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Diabetes Management Incretin Mimetics
The Incretin System and Type 2 Diabetes
Anthony H Barnett, MD
Professor of Medicine, Consultant Physician, and Clinical Director of Diabetes and Endocrinology,
University of Birmingham and Heart of England NHS Foundation Trust
Abstract
While antidiabetes therapies target glycemic control, most do not address the underlying problems of excess bodyweight and deteriorating
pancreatic beta-cell function. Some therapies also provoke hypoglycemia and/or weight gain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone
secreted by the gut in response to nutrient intake and has a major role in the post-prandial insulin response in healthy individuals. The incretin
response is, however, impaired in individuals with type 2 diabetes. There are two therapeutic approaches that target the incretin system: GLP-1
receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1 receptor agonists provide pharmacological levels of GLP-1 activity, while
DPP-4 inhibitors restore physiological levels. The pharmacological levels of GLP-1 induced by GLP-1 receptor agonists provide effective glycemic
control and weight reduction. The DPP-4 inhibitors also improve glycemic control but are weight-neutral. Pre-clinical studies in animal models and
in vitro systems suggest that incretin-based therapies have the potential to preserve beta-cell mass and improve their function. Initial clinical data
show improvements in beta-cell function in patients treated with incretin-based therapies, supporting the pre-clinical observations. A further benefit
of incretin-based therapies is that they provide glucose-dependent glucose control, which means that they have a low inherent risk of inducing
hypoglycemia. These agents therefore look extremely promising in the management of type 2 diabetes, being efficacious and having positive benefits
on weight, low risk of hypoglycemia, and the potential to improve pancreatic islet cell function in the long term.
Keywords
Dipeptidyl peptidase-4 (DPP-4), DPP-4 inhibitor, exenatide, glucagon-like peptide-1 (GLP-1), GLP-1 receptor agonist, incretin, liraglutide, sitagliptin,
saxagliptin, type 2 diabetes
Disclosure: Anthony H Barnett, MD, has received honoraria for lectures and advisory work from NovoNordisk, Eli Lilly, MSD, Novartis, sanofi-aventis. and BMS/AstraZeneca.
Acknowledgments: This publication was supported by funding from Novo Nordisk. Editorial assistance was provided by Dr Michael Lappin of Watermeadow Medical.
Received: November 11, 2009 Accepted: December 7, 2009
Correspondence: Anthony H Barnett, MD, Undergraduate Centre, Heart of England NHS Foundation Trust, Bordesley Green East, Birmingham B9 5SS, UK.
E: anthony.barnett@heartofengland.nhs.uk
The Impact of Diabetes and Patient Needs diabetes promoting weight gain, there is a need for treatments that do not
With the increasing problem of obesity related to sedentary lifestyles exacerbate obesity and have a low risk for hypoglycemia.
and calorie-rich diets, the incidence and prevalence of type 2 diabetes
are increasing at an alarming pace. Diabetes has a major impact in The Incretin System
terms of patient quality of life and is associated with significant The incretin effect is the greater increment in plasma insulin levels
economic burden in terms of medical costs and lost productivity. In induced by an equivalent glucose load administered orally rather than
2007, it was estimated that 57 and 24 million North Americans had pre- intravenously. It is mediated via endocrine peptide hormones secreted by
diabetes and diabetes, respectively.
1
Estimated annual costs for the intestine in response to nutrient exposure. The two major incretin
diabetes in 2007 were $172 billion.
1
From a European perspective, it has hormones are glucagon-like peptide-1 (GLP-1) and glucose insulinotrophic
been estimated that diabetes affects approximately 3–4 million 20–39- polypeptide (GIP), which in healthy individuals may be responsible for
year-olds, 20 million 40–59-year-olds, and 30 million 60–79-year-olds.
2
around 70% of the post-prandial insulin response.
3
Pre-diabetes and type 2 diabetes are closely associated with obesity and There is a reduction of the incretin effect in individuals with type 2
other major cardiovascular risk factors, such as dyslipidemia and diabetes, which can be rectified through the administration of
hypertension. Diabetes can also exacerbate the risks posed by other exogenous native GLP-1.
3,4
Hence, continuous intravenous infusion of
cardiovascular risk factors.
1
With the incidence of diabetes increasing in GLP-1 in subjects with type 2 diabetes increases insulin secretion,
both older and younger age groups, society is facing a burden of diabetes- reduces glucagon secretion, and lowers plasma glucose.
5
The effect of
associated morbidity and mortality. In addition, with many treatments for GLP-1 is glucose-dependent, so despite ongoing infusion of GLP-1,
© TOUCH BRIEFINGS 2009 57
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