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)

The genomic organization of the human gene encoding the receptor for glucagon-like peptide-1 (GLP-1 (7-37)/(7-36) amide) was analyzed to reveal the relationship to other G-protein-coupled receptors. The coding sequence of the GLP-1 receptor is interrupted by 12 introns. These introns are uniformly distributed within the open reading frame. The length of the introns varies between 6.6 kb and 100 bp, in contrast to the relative constant length of 100 bp of the exons. All of the exon/intron splice junctions characterized followed the consensus GT-AG rule. A comparison of the genomic structure with other related receptor genes indicates that the exon/intron organization is well-conserved among the VIP/ glucagon/secretin receptor family.
Exp Clin Endocrinol Diabetes 1998
PMID:The genomic organization of the human GLP-1 receptor gene. 979 62

The insulinotropic hormone, glucagon-like peptide 1 (GLP-1), which has been proposed as a new treatment for type 2 diabetes, is metabolized extremely rapidly by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP-IV), resulting in the formation of a metabolite, which may act as an antagonist at the GLP-1 receptor. Because of this, the effects of single injections of GLP-1 are short-lasting, and for full demonstration of its antidiabetogenic effects, continuous intravenous infusion is required. To exploit the therapeutic potential of GLP-1 clinically, we here propose the use of specific inhibitors of DPP-IV. We have demonstrated that the administration of such inhibitors may completely protect exogenous GLP-1 from DPP-IV-mediated degradation, thereby greatly enhancing its insulinotropic effect, and provided evidence that endogenous GLP-1 may be equally protected. Preliminary studies by others in glucose-intolerant experimental animals have shown that DPP-IV inhibition greatly ameliorates the condition. GLP-1 has multifaceted actions, which include stimulation of insulin gene expression, trophic effects on the beta-cells, inhibition of glucagon secretion, promotion of satiety, inhibition of food intake, and slowing of gastric emptying, all of which contribute to normalizing elevated glucose levels. Because of this, we predict that inhibition of DPP-IV, which will elevate the levels of active GLP-1 and reduce the levels of the antagonistic metabolite, may be useful to treat impaired glucose tolerance and perhaps prevent transition to type 2 diabetes. The actions of DPP-IV, other than degradation of GLP-1, particularly in the immune system are discussed, but it is concluded that side effects of inhibition therapy are likely to be mild. Thus, DPP-IV inhibition may be an effective supplement to diet and exercise treatment in attempts to prevent the deterioration of glucose metabolism associated with the Western lifestyle.
Diabetes 1998 Nov
PMID:Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. 979 33

Glucagon-like peptide-1 is the main hormonal mediator of the enteroinsular axis. Recently, it has additionally received considerable attention as a possible new treatment for Type II (non-insulin-dependent) diabetes mellitus. Its major disadvantage is that its duration of action is too short to achieve good 24-h metabolic control. Exendin-4, which is produced in the salivary glands of Gila monster lizards, is structurally similar to glucagon-like peptide-1 and shares several useful biological properties with glucagon-like peptide-1. It binds the glucagon-like peptide-1 receptor, stimulates insulin release and increases the cAMP production in beta cells. We report that exendin-4 is a more potent insulinotropic agent when given intravenously to rats than is glucagon-like peptide-1 (ED50 0.19 nmol/kg for glucagon-like peptide-1 vs 0.0143 nmol/kg for exendin-4) and causes a greater elevation in cAMP concentrations in isolated islets. Of even greater interest we found that when given intraperitoneally only once daily to diabetic mice it had a prolonged effect of lowering blood glucose. After 1 week of treatment blood glucoses were 5.0+/-2.6 mmol/l compared to diabetic concentrations of 13.2+/-2.8 mmol/l. After 13 weeks of daily treatment HbA1c was 8.8+/-0.4% in non-treated diabetic animals compared with 4.7+/-0.25% in treated diabetic animals. Blood glucoses also were lower (p < 0.005) and insulin concentrations higher (p < 0.02) in the treated animals. Exendin-4 could therefore be preferable to glucagon-like peptide-1 as a long-term treatment of Type II diabetes.
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PMID:Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations. 1002 77

