence for suggestive linkage was found between a more severe form of NIDDM, defined as overt NIDDM diagnosed before 45 years of age, and the CCKBR locus (11p15.4; P = 0.004). Analyses of six additional markers spanning 27 cM on chromosome 11p confirmed the suggestive linkage in this region. Whether an NIDDM susceptibility gene lies on chromosome 11p in our population must be determined by further analyses.
Diabetes 1997 Jun
PMID:Genetics of NIDDM in France: studies with 19 candidate genes in affected sib pairs. 916 80

The proglucagon gene encodes several hormones that have key roles in the regulation of metabolism. In particular, glucagon-like peptide (GLP-1), a potent stimulus of insulin secretion, is being developed as a therapy for the treatment of non-insulin-dependent diabetes mellitus. To define structural moieties of the molecule that convey its insulinotropic activity, we have cloned and characterized the proglucagon gene from the amphibian, Xenopus laevis. Unexpectedly, these cDNAs were found to encode three unique glucagon-like-1 peptides, termed xenGLP-1A, xenGLP-1B, and xenGLP-1C in addition to the typical proglucagon-derived hormones glucagon and GLP-2. xenGLP-1A, -1B, and -1C were synthesized and tested for their ability to bind and activate the human GLP-1 receptor (hGLP-1R), and to stimulate insulin release from rat pancreas. All three Xenopus GLP-1-like peptides bind effectively to the hGLP-1R and stimulate cAMP production. Surprisingly, xenGLP-1B(1-30) demonstrated higher affinity for the hGLP-1R than hGLP-1 (IC50 of 1.1 +/- 0.4 nM vs. 4.4 +/- 1.0 nM, respectively, P < 0.02) and was equipotent to hGLP-1 in stimulating cAMP production (EC50 of 0.17 +/- 0.02 nM vs. 0.6 +/- 0. 2 nM, respectively, P > 0.05). Further studies demonstrated that hGLP-1, xenGLP-1A, -1B, and -1C stimulate comparable insulin release from the pancreas. These results demonstrate that despite an average of nine amino acid differences between the predicted Xenopus GLPs and hGLP-1, all act as hGLP-1R agonists.
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PMID:The Xenopus proglucagon gene encodes novel GLP-1-like peptides with insulinotropic properties. 922 87

Basic research on the cellular mechanisms that control the expression of the gene encoding glucagon has led to the discovery of proglucagon. This precursor is processed by tissue-specific proteolysis to produce glucagon in pancreatic alpha-cells and a glucagon-like peptide-1 (GLP-1) in the intestine. GLP-1 is a hormone that is released by intestinal cells into the circulation in response to food intake. GLP-1 and gastric inhibitory peptide (GIP) which has also been termed glucose-dependent insulinotropic peptide appear to account for most of the incretin effect in the augmentation of glucose-stimulated insulin secretion. These two hormones have specific beta-cell receptors that are coupled to GTP binding proteins to induce production of cyclic AMP and activation of cyclic AMP-dependent protein kinase. It is proposed that at least one factor contributing to the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) is desensitization of the GLP-1 receptor on beta-cells. At pharmacological doses, infusion of GLP-1, but not of GLP, can improve and enhance postprandial insulin response in NIDDM patients. Agonists of GLP-1 receptor have been proposed as new potential therapeutic agents in NIDDM patients. The observations that GLP-1 induces both secretion and production of insulin, and that its activities are mainly glucose-dependent, led to the suggestion that GLP-1 may present a unique advantage over sulfonylurea drugs in the treatment of NIDDM.
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PMID:Glucagon-like peptide-1 structure, function and potential use for NIDDM. 939 46

