Gliptin Therapies for Inhibiting Dipeptidyl Peptidase-4 in Type 2 Diabetes

European Endocrinology, 2010;6(2):19-25 DOI:


Discovery of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) has led to the clinical development of incretin-based therapies for type 2 diabetes. Incretins are intestinal peptide hormones that stimulate post-prandial insulin secretion and improve glycaemic control. Gliptins are drugs that inhibit a ubiquitous enzyme, dipeptidyl peptidase-4 (DPP-4), preventing the physiological breakdown of incretins and thereby enhancing endogenous incretin action. Three ‘gliptins’ have recently been introduced into clinical practice: sitagliptin, vildagliptin and saxagliptin. This review provides an overview of these new antidiabetic agents and comments onsome exciting future prospects for incretins and agents that enhance incretin action.

Diabetes, incretin, gliptin, antidiabetic drugs, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), dipeptidyl peptidase-4 (DPP-4)

Disclosure: Brian D Green has no conflicts of interest to declare. Clifford J Bailey has undertaken ad-hoc consultancy in the past for pharmaceutical companies including Merck Sharp & Dohme and Takeda. Peter R Flatt has undertaken research sponsored by pharmaceutical companies, but not related to this manuscript.
Received: 2 December 2009 Accepted: 8 June 2010 Citation: European Endocrinology, 2010;6(2):19–25
Correspondence: Brian D Green, School of Biological Sciences, Queens University Belfast, Belfast, Northern Ireland, BT9 5AG, UK. E:

Intestinal Hormones and Glucose Regulation

The importance of the intestine in regulating post-prandial glucose levels unfolded over the latter half of the 20th century. Observations in the early 20th century demonstrated that intestinal extracts could alleviate diabetes, but these studies were overlooked.1,2 It was not until the 1960s that the ‘enteroinsular axis’ and the incretin effect were defined. The enteroinsular axis is a network of neural and endocrine signals between the intestine and the pancreas that promote insulin release in response to feeding.3 Incretins are intestinal endocrine hormones and are important components of the enteroinsular axis.3 Thus far, two incretin hormones that potently stimulate insulin secretion at physiological concentrations have been identified: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).

The Incretin Hormones – Discovery and Physiological Actions

GLP-1 was discovered in complementary DNA (cDNA) derived from the anglerfish when molecular biology techniques were employed to investigate the proglucagon gene.4 Subsequent work revealed the mammalian sequences of GLP-1 and identified GLP-1(7–36) amide as the major bioactive peptide, characterised by a potent dose-dependent insulinotropic action.5,6 GIP was identified much earlier than GLP-1 in an impure porcine enterogastrone extract.7 Initial effects on the stomach gave rise to the original name ‘gastric inhibitory polypeptide’, which was later changed to reflect its potent insulin secretory action on pancreatic beta-cells.8–11 GLP-1 and GIP are released post-prandially from intestinal L- and K-cells, respectively, and they are effective modulators of glucose-dependent insulin secretion.6,12 This glucose-dependent character has been a key feature in the clinical exploitation of incretins because it limits the risk of hypoglycaemia. In vitro studies have shown that GLP-1 and GIP can upregulate pro-insulin gene transcription and enhance the growth, differentiation, proliferation and survival of pancreatic beta-cells.13–15 Furthermore, GLP-1 and GIP appear to act as a beta-cell mitogenic and anti-apoptotic factor.16,17 The hormones have a range of extrapancreatic effects (see Figure 1), which are reviewed elsewhere.6 Regulatory actions of incretins involve effects on glucose and energy metabolism as well as having actions on the liver, skeletal muscle and adipose tissues.5,6,18–20 As a consequence of the early work characterising biological actions, the incretin hormones gradually gained a reputation as novel therapeutic agents for the treatment of diabetes and related metabolic disorders.6
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