Glucagon-like peptide-1 (GLP-1) was predicted, based on the proglucagon gene sequence. It is synthesised by specific post-translational processing in L cells (lower intestine) and secreted mainly as "truncated" GLP-1 [7-36 amide] in response to nutrient ingestion. Glucagon-like peptide-1 stimulates insulin secretion during hyperglycaemia, suppresses glucagon secretion, stimulates (pro)insulin biosynthesis and decelerates gastric emptying and acid secretion. On intracerebroventricular injection, GLP-1 reduces food intake in rodents. A GLP-1 receptor antagonist or GLP-1 antisera have been shown to reduce meal-stimulated insulin secretion in animals, suggesting that GLP-1 has a physiological "incretin" function (augmentation of postprandial insulin secretion due to intestinal hormones) for GLP-1. In healthy human subjects, exogenous GLP-1 slows gastric emptying. Consequently, postprandial insulin secretion is reduced, not augmented. Thus, a participation of this peptide in the incretin effect of non-diabetic humans has not been definitely proven. Nevertheless, it has potent insulinotropic activity, especially during hyperglycaemia. This suggests new therapeutic options for patients with Type II (non-insulin-dependent) diabetes mellitus. On the other hand, most L cells are located in the lower small intestine. Potent inhibitory actions of GLP-1 on upper gastrointestinal motor and digestive functions (e. g. gastric emptying and acid secretion) in response to nutrients placed into the ileal lumen, argue for a role of this peptide as an "ileal brake". Malassimilation and diarrhea leading to the erroneous presence of nutrients in the lower gut may, via GLP-1, delay gastric emptying and reduce upper gut motility and thereby prevent further caloric losses.
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PMID:Is glucagon-like peptide 1 an incretin hormone? 1044 29

To determine whether glucagon-like peptide (GLP)-1 increases insulin sensitivity in addition to stimulating insulin secretion, we studied totally depancreatized dogs to eliminate GLP-1's incretin effect. Somatostatin was infused (0.8 microg x kg(-1) x min(-1)) to inhibit extrapancreatic glucagon in dogs, and basal glucagon was restored by intraportal infusion (0.65 ng x kg(-1) x min(-1)). To simulate the residual intraportal insulin secretion in type 2 diabetes, basal intraportal insulin infusion was given to obtain plasma glucose concentrations of approximately 10 mmol/l. Glucose was clamped at this level for the remainder of the experiment, which included peripheral insulin infusion (high dose, 5.4 pmol x kg(-1) x min(-1), or low dose, 0.75 pmol x kg(-1) x min(-1)) with or without GLP-1(7-36) amide (1.5 pmol x kg(-1) x min(-1)). Glucose production and utilization were measured with 3-[3H]glucose, using radiolabeled glucose infusates. In 12 paired experiments with six dogs at the high insulin dose, GLP-1 infusion resulted in higher glucose requirements than saline (60.9+/-11.0 vs. 43.6+/-8.3 micromol x kg(-1) x min(-1), P< 0.001), because of greater glucose utilization (72.6+/-11.0 vs. 56.8+/-9.7 micromol x kg(-1) x min(-1), P<0.001), whereas the suppression of glucose production was not affected by GLP-1. Free fatty acids (FFAs) were significantly lower with GLP-1 than saline (375.3+/-103.0 vs. 524.4+/-101.1 micromol/l, P<0.01), as was glycerol (77.9+/-17.5 vs. 125.6+/-51.8 micromol/l, P<0.05). GLP-1 receptor gene expression was found using reverse transcriptase-polymerase chain reaction of poly(A)-selected RNA in muscle and adipose tissue, but not in liver. Low levels of GLP-1 receptor gene expression were also found in adipose tissue using Northern blotting. In 10 paired experiments with five dogs at the low insulin dose, GLP-1 infusion did not affect glucose utilization or FFA and glycerol suppression when compared with saline, suggesting that GLP-1's effect on insulin action was dependent on the insulin dose. In conclusion, in depancreatized dogs, GLP-1 potentiates insulin-stimulated glucose utilization, an effect that might be contributed in part by GLP-1 potentiation of insulin's antilipolytic action.
Diabetes 1999 May
PMID:Glucagon-like peptide 1 increases insulin sensitivity in depancreatized dogs. 1033 9

