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