cAMP is required for normal glucose-induced insulin release by pancreatic beta-cells. In a previous study, we showed that cAMP production in beta-cells depends on the expression of receptors for glucagon, glucagon-like peptide 1(7-36) amide [GLP-1(7-36) amide], and glucose-dependent insulinotropic polypeptide. Although the latter two peptides are thought to amplify meal-induced insulin release (incretin effect), the role of glucagon in the regulation of insulin release remains elusive. In the present study, we analyzed the interaction of glucagon with its own receptor and with the glucagon-like peptide 1 (GLP-1) receptor using purified rat beta-cells. Glucagon binding was partially displaced by 1 micromol/l des-His1-[Glu9]glucagon-amide, a glucagon receptor antagonist, and by 1 micromol/l GLP-1. Conversely, GLP-1 binding was competitively inhibited by high glucagon concentrations (Ki = 0.3 micromol/l). Glucagon-induced cAMP production in beta-cells was inhibited both by 1 micromol/l des-His1-[Glu9]glucagon-amide and exendin-(9-39)-amide, a specific GLP-1 receptor antagonist, whereas GLP-1-induced cAMP formation was suppressed only by exendin-(9-39)-amide. Finally, addition of 1 micromol/l exendin-(9-39)-amide to 20 mmol/l glucose-stimulated beta-cells did not antagonize the potentiating effect of 1 nmol/l glucagon, although it prevented 45% of glucagon potentiation when the peptide was administered at 10 nmol/l. Our data suggest that glucagon recognition via two distinct receptors allows pancreatic beta-cells to detect this peptide both when diluted in the systemic circulation and when concentrated as local signal in the islet interstitium.
Diabetes 1998 Jan
PMID:Dual glucagon recognition by pancreatic beta-cells via glucagon and glucagon-like peptide 1 receptors. 942 76

Glucagon-like peptide-1 (GLP-1) acts to control blood glucose via multiple mechanisms, including regulation of insulin and glucagon secretion, gastric emptying, satiety, and peripheral insulin sensitivity. However, the relative importance of these actions for regulation of blood glucose remains unclear. We demonstrate here a gene dosage effect for the incretin action of GLP-1, as heterozygous GLP-1R +/- mice exhibit an abnormal glycemic response to oral glucose challenge in association with reduced circulating levels of glucose-stimulated insulin. In contrast, GLP-1 signaling is not required for normal control of fasting and postabsorptive glucagon levels, and no significant changes were detected in the tissue content of pancreatic and intestinal proglucagon mRNA, glucagon-like immunoreactivity, or GLP-1 in GLP-1R -/- or +/- mice. Despite the demonstration that GLP-1 stimulates proinsulin gene transcription, pancreatic insulin mRNA transcripts were similar in wild-type and GLP-1R -/- mice. Furthermore, despite suggestions that GLP-1 regulates peripheral glucose disposal, whole-body glucose utilization was similar in wild-type and GLP-1R -/- mice under both basal and hyperinsulinemic conditions. These observations demonstrate that of the numerous physiological activities ascribed to GLP-1, only the incretin effect on pancreatic beta-cells appears essential for regulation of glucose homeostasis in vivo.
Diabetes 1998 Apr
PMID:Identification of glucagon-like peptide 1 (GLP-1) actions essential for glucose homeostasis in mice with disruption of GLP-1 receptor signaling. 956 97

Previous work suggested that glucagon-like peptide 1 (GLP-1) can acutely regulate insulin secretion in two ways, 1) by acting as an incretin, causing amplification of glucose-induced insulin release when glucose is given orally as opposed to intravenous glucose injection; and 2) by keeping the beta-cell population in a glucose-competent state. The observation that mice with homozygous disruption of the GLP-1 receptor gene are diabetic with a diminished incretin response to glucose underlines the first function in vivo. Isolated islets of Langerhans from GLP-1 receptor -/- mice were studied to assess the second function in vitro. Absence of pancreatic GLP-1 receptor function was observed in GLP-1 receptor -/- mice, as exemplified by loss of [125I]GLP-1 binding to pancreatic islets in situ and by the lack of GLP-1 potentiation of glucose-induced insulin secretion from perifused islets. Acute glucose competence of the beta-cells, assessed by perifusing islets with stepwise increases of the medium glucose concentration, was well preserved in GLP-1 receptor -/- islets in terms of insulin secretion. Furthermore, neither islet nor total pancreatic insulin content was significantly changed in the GLP-1 receptor -/- mice when compared with age-and sex-matched controls. In conclusion, mouse islets exhibit preserved insulin storage capacity and glucose-dependent insulin secretion despite the loss of functional GLP-1 receptors. The results demonstrate that the glucose responsiveness of islet beta-cells is well preserved in the absence of GLP-1 receptor signaling.
Diabetes 1998 Apr
PMID:Mouse pancreatic beta-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene. 956 99