As part of an ongoing search for susceptibility genes in obese families, we performed linkage analyses in 101 French families between qualitative and quantitative traits related to morbid obesity and polymorphisms located in or near 15 candidate genes whose products are involved in body weight regulation. These included cholecystokinin A and B receptors (CCK-AR and CCK-BR), glucagon-like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-1 gene (Isl-1), the caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta3-adrenoceptor (beta3-AR), the fatty acid-binding protein 2 (FABP-2), the hormone-sensitive lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2), the insulin receptor substrate-1 (IRS-1), the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the liver carnitine palmitoyltransferase-1 (CPT-1). Phenotypes related to obesity such as BMI, adult life body weight gain, fasting leptin, insulin, fasting glycerol, and free fatty acids were used for nonparametric sib-pair analyses. A weak indication for linkage was obtained between the Isl-1 locus and obesity status defined by a z score over one SD of BMI (n = 226 sib pairs, pi = 0.54 +/- 0.02, P = 0.03). Moreover, a suggestive indication for linkage was found between the Isl-1 locus and BMI and leptin values (P = 0.001 and 0.0003, respectively) and leptin adjusted for BMI (P = 0.0001). Multipoint analyses for leptin trait with Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logarithm of odds (LOD) score is 1.73, coinciding with the Isl-1 locus. Although marginally positive indications for linkage in subgroups of families were found with IRS-1, CPT-1, and HSL loci, our data suggested that these genes are not major contributors to obesity. Whether an obesity susceptibility gene (Isl-1 itself or another nearby gene) lies on chromosome 5q should be determined by further analyses.
Diabetes 1999 Feb
PMID:A sib-pair analysis study of 15 candidate genes in French families with morbid obesity: indication for linkage with islet 1 locus on chromosome 5q. 1033 20

The intestinal hormone glucagon-like peptide-1-(7-36)-amide (GLP-1) has recently been implicated as a possible therapeutic agent for the management of type 2 non-insulin-dependent diabetes mellitus (NIDDM). However, a major difficulty with the delivery of peptide-based agents is their short plasma half-life, mainly due to rapid serum clearance and proteolytic degradation. Using a peptide analog of GLP-1, the GLP-1 receptor antagonist exendin(9-39), we investigated whether the conjugation of a carbohydrate structure to exendin(9-39) would generate a peptide with intact biological activity and improved survival in circulation. The C-terminal portion of exendin(9-39) was reengineered to generate an efficient site for enzymatic O-glycosylation. The modified exendin(9-39) peptide (exe-M) was glycosylated by recombinant UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 1 (GalNAc-T1) alone or in conjunction with a recombinant GalNAc alpha2,6-sialyltransferase (Sialyl-T), resulting in exe-M peptides containing either the monosaccharide GalNAc or the disaccharide NeuAc alpha2,6GalNAc. The nonglycosylated and glycosylated forms of exe-M competed with nearly equal potency (> 90% of control) with the binding of [125I]GLP-1 to human GLP-1 receptors expressed on stably transfected COS-7 cells. In addition, each peptide was equally effective for inhibiting GLP-1-induced cyclic adenosine monophosphate (cAMP) production in vitro. Studies with rats demonstrated that the modified and glycosylated forms of exendin(9-39) could antagonize exogenously administered GLP-1 in vivo. Interestingly, glycosylated exendin(9-39) homologs were more than twice as effective as the nonglycosylated peptide for inhibiting GLP-1-stimulated insulin production in vivo, suggesting a longer functional half-life in the circulation for glycosylated peptides. Results from in vivo studies with 3H-labeled peptides suggest that the glycosylated peptides may be less susceptible to modification in the circulation.
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PMID:Properties of native and in vitro glycosylated forms of the glucagon-like peptide-1 receptor antagonist exendin(9-39). 1038 Nov 45

