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

December 1, 2009|Cleveland Clinic Journal of Medicine
Jeffrey S. Freeman, DO
Author and Disclosure Information

Jeffrey S. Freeman, DO
Professor of Internal Medicine and Chairman, Division of Endocrinology and Metabolism, Philadelphia College of Osteopathic Medicine, Philadelphia, PA

Correspondence: Jeffrey S. Freeman, DO, Professor of Internal Medicine and Chairman, Division of Endocrinology and Metabolism, Philadelphia College of Osteopathic Medicine, 4190 City Ave., Suite 324, Philadelphia, PA 19131-1626; jeffreyfreemando@aol.com

Dr. Freeman reported that he has received speakers’ bureau fees from Glaxo­SmithKline, Merck & Co., Inc., and Novo Nordisk Inc. He reported that he did not receive an honorarium for writing this article.

Dr. Freeman reported that he wrote this article and received no assistance with content development from unnamed contributors. He reported that BlueSpark Healthcare Communications, a medical communications company, assisted with preliminary literature searches, reference verification, proofing for grammar and style, table and figure rendering based on author instructions, copyright permission requests, and identification of topical overlap with other manuscripts in this supplement.

ABSTRACT

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.

KEY POINTS

  • 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.

Effects of incretin-based therapies

The number of people with T2DM, overweight/obesity, or CVD, alone or in combination, is approaching epidemic proportions, with the mechanisms of these conditions interrelated. Approximately 24 million Americans have diabetes, and T2DM accounts for more than 90% of these cases.61 Most patients with T2DM are not achieving HbA1c targets.62–64 About 60% of deaths among patients with T2DM are caused by CVD.65 Compounding the problem, overweight/obesity enhances the risk for CV-related morbidities in patients with diabetes.66 A cluster of metabolic disorders referred to as the metabolic syndrome (which includes hyperglycemia, measures of central obesity, and a series of significant CV risk factors) is common in patients with T2DM and CVD.67 Unfortunately, many antidiabetes drugs that successfully manage glycemic control also cause weight gain, which in theory may increase CV risk in patients with T2DM.68

Data from studies of patients with T2DM show that exenatide improves glycemic control and reduces body weight. Exenatide administered BID significantly reduced HbA1c (–0.40% to –0.86%) and weight (–1.6 kg to –2.8 kg) relative to baseline in three 30-week, placebo-controlled clinical trials.31,33,34 In subsequent 2-year, open-label extension studies, exenatide produced significant reductions from baseline in HbA1c (–20.9% at 30 weeks) and weight (–2.1 kg at 30 weeks). Both decreases were sustained through 2 years (HbA1c –1.1%, weight –4.7 kg) with a low incidence of hypoglycemia.31 Further post hoc analysis of the open-label extension of the 30-week trials followed patients treated with exenatide BID for 3 years or longer.69 In addition to markedly decreasing HbA1c from baseline levels (–1.1% at 3 years and –0.8% at up to 3.5 years; P < .0001), adjunctive exenatide produced significant reductions in body weight—up to –5.3 kg after 3.5 years of therapy.31,69 At 3.5 years, continued exenatide therapy resulted in a –6% reduction in low-density lipoprotein cholesterol, a 24% mean increase in high-density lipoprotein cholesterol, and a mean reduction in blood pressure of –2% to –4% from baseline levels. Improvements in hepatic biomarkers and homeostasis model assessment-B, a measure of beta-cell function, were seen after 2 and 3 years of exenatide treatment.31 Hypoglycemia was generally mild and transient.

In comparative head-to-head studies, exenatide BID and insulin analogues reduced HbA1c by similar magnitudes; yet exenatide treatment resulted in better control in terms of PPG and weight loss, while insulin glargine and insulin aspart produced weight gain.70–73

Mechanisms of cardioprotective effects

Although the mechanisms for the potential cardioprotective effects of GLP-1 and its receptor agonists remain to be fully elucidated, a recent study suggested that two novel pathways could be involved—one that is dependent on the known GLP-1 receptor pathway, and one that is independent of the GLP-1 receptor pathway.74 Correlating with observations of a potential cardioprotective effect, an infusion of recombinant GLP-1 in patients with acute myocardial infarction, when added to standard therapy, resulted in improved left ventricular function and was associated with reduced mortality.75 Evidence continues to accumulate for potential cardioprotective effects of the GLP-1 receptor agonists, indicating that they may have a positive impact on macro­vascular complications in patients with T2DM.

CONCLUSION

T2DM, which is often associated with overweight and obesity, remains a significant challenge worldwide. The broad spectrum of glucoregulatory actions of the incretin hormones GLP-1 and GIP, and their importance in maintaining glucose homeostasis, have been recognized and correlated with the pathogenesis of T2DM. An improved understanding of the roles played by GLP-1 and GIP in the pathogenesis of T2DM may provide clinicians with important details regarding the therapeutic application of incretin-based therapies, including the GLP-1 receptor agonist exenatide and the DPP-4 inhibitors sitagliptin and saxagliptin. Antidiabetes agents whose development is based on the multiple pharmacologic effects of incretin hormones can address the multifaceted nature of T2DM and overcome some current limitations of traditional therapies, especially those related to weight. This becomes more compelling given the close link among T2DM, obesity, and increased CV risk.

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