Elsevier

Regulatory Peptides

Volume 128, Issue 2, 15 June 2005, Pages 97-107
Regulatory Peptides

Review
Glucagon-related peptide 1 (GLP-1): hormone and neurotransmitter

https://doi.org/10.1016/j.regpep.2004.08.026Get rights and content

Abstract

The interest in glucagon-like petide-1 (GLP-1) and other pre-proglucagon derived peptides has risen almost exponentially since seminal papers in the early 1990s proposed to use GLP-1 agonists as therapeutic agents for treatment of type 2 diabetes. A wealth of interesting studies covering both normal and pathophysiological role of GLP-1 have been published over the last two decades and our understanding of GLP-1 action has widened considerably. In the present review, we have tried to cover our current understanding of GLP-1 actions both as a peripheral hormone and as a central neurotransmitter. From an initial focus on glycaemic control, GLP-1 research has been diverted to study its role in energy homeostasis, neurodegeneration, cognitive functions, anxiety and many more functions. With the upcoming introduction of GLP-1 agonists on the pharmaceutical venue, we have witnessed an outstanding example of how initial ideas from basic science laboratories have paved their way to become a novel therapeutic strategy to fight diabetes.

Section snippets

L-cells and GI tract GLP-1 synthesis

GLP-1 is a product of the glucagon gene [1]. The gene is expressed in the alpha cells of the pancreas, and here the primary translation product, proglucagon, which contains three glucagon like sequences, viz glucagon itself, and the glucagon-like peptides GLP-1 and GLP-2, is cleaved to release glucagon and a large peptide, major proglucagon fragment, which comprises both of the glucagon-like peptides [2]. This peptide, which corresponds to proglucagon 72–158, is probably biologically inactive

Anatomy of central preproglucagon synthesising neurones and their receptors

In the central nervous system, pre-proglucagon encoding mRNA is exclusively expressed in neurones of the nucleus of the solitary tract (NTS). Chromatographic analysis of pre-proglucagon immunoreactive material in the brain confirm a processing pattern similar to that seen in interstinal L-cells, i.e. giving rise to equimolar amounts of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and oxyntomodulin (OXM). In the NTS, pre-proglucagon expression is confined to a subset of

Cross roads between peripheral and central GLP-1

Peripheral administration of native GLP-1 as well as stable GLP-1 agonists/derivatives have collectively shown that they share several functions in common with central administration of much smaller doses of GLP-1. This observation has led many to believe that GLP-1 released from instinal L-cells addresses functional receptors within the brain. However, due to methodological shortcomings it has not been possible to provide unequivocal evidence confirming the degree of cross talk between

References (125)

  • M. Nishizawa et al.

    The hepatic vagal nerve is receptive to incretin hormone glucagon-like peptide-1, but not to glucose-dependent insulinotropic polypeptide, in the portal vein

    J. Auton. Nerv. Syst.

    (1996)
  • M. Zander et al.

    Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study

    Lancet

    (2002)
  • P.J. Larsen et al.

    Ups and downs for neuropeptides in body weight homeostasis: pharmacological potential of cocaine amphetamine regulated transcript and pre-proglucagon-derived peptides

    Eur. J. Pharmacol.

    (2002)
  • P.J. Larsen et al.

    Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem

    Neuroscience

    (1997)
  • S. Sarkar et al.

    Glucagon like peptide-1 (7–36) amide (GLP-1) nerve terminals densely innervate corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus

    Brain Res.

    (2003)
  • A.P. Goldstone et al.

    Leptin interacts with glucagon-like peptide-1 neurons to reduce food intake and body weight in rodents

    FEBS Lett.

    (1997)
  • G.I. Bell et al.

    Exon duplication and divergence in the human preproglucagon gene

    Nature

    (1983)
  • A.J. Moody et al.

    Relationship of glicentin to proglucagon and glucagon in the porcine pancreas

    Nature

    (1981)
  • M. Furuta et al.

    Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • X. Zhu et al.

    Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • C. Orskov et al.

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

    Endocrinology

    (1986)
  • R. Ugleholdt et al.

    Impaired intestinal proglucagon processing in mice lacking prohormone convertase 1

    Endocrinology

    (2004)
  • F. Sundler et al.

    Ultrastructural identification of cells storing pancreatic-type glucagon in dog stomach

    Histochemistry

    (1976)
  • P.J. Lefebvre et al.

    Neurotransmitters and glucagon release from the isolated, perfused canine stomach

    Diabetes

    (1980)
  • J.J. Holst

    Extrapancreatic glucagons

    Digestion

    (1978)
  • J.J. Holst et al.

    Content and gel filtration profiles of glucagon-like and somatostatin-like immunoreactivity in human fundic mucosa

    J. Clin. Endocrinol. Metab.

    (1983)
  • J.J. Holst et al.

    Circulating glucagon after total pancreatectomy in man

    Diabetologia

    (1983)
  • J.B. Knudsen et al.

    Identification of cells with pancreatic-type and gut-type glucagon immunoreactivity in the human colon

    Acta Pathol. Microbiol. Scand.

    (1975)
  • R. Eissele et al.

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

    Eur. J. Clin. Invest.

    (1992)
  • L. Hansen et al.

    Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine

    Endocrinology

    (1999)
  • L. Hansen et al.

    Somatostatin restrains the secretion of glucagon-like peptide-1 and-2 from isolated perfused porcine ileum

    Am. J. Physiol. Endocrinol. Metab.

    (2000)
  • C.F. Deacon et al.

    Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig

    Am. J. Physiol.

    (1996)
  • T. Vilsboll et al.

    Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects

    J. Clin. Endocrinol. Metab.

    (2003)
  • J.J. Meier et al.

    Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects

    Diabetes

    (2004)
  • T. Vilsboll et al.

    Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients

    Diabetes

    (2001)
  • C. Orskov et al.

    Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans

    Diabetes

    (1994)
  • M. Toft-Nielsen et al.

    The effect of glucagon-like peptide I (GLP-I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones

    Diabetes

    (1996)
  • C. Orskov et al.

    Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day

    Scand. J. Gastroenterol.

    (1996)
  • B. Ahren et al.

    The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia

    Diabetes

    (2001)
  • P. Layer et al.

    Regulation of gastrointestinal functions by the ileocecal area

    Z. Gastroenterol.

    (1992)
  • T. Vilsboll et al.

    Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus

    J. Clin. Endocrinol. Metab.

    (2003)
  • J. Miholic et al.

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

    Dig. Dis. Sci.

    (1991)
  • M.A. Nauck et al.

    Release of glucagon-like peptide 1 (GLP-1 [7-36 amide]), gastric inhibitory polypeptide (GIP) and insulin in response to oral glucose after upper and lower intestinal resections

    Z. Gastroenterol.

    (1996)
  • C. Qualmann et al.

    Glucagon-like peptide 1 (7-36 amide) secretion in response to luminal sucrose from the upper and lower gut. A study using alpha-glucosidase inhibition (acarbose)

    Scand. J. Gastroenterol.

    (1995)
  • J.J. Andreasen et al.

    Secretion of glucagon-like peptide-1 and reactive hypoglycemia after partial gastrectomy

    Digestion

    (1994)
  • B. Gebhard et al.

    Postprandial GLP-1, norepinephrine, and reactive hypoglycemia in dumping syndrome

    Dig. Dis. Sci.

    (2001)
  • M. Toft-Nielsen et al.

    Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia

    Diabetologia

    (1998)
  • K. Sugiyama et al.

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

    Digestion

    (1994)
  • F.M. Gribble et al.

    A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line

    Diabetes

    (2003)
  • D.J. Drucker et al.

    Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line

    Mol. Endocrinol.

    (1994)
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