Glucagonlike peptide 1: A newly discovered gastrointestinal hormone

doi:10.1016/0016-5085(94)90831-1

Gastroenterology

Volume 107, Issue 6, December 1994, Pages 1848-1855

https://doi.org/10.1016/0016-5085(94)90831-1 Get rights and content

Abstract

Glucagonlike peptide (GLP) 1, a peptide of 30 amino acids with 50% sequence homology to glucagon, results from expression of the glucagon gene in the L cells of the distal intestinal mucosa. It is secreted early in response to mixed meals by mechanisms involving the presence of unabsorbed nutrients in the gut lumen or the absorptive process itself, but other mechanisms may also be involved. GLP-1 has two important actions. First, it stimulates insulin secretion and inhibits glucagon secretion and thereby inhibits hepatic glucose production and lowers blood glucose levels. It may have effects on glucose clearance independent of its pancreatic effects. It acts on recently cloned G protein-coupled specific receptors and seems to increase insulin secretion via cyclic adenosine monophosphate-dependent increases in intracellular calcium. It has been suggested that activation of the β cells by GLP-1 is a prerequisite for glucose-induced insulin secretion. Second, it also potently inhibits gastrointestinal secretion and motility and is likely to act as an “ileal brake,” possibly after activation of cerebral receptors. Therefore, GLP-1 physiologically seems to signal nutritional abundancy and enhance deposition of nutrients. Because of these effects, however, the peptide can completely normalize blood glucose levels in type 2 diabetics and is therefore of considerable pharmaceutical interest.

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Citation Excerpt :
Glucagon-like peptide-1 (GLP-1) is a peptide hormone that is secreted by intestinal L cells. After food intake, GLP-1 secretion is significantly increased, which can promote the secretion of insulin by β cells and inhibits the secretion of glucagon by α cells in the pancreas [10–13]. In addition, GLP-1 has been shown to delay gastric emptying, increase energy consumption, and control weight gain [14–16].
Nanomaterials have attracted increased attention because of their excellent drug-carrying capacity. However, these nanomaterials are rarely used in the treatment of metabolic diseases. Liraglutide, a glucagon-like peptide-1 receptor agonist, has been widely used in the treatment of type 2 diabetes mellitus (T2DM). Furthermore, fibroblast growth factor 21 (FGF-21) has been found to improve glucose metabolism and insulin resistance (IR). To investigate whether these two molecules have synergistic effects in vivo, we developed a novel drug delivery system using amino-functionalized and embedded dual-mesoporous silica nanoparticles (N-EDMSNs) to simultaneously carry liraglutide and FGF-21, and observed their biological effects. The resultant N-EDMSNs possessed unique hierarchical porous structures consisting of open large pores (>10 nm) and small mesopores (~2.5 nm) in the silica framework, highly positively charged surfaces and good disperisity in aqueous solution. We found that N-EDMSNs had a high loading capacity for exogenous genes and low toxicity to Hepa1-6 cells. Moreover, N-EDMSNs can simultaneously carry FGF-21 plasmids and liraglutide and successfully transfect them into Hepa1-6 cells. The transfection efficiency of N-EDMSNs was higher than that of Lipofectamine 2000 in vitro. In mice experiments, N-EDMSNs/pFGF21 treatment resulted in higher FGF-21 expression in the liver than pFGF21 treatment with hydrodynamic delivery. Compared with both pFGF21 and liraglutide, N-EDMSNs/pFGF21/Lira treatment significantly reduced the food intake, body weight, and blood glucose; increased the energy expenditure and improved hepatic IR in high-fat diet (HFD)-fed mice. Our results demonstrated that the biological effects of N-EDMSNs/pFGF21/Lira complexes were better than those of pFGF21 combined with liraglutide in vivo.
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Treatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss.
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Special report and reviewGlucagonlike peptide 1: A newly discovered gastrointestinal hormone

Abstract

Trends Endocrinol Metab

J Biol Chem

Biochim Biophys Acta

J Biol Chem

FEBS Lett

Gastroenterology

FEBS Lett

FEBS Lett

J Biol Chem

FEBS Lett

J Biol Chem

Biochem Biophys Res Commun

Regul Pept

Metabolism

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

Trends Biochem Sci

Biochem Biophys Res Commun

FEBS Lett

Neuropeptides

Diabetes Res Clin Pract

Glucagon-like peptide-1, a new hormone of the enteroinsular axis

Diabetologia

The enteroinsular axis

Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1 (7–36) amide infused at near-physiological insulinotropic and glucose concentrations

J Clin Endocrinol Metab

Regulation of gastrointestinal functions by the ileocecal area

Z Gastroenterol

Glucagon-like peptide 1: on its way to clinical application

Digestion

Hamster preproglucagon contains the sequence of glucagon and two related peptides

Nature

Exon duplication and divergence in the human preproglucagon gene

Nature

Identical mRNA for preproglucagon in pancreas and gut

Eur J Biochem

Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from the pig small intestine, but not pancreas

Endocrinology

Relationship of glicentin to proglucagon and glucagon in the porcine pancreas

Nature

Production and secretion of amidated and glycine-extended glucagon-like peptide-1 (GLP-1) in man

Diabetes

The primary structure of glicentin (proglucagon)

Regul Pept

Evidence that enteroglucagon (II) is identical with the C-terminal sequence (residues 33–69) of glicentin

Biochem J

Glucagon and other proglucagon-derived peptides

The metabolic rate and the biological effects of GLP-1 7–36amide and GLP-1 7–37 in healthy volunteers are identical

Diabetes

Glucagon-like peptide-1 (7–36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns

J Endocrinol

Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy

Dig Dis Sci

Pancreatic and intestinal processing of proglucagon in man

Diabetologia

Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man

Eur J Clin Invest

Relationship between molecular structures of sugars and their ability to stimulate the release of glucagon-like peptide-1 (GLP-1) from canine ileal loops

Acta Endocrinol

Stimulation of truncated glucagon-like peptide-1 release from isolated perfused canine ileum by glucose absorption

Digestion

Regulation of glucagon-like peptide (GLP-1) release from the isolated perfused rat ileum by nutrients, peptides and neuromediators

Digestion

Special report and review
Glucagonlike peptide 1: A newly discovered gastrointestinal hormone