Elsevier

The Lancet

Volume 368, Issue 9548, 11–17 November 2006, Pages 1696-1705
The Lancet

New Drug Class
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes

https://doi.org/10.1016/S0140-6736(06)69705-5Get rights and content

Summary

Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) (1–2%), associated with weight loss (2–5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA1c by 0·5–1·0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand β-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.

Introduction

Eating provokes the secretion of multiple gastrointestinal hormones involved in the regulation of gut motility, secretion of gastric acid and pancreatic enzymes, gall bladder contraction, and nutrient absorption. Gut hormones also facilitate the disposal of absorbed glucose through the stimulation of insulin secretion from the endocrine pancreas. The observation that enteral nutrition provided a more potent insulinotropic stimulus compared with isoglycaemic intravenous challenge led to the development of the incretin concept.1 The first incretin to be identified, glucose-dependent insulinotropic polypeptide (GIP), was purified from porcine intestinal extracts and had weak effects on gastric acid secretion but more potent insulinotropic actions in human beings.2 GIP is a 42-aminoacid hormone synthesised in duodenal and jejunal enteroendocrine K cells in the proximal small bowel.

A second incretin hormone, glucagon-like peptide-1 (GLP-1) was identified after the cloning of the cDNAs and genes encoding proglucagon (figure 1). GLP-1 exists in two circulating equipotent molecular forms, GLP-1(7-37) and GLP-1(7-36)amide, although GLP-1(7-36)amide is more abundant in the circulation after eating. Most GLP-1 is made in enteroendocrine L cells in the distal ileum and colon, but plasma levels of GLP-1, like GIP, also increase within minutes of eating. Hence a combination of endocrine and neural signals probably promote the rapid stimulation of GLP-1 secretion well before digested food transits through the gut to directly engage the L cell in the small bowel and colon. More proximally located L cells in the duodenum and jejunum have also been described; however, the precise contributions of the proximal and distal L cells to the early rapid increase in plasma GLP-1 remains unclear.

Plasma levels of GLP-1 are low in the fasted state, in the range of 5–10 pmol/L, and increase rapidly after eating, reaching 15–50 pmol/L. The circulating levels of intact GLP-1 and GIP decrease rapidly because of enzymatic inactivation, mainly dipeptidyl peptidase-4 (DPP-4), and renal clearance.3 Whether additional proteases, such as human neutral endopeptidase 24·11, are also essential determinants of GLP-1 inactivation is being investigated. Both GIP and GLP-1 contain alanine at position 2, and hence are excellent substrates for DPP-4. Indeed, DPP-4 is essential for incretin inactivation, and mice with targeted inactivation of the DPP-4 gene have raised levels of plasma GIP and GLP-1, increased insulin secretion, and reduced glucose excursion after glycaemic challenge.4 As a result of DPP-4 activity, intact, biologically active GLP-1 represents only 10–20% of total plasma GLP-1.5

Both GIP and GLP-1 exert their actions by the engagement of structurally distinct G-protein-coupled receptors (GPCRs). The GIP receptor is predominantly expressed on islet β cells, and to a lesser extent, in adipose tissue and in the central nervous system. By contrast, the GLP-1 receptor (GLP-1R) is expressed in islet α and β cells and in peripheral tissues, including the central and peripheral nervous systems, heart, kidney, lung, and gastrointestinal tract (figure 1). Activation of both incretin receptors on β cells leads to rapid increases in levels of cAMP and intracellular calcium, followed by insulin exocytosis, in a glucose-dependent manner.6 More sustained incretin receptor signalling is associated with activation of protein kinase A, induction of gene transcription, enhanced levels of insulin biosynthesis, and stimulation of β-cell proliferation.7 Both GLP-1R and GIP receptor activation also promote resistance to apoptosis and enhanced β-cell survival, in both rodent8 and human islets.9 Consistent with the distribution of GLP-1R expression, GLP-1 also inhibits glucagon secretion, gastric emptying, and food ingestion, and promotes enhanced glucose disposal through neural mechanisms,10 actions that also contribute to the control of glucoregulation. Notably, effects on glucagon secretion, like those on insulin secretory responses, are glucose-dependent, whereas counter-regulatory release of glucagon in response to hypoglycaemia is fully preserved even in the presence of pharmacological concentrations of GLP-1.11

