Gastroenterology

Gastroenterology

Volume 132, Issue 6, May 2007, Pages 2131-2157
Gastroenterology

Biology of Incretins: GLP-1 and GIP

https://doi.org/10.1053/j.gastro.2007.03.054Get rights and content

This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet β-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of β-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1–receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1–receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes.

Section snippets

Proglucagon Gene Structure and Tissue-Specific Regulation of Proglucagon Gene Expression

The proglucagon gene is located on the long arm of human chromosome 2 and comprises 6 exons and 5 introns, with the entire coding sequence for GLP-1 contained within exon 4 (Figure 1A).10 The proglucagon gene is expressed in the α-cells of the endocrine pancreas, the L-cells of the intestine, and neurons located in the caudal brainstem and hypothalamus; mammalian proglucagon gene transcription generates a single messenger RNA (mRNA) transcript that is structurally identical in all 3 cell types (

Posttranslational Processing of Proglucagon

The proglucagon mRNA is translated into a single 180 amino acid precursor protein that undergoes tissue-specific posttranslational processing to yield specific peptide profiles in the pancreas, intestine, and brain (Figure 1C and D).11 Although several prohormone convertase (PC) enzymes have been identified, only PC1/3 and PC2 appear to be important for proglucagon processing.31

In pancreatic α-cells, the predominant proglucagon posttranslational processing products are glicentin-related

GLP-1 Secretion, Metabolism, and Clearance

GLP-1 is secreted from intestinal endocrine L-cells, which are located mainly in the distal ileum and colon. In contrast, GIP is released from intestinal K-cells that are localized to more proximal regions (duodenum and jejunum) of the small intestine. However, endocrine cells that produce GLP-1 or GIP, as well as cells that produce both peptides, can be found throughout all regions of the porcine, rat, and human small intestine.47, 48 The L-cell is an open-type intestinal epithelial endocrine

The GLP-1 Receptor

The GLP-1 receptor (GLP-1R) belongs to the class B family of 7-transmembrane–spanning, heterotrimeric G-protein–coupled receptors, which also includes receptors for glucagon, GLP-2, and GIP.85 The rat and human GLP-1R cDNAs were cloned and sequenced in the early 1990s from their respective pancreatic islet cDNA libraries. Both receptors are 463 amino acids in length and exhibit 90% amino acid sequence identity. The human GLP-1R gene spans 40 kb, consists of at least 7 exons, and has been mapped

Pancreas

GLP-1R agonists produce several biological actions in the pancreas (Figure 3) including stimulation of glucose-dependent insulin secretion.8, 9, 96 The binding of GLP-1 to its specific receptor on pancreatic β-cells leads to activation of adenylate cyclase activity and production of cAMP (Figure 4). Subsequently, GLP-1 stimulates insulin secretion via mechanisms that include the following: (1) direct inhibition of KATP channels, which leads to β-cell membrane depolarization; (2) increases in

Structure and Regulation of the GIP Gene

The human GIP gene (Figure 5) is comprised of 6 exons, with the majority of GIP-encoding sequences found in exon 3, and has been localized to the long arm of chromosome 17. GIP gene expression has been detected in the stomach and intestinal K-cells in both rodents and humans, whereas submandibular salivary gland expression is found exclusively in the rat. Rat duodenal and salivary gland GIP mRNA levels are increased after glucose- or fat-rich meals and are decreased in response to prolonged

GIP Biosynthesis, Secretion, Metabolism, and Clearance

The predicted amino acid sequence for both the rat and human GIP cDNAs indicate that GIP is derived from a larger proGIP prohormone precursor that encodes a signal peptide, an N-terminal peptide, GIP, and a C-terminal peptide (Figure 5). Studies using specific PC knockout mice or cell lines that overexpress PC enzymes demonstrate that the mature 42-amino acid bioactive form of GIP is released from its 153-amino acid proGIP precursor via PC1/3-dependent posttranslational cleavage at flanking

The GIP Receptor

The GIP receptor (GIPR) initially was cloned from a rat cerebral cortex cDNA library and was followed by the cloning of the hamster and human GIPRs. The human GIPR gene comprises 14 exons that span approximately 14 kb189 and is localized to chromosome 19, band q13.3. The GIPR gene is expressed in the pancreas, stomach, small intestine, adipose tissue, adrenal cortex, pituitary, heart, testis, endothelial cells, bone, trachea, spleen, thymus, lung, kidney, thyroid, and several regions in the

Biological Actions of GIP

The actions of GIP on the pancreatic β-cell are analogous to those of GLP-1. However, GIP also exhibits unique physiologic actions in extrapancreatic tissues (Figure 6).

Incretins and Incretin Mimetics as Therapeutic Agents for the Treatment of Type 2 Diabetes

Several studies have shown that the magnitude of nutrient-stimulated insulin secretion is diminished in subjects with T2DM, prompting investigation as to whether incretin secretion and/or incretin action is diminished in diabetic subjects. Plasma levels of GIP appear normal to increased in subjects with T2DM, whereas meal-stimulated plasma levels of GLP-1 are modestly but significantly diminished in patients with impaired glucose tolerance and in subjects with T2DM.79 Whether successful

Inhibition of DPP-4 Activity to Enhance Incretin Action for the Treatment of Type 2 Diabetes

The observation that native GLP-1 and GIP are cleaved rapidly by DPP-4 at the position 2 alanine leading to their inactivation has fostered considerable interest in the role of DPP-4 as a critical determinant of incretin action. Insight into the role of DPP-4 in the control of incretin biology has been derived from studies of rodents with inactivating mutations in the DPP-4 gene, and from the results of experiments using small-molecule chemical inhibitors of DPP-4 activity. Fischer (F344/DuCrj)

Summary and Future Directions

The unexpected success of Exenatide as a twice-daily injectable therapy is related in part to the ability of GLP-1R agonists to reduce HbA1c without associated weight gain in the majority of treated subjects. Indeed, most Exenatide-treated subjects experience weight loss, which in about 20% of patients can be substantial, and stands in marked contrast to the weight gain commonly seen with standard antidiabetic agents, including insulin, sulphonylureas, or thiazolidinediones. Whether chronic

References (247)

  • Y. Rouille et al.

    Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide

    J Biol Chem

    (1995)
  • J.C. Parker et al.

    Glycemic control in mice with targeted disruption of the glucagon receptor gene

    Biochem Biophys Res Commun

    (2002)
  • L.L. Baggio et al.

    Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure

    Gastroenterology

    (2004)
  • J. Lovshin et al.

    Glucagon-like peptide (GLP)-2 action in the murine central nervous system is enhanced by elimination of GLP-1 receptor signaling

    J Biol Chem

    (2001)
  • M.E. Rothenberg et al.

    Processing of mouse proglucagon by recombinant prohormone convertase 1 and immunopurified prohormone convertase 2 in vitro

    J Biol Chem

    (1995)
  • Y. Rouille et al.

    Role of the prohormone convertase PC3 in the processing of proglucagon to glucagon-like peptide 1

    J Biol Chem

    (1997)
  • R. Ugleholdt et al.

    Prohormone convertase 1/3 is essential for processing of the glucose-dependent insulinotropic polypeptide precursor

    J Biol Chem

    (2006)
  • K. Mortensen et al.

    GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine

    Regul Pept

    (2003)
  • A. Wettergren et al.

    Amidated and non-amidated glucagon-like peptide-1 (GLP-1): non-pancreatic effects (cephalic phase acid secretion) and stability in plasma in humans

    Regul Pept

    (1998)
  • R. Mentlein

    Dipeptidyl-peptidase IV (CD26)–role in the inactivation of regulatory peptides

    Regul Pept

    (1999)
  • C.F. Deacon

    What do we know about the secretion and degradation of incretin hormones?

    Regul Pept

    (2005)
  • Q. Xiao et al.

    Secretion of the intestinotropic hormone glucagon-like peptide 2 is differentially regulated by nutrients in humans

    Gastroenterology

    (1999)
  • M. Hallbrink et al.

    Different domains in the third intracellular loop of the GLP-1 receptor are responsible for Galpha(s) and Galpha(i)/Galpha(o) activation

    Biochim Biophys Acta

    (2001)
  • G.G. Holz et al.

