GLP-1 and type 2 diabetes: physiology and new clinical advances

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The first antidiabetic treatment (exenatide; Byetta) based on the incretin hormone glucagon-like peptide-1 (GLP-1) was approved in 2005 as an adjunctive therapy in diabetic patients in whom sulfonylurea, metformin or both had failed. Many GLP-1 mimetics or dipeptidyl peptidase IV inhibitors are currently in clinical development for the treatment of type 2 diabetes and show promising results in the improvement of glucose homeostasis. Furthermore, the ability of GLP-1 to enhance pancreatic β-cell mass could delay progression of the disease. However, only several years of treatment in humans will confirm the long-term efficacy of GLP-1 mimetics and enhancers on glycemic control. To take advantage of the multifaceted actions of GLP-1, a better understanding of the physiological roles of GLP-1 is required.

Introduction

Gastrointestinal glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are ‘incretin hormones’ released from the gut after a meal and are responsible for 70% of postprandial insulin secretion. In diabetic patients, GLP-1 secretion and GIP action are impaired, and the above-mentioned incretin effect is decreased to 30%. GLP-1 contributes to the normalization of elevated glucose levels through regulation of insulin and glucagon secretion [1, 2], gastric emptying [3], satiety [4] and body weight [5]. Finally, GLP-1 can enhance pancreatic β-cell mass through the stimulation of β-cell proliferation and neogenesis in healthy and diabetic rodents [6, 7, 8, 9]. GIP has a similar insulinotropic effect to GLP-1 at glucose concentrations between 5.5 mM and 7.8 mM [10]. However, GIP does not suppress glucagon secretion, and its effects on feeding behavior, if any, are unknown. Collectively, these characteristics render GLP-1 more attractive than GIP as a target for the treatment of type 2 diabetes.

The fact that GLP-1 is rapidly degraded by dipeptidylpeptidase IV (DPPIV) in vivo, however, reduces its usefulness in treating patients. Thus, to improve therapeutic efficacy, two approaches can be used: the development of GLP-1 analogues resistant to degradation by DPPIV or the development of DPPIV inhibitors. This review focuses on the knowledge recently gained on GLP-1 biology, which should permit a better understanding of new drug candidates based on GLP-1 therapy.

Section snippets

Synthesis and secretion

GLP-1 is produced in intestinal L-cells through post-translational processing of the pro-glucagon gene by the hormone convertase 1/3 [11]. Its secretion is postprandially induced and increases in proportion to the size of the meal (10–30 pM) [12], although basal secretion of GLP-1 is observed even in the fasting state (5–10 pM). Postprandial secretion is biphasic: the early phase begins within a few minutes and lasts up to 60 min; this is followed by a second phase continuing up to 120 min after a

GLP-1-based therapies for type 2 diabetes: efficacy and safety issues

GLP-1-based therapies for type 2 diabetes include injected DPPIV-resistant GLP-1 mimetics or orally active DPPIV inhibitors [49, 50, 51, 52•]. The compounds that have been tested in late-stage clinical trials are summarized in Table 1.

Conclusions

GLP-1 mimetics and DPPIV inhibitors are both effective antidiabetic agents in once- or twice-daily dosing, and have been shown to maintain decreased HbA1c levels for at least one year. Both approaches have been evaluated as monotherapy or in combination. The main advantage of GLP-1 mimetics is their induction of weight loss, whereas their strongest limitations are the potential for immunogenicity, the frequent occurrence of nausea and vomiting, a requirement for subcutaneous administration and

Update

After the FDA in March 2006, Novartis announced in August 2006 that it has submitted Galvus (vildagliptin) for European approval for the treatment of type 2 diabetes (http://www.pharma.us.novartis.com/newsroom/pressReleases/index.jsp).

Sitagliptin was registered in Mexico in August 2006 and is now the first in class (DPPIV inhibitor). Furthermore, the US FDA has announced that it accepted the New Drug Application for MK 0431A (sitagliptin/metformin) for the treatment of type 2 diabetes (//www.merck.com/newsroom/%23research_and_development_news

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors would like to thank Dr Elizabeth Harley for helpful discussions.

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