title: Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actions.
abstract: The pharmacological actions of the glucagon-like peptide-1 receptor agonists (GLP-1RA) are largely predictable as they interact directly with GLP-1 receptors on beta cells to mediate their glucose lowering effects by increasing GLP-1 in pharmacological range and not at all dependent upon endogenous GLP-1 secretion. The mechanism of action of dipeptidyl peptidase-4 inhibitors (DPP-4I) are relatively less clear although classical mechanism is to inhibit the endogenous GLP-1 metabolism and thereby increasing GLP-1 level in the physiological range. DPP-4I also increase the half-life of GLP-1 to some extent by inhibiting their quick degradation by DPP enzyme ubiquitously present in the body. Interestingly, even with the effective blockade with currently existing DPP-4I, the half-life of GLP-1 only increases from 1 min to 5 min and therefore its residual time in plasma still remains pretty short. Intriguingly, this GLP-1 rise is so modest and so short-lived that it may be difficult to believe that this would sufficiently engage and activate the GLP-1 receptor in beta cell to produce significant insulinotropic effect. However, in clinical trials as well as in real life scenario, the anti-glycemic efficacies seen with DPP-4I are quite satisfactory and sometime very much competitive to GLP-1RA as evident from their head-to-head trials including meta-analysis. This efficacy outcome challenges the "only" GLP-1 dependent mechanism of glucose lowering and provokes an insight that other neuro-endocrine pathway may be playing a second fiddle. This review will collate those emerging concept and put a perspective as to how DPP-4I might be working though other pathway besides direct GLP-1 mediated receptor activation.
authors.affiliation: Senior Consultant Endocrinologist, G. D. Diabetes Hospital, Kolkata, West Bengal, India ; Sun Valley Diabetes Hospital, Guwahati, Assam, India.
authors.forename: Awadhesh Kumar
authors.initials: AK
authors.lastname: Singh
keywords: Dipeptidyl peptidase-4 inhibitors; glucagon-like peptide-1; glucagon-like peptide-1 agonist; glucose-dependent intestinal polypeptide; incretin; type 2 diabetes