1-Cells from rodents and humans express different receptors recognizing hormones of the secretin-glucagon family, which--when activated--synergize with glucose in the control of insulin release. We have recently reported that isolated islets from mice homozygous for a GLP-1 receptor null mutation (GLP-1R(-/-)) exhibit a well-preserved insulin-secretory response to glucose. This observation can be interpreted in two different ways: 1) the presence of GLP-1R is not essential for the secretory response of isolated islets to glucose alone; 2) beta-cells in GLP-1R(-/-) pancreases underwent compensatory changes in response to the null mutation. To explore these possibilities, we studied islets from control GLP-IR(+/+) mice in the absence or presence of 1 pmol/l exendin (9-39)amide, a specific and potent GLP-1R antagonist. Exendin (9-39)amide (15-min exposure) reduced glucose-induced insulin secretion from both perifused and statically incubated GLP-1R(+/+) islets by 50% (P < 0.05), and reduced islet cAMP production in parallel (P < 0.001). Furthermore, GLP-1R(-/-) islets exhibited: 1) reduced cAMP accumulation in the presence of 20 mmol/l glucose (knockout islets versus control islets, 12 +/- 1 vs. 27 +/- 3 fmol x islet(-1) x 15 min(-1); P < 0.001) and exaggerated acceleration of cAMP production by 10 nmol/l glucose-dependent insulinotropic peptide (GIP) (increase over 20 mmol/l glucose by GIP in knockout islets versus control islets: 66 +/- 5 vs. 14 +/- 3 fmol x islet(-1) x 15 min(-1); P < 0.001); 2) increased mean cytosolic [Ca2+] ([Ca2+]c) at 7, 10, and 15 mmol/l glucose in knockout islets versus control islets; and 3) signs of asynchrony of [Ca2+]c oscillations between different islet subregions. In conclusion, disruption of GLP-1R signaling is associated with reduced basal but enhanced GIP-stimulated cAMP production and abnormalities in basal and glucose-stimulated [Ca2+]c. These abnormalities suggest that GLP-1R signaling is an essential upstream component of multiple beta-cell signaling pathways.
Diabetes 1999 Oct
PMID:Altered cAMP and Ca2+ signaling in mouse pancreatic islets with glucagon-like peptide-1 receptor null phenotype. 1051 62

Glucagon-like peptide-1 (GLP-1) is an insulinotropic hormone secreted from endocrine cells in the gut mucosa in response to meal ingestion. It is an important incretin hormone; mice with a null mutation in the GLP-1 receptor gene develop glucose intolerance. In addition, it inhibits gastrointestinal secretion and motility and is thought to be part of the "ileal brake" mechanism. Perhaps because of the latter actions it inhibits food intake, but intracerebral injection of GLP-1 also inhibits food intake. The insulinotropic effect is preserved in patients with type 2 diabetes mellitus, in whom also glucagon secretion is inhibited. Thus upon i.v. GLP-1 infusion blood glucose may be completely normalised. Because its actions are glucose-dependent hypoglycaemia does not develop. However, GLP-1 is metabolised extremely rapidly in vivo, initially by a mechanism that involves the enzyme dipeptidyl peptidase-IV. It is currently being investigated how GLP-1 or analogues thereof can be employed in practical diabetes therapy. Promising solutions include the development of stable analogues and inhibitors of the degrading enzyme.
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PMID:Glucagon-like peptide-1, a gastrointestinal hormone with a pharmaceutical potential. 1051 10

A subset of prolyl oligopeptidases, including dipeptidyl-peptidase IV (DPP IV or CD26, EC ), specifically cleave off N-terminal dipeptides from substrates having proline or alanine in amino acid position 2. This enzyme activity has been implicated in the regulation of the biological activity of multiple hormones and chemokines, including the insulinotropic peptides glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Targeted inactivation of the CD26 gene yielded healthy mice that have normal blood glucose levels in the fasted state, but reduced glycemic excursion after a glucose challenge. Levels of glucose-stimulated circulating insulin and the intact insulinotropic form of GLP-1 are increased in CD26(-/-) mice. A pharmacological inhibitor of DPP IV enzymatic activity improved glucose tolerance in wild-type, but not in CD26(-/-), mice. This inhibitor also improved glucose tolerance in GLP-1 receptor(-/-) mice, indicating that CD26 contributes to blood glucose regulation by controlling the activity of GLP-1 as well as additional substrates. These data reveal a critical role for CD26 in physiological glucose homeostasis, and establish it as a potential target for therapy in type II diabetes.
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PMID:Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. 1082 14


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