Glucagon-like peptide-1 (GLP-1 is an insulinotropic hormone, which is secreted from endocrine cells of the intestinal mucosa in relation to meal ingestion. It plays an important role as an incretin hormone; thus, mice with a null-muation in the gene encoding the GLP-1 receptor are glucose intolerant. In addition, GLP-1 inhibits gastrointestinal secretion and motility and is thought to act as one of the hormones of the "ileal brake". The insulinotropic effect of GLP-1 is preserved in patients with non insulin-dependent diabetes mellitus (NIDDM) and, because GLP-1 also inhibits glucagon secretion, it effectively lowers blood glucose in such, and given as an intravenous infusion it may completely normalise blood glucose. Furthermore, because its actions on insulin and glucagon secretion are dependent on the blood glucose levels it will not cause hypoglycemia. Efforts are therefore currently being made to employ GLP-1 or analogues thereof in clinical diabetes treatment, not least because recent investigations have shown that GLP-1, perhaps due to its gastrointestinal actions, is capable of reducing food intake in humans.
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PMID:[Glucagon-like peptide-1--a new hormone and a new drug]. 957 9

Disruption of glucagon-like peptide-1 (GLP-1) receptor signaling in mice results in mild glucose intolerance, principally due to elimination of the incretin effect of GLP-1. Despite the inhibitory effects of GLP-1 on food intake, 6- to 8-week-old GLP-1 receptor -/-(GLP-1R-/-) mice were not obese and did not exhibit disturbances of feeding behavior. As both diabetes and obesity frequently become more phenotypically evident in older rodents, we studied the consequences of aging and a high fat diet on glucose control and body weight in GLP-1R-/- mice. No evidence of obesity or deterioration in glucose control was detected in 11- and 16-month-old GLP-1R-/- mice (mean weight, 34.7 +/- 2.0, 30.5 +/- 1.5, and 34.6 +/- 2.8 g in male and 25.3 +/-1.6, 28.4 +/-1.2, and 31.9 +/- 2.9 g in female GLP-1R+/+, GLP-1R+/-, and GLP-1R-/- mice, respectively; P = NS). After 18 weeks of high fat feeding, GLP-1R-/- mice gained similar (males) or less (females) weight than age- and sex-matched CD1 controls. No significant deterioration in glucose tolerance was observed after high fat feeding in GLP-1R-/- mice. These observations demonstrate that long term disruption of GLP-1 signaling in the central nervous system and peripheral tissues of older mice is not associated with the development of obesity or deterioration in glucose homeostasis.
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PMID:Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor -/- mice. 964 85

Incretins are gastrointestinal hormones that act on the pancreas to potentiate glucose-stimulated insulin secretion. Despite the physiological importance of the enteroinsular axis, disruption of glucagon-like peptide (GLP)-1 action is associated with only modest glucose intolerance in GLP-1 receptor -/- (GLP-1R -/-) mice. We show here that GLP-1R -/- mice exhibit compensatory changes in the enteroinsular axis via increased glucose-dependent insulinotropic polypeptide (GIP) secretion and enhanced GIP action. Serum GIP levels in GLP-1R -/- mice were significantly elevated versus those in +/+ control mice after an oral glucose tolerance test (369 +/- 40 vs. 236 +/- 28 pmol/l; P < or = 0.02). Furthermore, GIP perfusion of mice pancreas and isolated islets in the presence of elevated glucose concentrations elicited a significantly greater insulin response in GLP-1R -/- than in +/+ mice (P < or = 0.02-0.05). In contrast, no significant perturbation in the insulin response to perfused glucagon was detected under conditions of low (4.4 mmol/l) or high (16.6 mmol/l) glucose in GLP-1R -/- mice. Total pancreatic insulin but not glucagon content was significantly reduced in GLP-1R -/- compared with in +/+ mice (77 +/- 9 vs. 121 +/- 10 pmol/mg protein; P < or = 0.005). These observations suggest that upregulation of the GIP component of the enteroinsular axis, at the levels of GIP secretion and action, modifies the phenotype resulting from interruption of the insulinotropic activity of GLP-1 in vivo.
Diabetes 1998 Jul
PMID:Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice. 964 27


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