Truncated glucagon‐like peptide I, an insulin‐releasing hormone from the distal gut

Holst, Jens J.; Ørskov, Cathrine; Nielsen, O.B.; Schwartz, Thue W.

doi:10.1016/0014-5793(87)81430-8

Cited by 542 publications

(281 citation statements)

References 19 publications

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“…However, the arginine residue at position 6 of GLP-1 was a possible monobasic cleavage site [4]. The isolation and partial sequence analysis of the first 17 amino acids of pig intestinal GLP-1 confirmed that cleavage does indeed occur at this residue 6 [5]. However, the proglucagon sequence 104 to 110 is Val-Lys-Gly-Arg-Gly-Arg-Arg.…”

Section: Introductionmentioning

confidence: 87%

Isolation and characterisation of GLP‐1 7–36 amide from rat intestine Elevated levels in diabetic rats

et al. 1988

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Glucagon-like peptide-1 (GLP-I) was purified to homogeneity by HPLC and anion-exchange chromatography. A molecular mass of 3297.4 Da was obtained by FAB mass spectrometry which corresponded exactly to GLP-1 7-36 NH 2, providing evidence that amidation occurs at an arginine residue during the post-translational processing of GLP-1. The distribution of GLP-1 7-36 NI-I2-1ike immunoreactivity (GLP-1 7-36 NH 2 IR) was determined in the rat gastrointestinal tract. Highest concentrations were found in terminal ileum and colon. Streptozocin-induced diabetic rats, who showed a significant increase in food intake, had a significant increase of GLP-1 7-36 NH 2 IR in the colon.

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Section: Introductionmentioning

confidence: 87%

Isolation and characterisation of GLP‐1 7–36 amide from rat intestine Elevated levels in diabetic rats

et al. 1988

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“…This peptide was strongly insulinotropic. When sequenced, we found that it represented a truncated form of GLP-1, corresponding to residues 7-37 [24] of the predicted molecule. Clearly, natural GLP-1 was not processed at the dibasic site in proglucagon, but at a monobasic site corresponding to residue no.…”

Section: Discovery Of Glucagon-like Peptide-1mentioning

confidence: 99%

“…Clearly, natural GLP-1 was not processed at the dibasic site in proglucagon, but at a monobasic site corresponding to residue no. 77 in proglucagon [24]. In addition, natural GLP-1 turned out to be C-terminally amidated [25], hence the designation 'GLP-1 (7-36) amide.'…”

Section: Discovery Of Glucagon-like Peptide-1mentioning

confidence: 99%

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

2006

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The incretin hormones are intestinal polypeptides that enhance postprandial insulin secretion. Gastric inhibitory polypeptide (GIP) was initially thought to regulate gastric acid secretion, whereas glucagon-like peptide-1 (GLP-1) was discovered as a result of a systematic search for intestinal insulinotropic products of proglucagon gene expression. The incretin effect is markedly impaired or absent in patients with type 2 diabetes because of decreased secretion of GLP-1 and a loss of the insulinotropic effects of GIP. Metabolic control can be restored or greatly improved by administration of exogenous GLP-1, but this peptide is almost immediately degraded by dipeptidyl peptidase IV (DPP-IV), and therefore has little clinical value. DPP-IV-resistant analogues (incretin mimetics) have been identified or developed, and inhibitors of DPP-IV have also proved effective in protecting endogenous GLP-1 (and GIP) from degradation. Both principles have been tested in clinical studies. The incretin mimetics, administered by sc injection, have demonstrated lasting improvement in HbA 1 c in patients insufficiently treated with conventional oral therapy, and their use has been associated with steady weight loss for up to 2 years. The DPP-IV inhibitors, given once or twice daily by mouth, also appear to provide lasting improvement in HbA 1 c, but are weight-neutral. The first incretin mimetic has reached the market in the US, and applications for approval of the first inhibitors are expected to be filed early in 2006.

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“…4,44,45 The binding of GLP-1 to its specific receptor (GLP-1R) on pancreatic b-cells leads to the activation of adenylate cyclase activity and production of cAMP. Subsequently, GLP-1 stimulates insulin secretion via mechanisms that include an increase in intracellular Ca 2+ levels resulting from GLP-1-dependent influx of extracellular Ca 2+ through voltage-dependent Ca 2+ and direct effects on b-cell insulin storage granule exocytosis that occurs downstream to ATP and intracellular Ca 2+ increase.…”

Section: Discussionmentioning

confidence: 99%

“…4 GLP-1 originates from enzymatic processing of the glucagon precursor, pro-glucagon, a 180-amino-acid peptide. This conversion is catalyzed by the protein convertase PC3 to yield an active GLP-1 (ref.…”

Section: Introductionmentioning

confidence: 99%

Effective and safe gene-based delivery of GLP-1 using chitosan/plasmid-DNA therapeutic nanocomplexes in an animal model of type 2 diabetes

et al. 2011

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates blood glucose level post-prandially. It has been proposed that GLP-1 can be used in type 2 diabetes (T2D) mellitus treatment because of its insulinotropic action. Despite its remarkable advantages, GLP-1 suffers the disadvantage of an extremely short half-life owing to its degradation by the dipeptidyl peptidase IV protease. One way of overcoming this drawback is GLP-1 gene delivery. Here we show effective and safe gene-based delivery of GLP-1 using chitosan/plasmid-DNA therapeutic nanocomplexes (TNCs) in Zucker diabetic fatty (ZDF) animal model of T2D. The expression plasmid fused the GLP-1 gene to a Furin cleavage site was driven by a cytomegalovirus promoter/enhancer. TNCs were prepared by mixing this plasmid with chitosans of specific molecular weight (MW), degree of deacetylation (DDA) and ratio of chitosan amine to DNA phosphate (N:P ratio). Animals injected with the TNC chitosan 92-10-5 (DDA-MW-N:P) showed GLP-1 plasma levels of about fivefold higher than that in non-treated animals and the insulinotropic effect of recombinant GLP-1 was shown by a threefold increase in plasma insulin concentration when compared with untreated animals. Intraperitoneal glucose tolerance tests revealed an efficacious decrease of blood glucose compared with controls for up to 24 days after treatment, where injections of this formulation allowed near-normalization of blood glucose level. TNCs composed of specific chitosans and GLP-1-expressing plasmid constructs showed an impressive ability to harness the profound therapeutic potential of GLP-1 for the treatment of T2D mellitus.

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Truncated glucagon‐like peptide I, an insulin‐releasing hormone from the distal gut

Cited by 542 publications

References 19 publications

Isolation and characterisation of GLP‐1 7–36 amide from rat intestine Elevated levels in diabetic rats

Isolation and characterisation of GLP‐1 7–36 amide from rat intestine Elevated levels in diabetic rats

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

Effective and safe gene-based delivery of GLP-1 using chitosan/plasmid-DNA therapeutic nanocomplexes in an animal model of type 2 diabetes

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