Initial Combination Therapy With Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin for Patients With Type 2 Diabetes Mellitus

Tina Vilsbøll


Expert Rev Endocrinol Metab. 2008;3(1):13-19. 

In This Article

Dipeptidyl Peptidase-4

The fact that native GLP-1 and GIP are cleaved rapidly by DPP-4 leading to inactivation has focused attention on the role of DPP-4 as a determinant of incretin action. DPP-4 is a widely distributed serine protease that cleaves off two amino acids from small peptides containing alanine or proline in the second position of the N-terminal part of the peptide.[23] This enzyme, also known as the T-cell antigen CD26, is found in many locations, including intestinal and renal brush-border membranes, on hepatocytes and capillary endothelial cells and in a soluble form in plasma.[24] Deacon et al. showed that in vivo N-terminal truncation of both endogenous and exogenous GLP-1 was likely to have a physiological role in mediating the rapid degradation of native GLP-1.[18,19] Inactivation of GLP-1 by DPP-4 is extremely extensive, which means that the peptide has an apparent plasma half-life of only 1-2 min and a metabolic clearance rate exceeding the cardiac output by a factor of two to three.[21] In patients with T2DM, studies suggest a correlation between glycemic control and plasma DPP-4 activity, but this does not seem to be correlated to the amount of intact biologically active hormone in plasma.[25] In 2000, Marguet et al.showed that mice with a targeted disruption of the CD26 gene had increased levels of intact endogenous GLP-1, supporting the importance of DPP-4 in GLP-1 metabolism.[26] Later, DPP-4 inhibition was shown to completely prevent the N-terminal degradation of native GLP-1 and GIP in vivoby Deacon et al., and this was also associated with enhancement of their insulinotropic effects.[27,28]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: