Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone with the potential to change diabetes. The physiological effects of GLP-1 are multiple, and many seem to ameliorate the different conditions defining the diverse physiopathology seen in type 2 diabetes. In animal studies, GLP-1 stimulates beta-cell proliferation and neogenesis and inhibits beta-cell apoptosis. In humans, GLP-1 stimulates insulin secretion and inhibits glucagon and gastrointestinal secretions and motility. It enhances satiety and reduces food intake and has beneficial effects on cardiovascular function and endothelial dysfunction. Enhancing incretin action for therapeutic use includes GLP-1 receptor agonists resistant to degradation (incretin mimetics) and dipeptidyl peptidase (DPP)-4 inhibitors. In clinical trials with type 2 diabetic patients on various oral antidiabetic regimes, both treatment modalities efficaciously improve glycaemic control and beta-cell function. Whereas the incretin mimetics induce weight loss, the DPP-4 inhibitors are considered weight neutral. In type 1 diabetes, treatment with GLP-1 shows promising effects. However, several areas need clinical confirmation: the durability of the weight loss, the ability to preserve functional beta-cell mass and the applicability in other than type 2 diabetes. As such, long-term studies and studies with cardiovascular end-points are needed to confirm the true benefits of these new classes of antidiabetic drugs in the treatment of diabetes mellitus.
Incretins, enhancers of insulin secretion, are essential for glucose tolerance, and a reduction in their function might contribute to poor beta-cell function in patients with type-2 diabetes mellitus. However, at supraphysiological doses, the incretin glucagon-like peptide-1 (GLP-1) protects pancreatic beta cells, and inhibits glucagon secretion, gastric emptying and food intake, leading to weight loss. GLP-1 mimetics, which are stable-peptide-based activators of the GLP-1 receptor, and incretin enhancers, which inhibit the incretin-degrading enzyme dipeptidyl peptidase-4, have emerged as therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here.
Title: Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials Madsbad S, Krarup T, Deacon CF, Holst JJ Ref: Curr Opin Clin Nutr Metab Care, 11:491, 2008 : PubMed
PURPOSE OF REVIEW: To discuss the virtues and shortcomings of the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes. RECENT FINDINGS: The injectable glucagon-like peptide-1 receptor agonists exenatide significantly improves glycaemic control, with average reductions in haemoglobin A1c of about 1.0%, fasting plasma glucose of about 1.4 mmol/l, and causes a weight loss of approximately 2-3 kg after 30 weeks of treatment in patients with type 2 diabetes. The adverse effects are transient nausea and vomiting. The long-acting glucagon-like peptide-1 receptor agonists liraglutide and exenatide long-acting release reduce haemoglobin A1c by about 1.0-2.0% and have fewer gastrointestinal side-effects. The orally available dipeptidyl peptidase-4 inhibitors, that is sitagliptin and vildagliptin reduce haemoglobin A1c by 0.5-1.0%, are weight neutral and without gastrointestinal side-effects. SUMMARY: The benefits and position of the glucagon-like peptide-1 analogues and the dipeptidyl peptidase-4 inhibitors in the diabetes treatment algorithm will be clarified when we have long-term trials with hard cardiovascular endpoints and data illustrating the effects on the progression of type 2 diabetes.
Title: Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake Ryskjaer J, Deacon CF, Carr RD, Krarup T, Madsbad S, Holst J, Vilsboll T Ref: European Journal of Endocrinology, 155:485, 2006 : PubMed
OBJECTIVE: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretin hormones, secreted in response to meal ingestion. The incretin hormones stimulate insulin secretion and are essential for the maintenance of normal plasma glucose concentrations. Both incretin hormones are metabolized quickly by the enzyme dipeptidyl peptidase-IV (DPP-IV). It is well known that type-2 diabetic patients have an impaired incretin effect. Therefore, the aim of the present study was to investigate plasma DPP-IV activity in the fasting and the postprandial state in type-2 diabetic patients and control subjects. DESIGN: The study included two protocols. Protocol one involved 40 fasting type-2 diabetic patients (28 men); age 61 +/- 1.4 (mean +/- s.e.m.) years; body mass index (BMI) 31 +/- 0.6 kg/m(2); HbAlc 7.2 +/- 0.2%; and 20 matched control subjects (14 men) were studied. Protocol two involved eight type-2 diabetic patients (six men); age 63 +/- 1.2 years; BMI 33 +/- 0.5 kg/m(2); HbAlc 7.5 +/- 0.4%; eight matched control subjects were included. METHODS: In protocol one, fasting values of DPP-IV activity were evaluated and in protocol two, postprandial DPP-IV activity during a standard meal test (566 kcal) was estimated. RESULTS: Mean fasting plasma DPP-IV activity (expressed as degradation of GLP-1) was significantly higher in this patient group compared with the control subjects (67.5 +/- 1.9 vs 56.8 +/- 2.2 fmol GLP-1/h (mean +/- s.e.m.); P=0.001). In the type-2 diabetic patients, DPP-IV activity was positively correlated to FPG and HbAlc and negatively to the duration of diabetes and age of the patients. No postprandial changes were seen in plasma DPP-IV activity in any of the groups. CONCLUSIONS: Plasma DPP-IVactivity increases in the fasting state and is positively correlated to FPG and HbAlc levels, but plasma DPP-IV activity is not altered following meal ingestion and acute changes in plasma glucose.