    Activation of a cAMP-regulated Ca2+-signaling pathway in pancreatic b-cells by the insulinotropic hormone glucagon-like peptide-1

    J Biol Chem

    (1995)
  • R. Goke et al.

    Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells

    J Biol Chem

    (1993)
  • J.J. Holst et al.

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

    FEBS Lett

    (1987)
  • W.M. Bayliss et al.

    On the causation of the so-called ‘peripheral reflex secretion’ of the pancreas

    Proc R Soc Lond Biol

    (1902)
  • B. Moore et al.

    On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane

    Biochem J

    (1906)
  • J. La Barre

    Sur les possibilites d’un traitement du diabete par l’incretine

    Bull Acad R Med Belg

    (1932)
  • H. Elrick et al.

    Plasma insulin response to oral and intravenous glucose administration

    J Clin Invest

    (1964)
  • K.B. Lauritsen et al.

    Gastric inhibitory polypeptide (GIP) and insulin release after small-bowel resection in man

    Scand J Gastroenterol

    (1980)
  • S. Mojsov et al.

    Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas

    J Clin Invest

    (1987)
  • J.W. White et al.

    Structure of the human glucagon gene

    Nucl Acids Res

    (1986)
  • L. St-Onge et al.

    Pax6 is required for differentiation of glucagon-producing a-cells in mouse pancreas

    Nature

    (1997)
  • M. Sander et al.

    Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development

    Genes Dev

    (1997)
  • R.S. Heller et al.

    The role of Brn4/Pou3f4 and Pax6 in forming the pancreatic glucagon cell identity

    Dev Biol

    (2004)
  • D.J. Drucker et al.

    Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine

    Proc Natl Acad Sci U S A

    (1989)
  • D.J. Drucker et al.

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

    Mol Endocrinol

    (1994)
  • P.L. Brubaker et al.

    Regulation of glucagon-like peptide-1 synthesis and secretion in the GLUTag enteroendocrine cell line

    Endocrinology

    (1998)
  • E.C. Hoyt et al.

    Effects of fasting, refeeding, and intraluminal triglyceride on proglucagon expression in jejunum and ileum

    Diabetes

    (1996)
  • R.A. Reimer et al.

    Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and insulin in rats

    Endocrinology

    (1996)
  • K.A. Tappenden et al.

    Short-chain fatty acids increase proglucagon and ornithine decarboxylase messenger RNAs after intestinal resection in rats

    JPEN J Parenter Enteral Nutr

    (1996)
  • D.K. Trinh et al.

    Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium

    Diabetes

    (2003)
  • M.E. Hill et al.

    Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription

    Mol Endocrinol

    (1999)
  • T. Jin et al.

    The proglucagon gene upstream enhancer contains positive and negative domains important for tissue-specific proglucagon gene transcription

    Mol Endocrinol

    (1995)
  • M. Nian et al.

    Divergent regulation of human and rat proglucagon gene promoters in vivo

    Am J Physiol

    (1999)
  • R.W. Gelling et al.

    Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice

    Proc Natl Acad Sci U S A

    (2003)
  • 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)
  • S. Myojo et al.

    Trophic effects of glicentin on rat small-intestinal mucosa in vivo and in vitro

    J Gastroenterol

    (1997)
  • B. Schjoldager et al.

    Oxyntomodulin from distal gutRole in regulation of gastric and pancreatic functions

    Dig Dis Sci

    (1989)
  • Cited by (0)

    1

    Dr Drucker has served as an advisor or consultant within the past 12 months to Amgen Inc., Amylin Pharmaceuticals, Arisaph Pharmaceuticals Inc., Bayer Inc., Chugai Inc., Conjuchem Inc., Eli Lilly Inc., Glaxo Smith Kline, Glenmark Pharmaceuticals, Johnson & Johnson, Merck Research Laboratories, Merck Fr., Novartis Pharmaceuticals, NPS Pharmaceuticals Inc., Phenomix Inc., Takeda, and Transition Pharmaceuticals Inc. Dr Baggio has served as a consultant to Merck.

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