Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus

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Nutrient intake stimulates the secretion of the gastrointestinal incretin hormones, glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert glucose-dependent insulinotropic effects and assist pancreatic insulin and glucagon in maintaining glucose homeostasis. GLP-1 also suppresses glucose-dependent glucagon secretion, slows gastric emptying, increases satiety, and reduces food intake. An impaired incretin system, characterized by decreased responsiveness to GIP and markedly reduced GLP-1 concentration, occurs in individuals with type 2 diabetes mellitus (T2DM). The administration of GLP-1 improves glycemic control, but GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase–4 (DPP-4). Exenatide, a DPP-4–resistant exendin-4 GLP-1 receptor agonist, exhibits the glucoregulatory actions of GLP-1 and reduces body weight in patients with T2DM. It may possess cardiometabolic actions with the potential to improve the cardiovascular risk profile of patients with T2DM. DPP-4 inhibitors such as sitagliptin and saxagliptin increase endogenous GLP-1 concentration and demonstrate incretin-associated glucoregulatory actions in patients with T2DM. DPP-4 inhibitors are weight neutral. A growing understanding of the roles of incretin hormones in T2DM may further clarify the application of incretin-based treatment strategies.


  • The incretin effect may be responsible for up to 70% of insulin secretion following oral glucose ingestion; reduction of the incretin effect contributes to T2DM pathophysiology.
  • It is unknown whether incretin defects are a cause or consequence of T2DM.
  • Incretin therapies effectively lower glucose with concomitant favorable effects on body weight. GLP-1 receptor agonists reduce weight, while DPP-4 inhibitors are weight neutral.



It has long been understood that the pathophysiology of type 2 diabetes mellitus (T2DM) is based on the triad of progressive decline in insulin-producing pancreatic beta cells, an increase in insulin resistance, and increased hepatic glucose production. 1,2 It is now evident that other factors, including defective actions of the gastrointestinal (GI) incretin hormones glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), also play significant roles. 2–5 The uncontrolled hyperglycemia resulting from such defects may lead to microvascular complications, including retinopathy, neuropathy, microangiopathy, and nephropathy, and macrovascular complications, such as coronary artery disease and peripheral vascular disease.

This review explores the growing understanding of the role of the incretins in normal insulin secretion, as well as in the pathogenesis of T2DM, and examines the pathophysiologic basis for the benefits and therapeutic application of incretin-based therapies in T2DM. 1,2


The GI system plays an integral role in glucose homeostasis. 6 The observation that orally administered glucose provides a stronger insulinotropic stimulus than an intravenous glucose challenge provided insight into the regulation of plasma glucose by the GI system of healthy individuals. 7 The incretin effect, as this is termed, may be responsible for 50% to 70% of the total insulin secreted following oral glucose intake. 8

Two GI peptide hormones (the incretins)—GLP-1 and GIP—were found to exert major glucoregulatory actions. 3,9,10 Within minutes of nutrient ingestion, GLP-1 is secreted from intestinal L cells in the distal ileum and colon, while GIP is released by intestinal K cells in the duodenum and jejunum. 3 GLP-1 and GIP trigger their insulinotropic actions by binding beta-cell receptors. 3 GLP-1 receptors are expressed on pancreatic glucagon-containing alpha and delta cells as well as on beta cells, whereas GIP receptors are expressed primarily on beta cells. 3,8 GLP-1 receptors are also expressed in the central nervous system (CNS), peripheral nervous system, lung, heart, and GI tract, while GIP receptors are expressed in adipose tissue and the CNS. 3 GLP-1 inhibits glucose-dependent glucagon secretion from alpha cells. 3 In healthy individuals, fasting glucose is managed by tonic insulin/glucagon secretion, but excursions of postprandial glucose (PPG) are controlled by insulin and the incretin hormones. 11

Additionally, in animal studies, GLP-1 has been shown to induce the transcriptional activation of the insulin gene and insulin biosynthesis, thus increasing beta-cell proliferation and decreasing beta-cell apoptosis. 12 GLP-1 stimulates a CNS-mediated pathway of insulin secretion, slows gastric emptying, increases CNS-mediated satiety leading to reduced food intake, indirectly increases insulin sensitivity and nutrient uptake in skeletal muscle and adipose tissue, and exerts neuroprotective effects. 8

Reprinted, with permission, from European Journal of Endocrinology (Van Gaal LF, et al. Eur J Endocrinol 2008; 158:773–784),13 Copyright © 2008 European Society of Endocrinology.

Figure 1. Biologic actions of GIP and GLP-1 in relation to the pathophysiology of type 2 diabetes mellitus. GIP = glucose-dependent insulinotropic polypeptide, GLP-1 = glucagon-like peptide–1; PP = postprandial; solid arrows = potentially beneficial actions; dashed arrows = potentially harmful actions; slashed arrows = actions with no effect.


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