The physiological importance of endogenous GIP and GLP-1 for glucose homoeostasis has been investigated in studies with receptor antagonists, or gene-knockout mice. Acute antagonism of GIP or GLP-1 lowers insulin secretion and increases plasma glucose after glycaemic challenge in rodents. Similarly, mice with inactivating mutations in the GIP or GLP-1 receptors also have defective glucose-stimulated insulin secretion and impaired glucose tolerance.12, 13 GLP-1, but not GIP, is also essential for control of fasting glycaemia, since acute antagonism or genetic disruption of GLP-1 action leads to increased levels of fasting glucose in rodents.13 Furthermore, GLP-1 is essential for glucose control in human beings: studies with the antagonist exendin(9-39) show defective glucose-stimulated insulin secretion, reduced glucose clearance, increased levels of glucagon, and quicker gastric emptying after disruption of GLP-1 action.14

The pleiotropic actions of GLP-1 and GIP on the control of blood glucose have fostered considerable interest in the use of these agents for the treatment of type 2 diabetes. Whereas in healthy human beings oral glucose elicits a considerably higher insulin secretory response than does intravenous glucose (even if leading to the same glycaemic increments), this incretin effect is substantially reduced or even lost in patients with type 2 diabetes.15 As an explanation for the acquired incretin defect, GIP but not GLP-1 shows noticeably attenuated insulinotropic action in patients with type 2 diabetes.16 Furthermore, those with type 2 diabetes show a small but significant reduction in meal-stimulated levels of GLP-1.17 Since GLP-1 action remains relatively preserved in diabetic patients, most pharmaceutical efforts directed at potentiation of incretin action for the treatment of type 2 diabetes have focused on GLP-1R agonists.

Section snippets

Antidiabetic actions of GLP-1

Short-term intravenous infusions of GLP-1 (1–1·2 pmol kg−1 min−1, leading to pharmacological plasma concentrations of total GLP-1 of 70–150 pmol/L, and of intact biologically active GLP-1 of 10–20 pmol/L) lowers blood glucose in patients with type 2 diabetes through a transient glucose-dependent stimulation of insulin and suppression of glucagon secretion and gastric emptying.18, 19, 20, 21 A 6-week subcutaneous infusion of GLP-1 in patients with type 2 diabetes, achieving plasma levels of

Exenatide

Exenatide (synthetic exendin-4) was discovered in the search for biologically active peptides in lizard venom.43 Exendin-4 shares roughly 50% of its aminoacid sequence with mammalian GLP-1, is encoded by a unique gene in the lizard,44 and is a potent degradation-resistant agonist at the mammalian GLP-1R (figure 2). Exenatide has been developed for the treatment of type 2 diabetes (table).47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,

DPP-4 inhibitors

The observation that GLP-1 is rapidly degraded by DPP-45, 89, 90 has fostered the development of specific protease inhibitors that prevent the rapid fall of GLP-1 in circulating plasma after eating. DPP-4 is a ubiquitous membrane-spanning cell-surface aminopeptidase widely expressed in many tissues, such as liver, lung, kidney, intestinal brush-border membranes, lymphocytes, and endothelial cells.91, 92, 93 The extracellular domain of DPP-4 can also be cleaved from its membrane-anchored form

Contrasting properties of GLP-1R agonists and DPP-4 inhibitors

Twice daily exenatide through subcutaneous injection is indicated for the treatment of patients with type 2 diabetes mellitus in whom one or more oral agents do not work, often as an alternative to insulin treatment. By contrast, once daily DPP-4 inhibitors could be used as first-line therapy, or as add-on therapy to patients failing one or more oral agents. While there does not seem to be a great difference in the HbA1c-lowering capacity of GLP-1R agonists compared with DPP-4 inhibitors, the

Future developments

Liraglutide and exenatide are first-generation GLP-1 receptor agonists, requiring once or twice daily parenteral administration, respectively. Much effort continues to be directed towards improvement of the pharmacokinetic profile of GLP-1R agonists, to minimise peak levels of the drug and thus reduce the extent of nausea. Longer-acting GLP-1R agonists should ideally provide more uniform and sustained GLP-1R activation over a 24-h period, but require less frequent administration.

Furthermore,

Search strategy and selection criteria

We searched the MEDLINE and PubMed databases (1987–2006) with the search terms “glp-1”, “glucagon”, “glucagon-like”, “gip”, “incretin”, “dipeptidyl peptidase-4”, and “diabetes”. We preferentially selected publications from the past 5 years, but did not exclude older publications that are commonly referenced or highly regarded. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant.

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