Biology of Incretins: GLP-1 and GIP
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
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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.