Dipeptidyl Peptidase-4 Inhibition in the Management of Type 2 Diabetes

European Endocrinology, 2007(1):42-6; DOI: http://doi.org/10.17925/EE.2007.00.01.42


Dipeptidyl Peptidase-4 in the Pathophysiology of Type 2 Diabetes
Dipeptidyl peptidase-4 (DPP-4) is a enzyme that is expressed in many different tissues and cell types and that exists in two principal forms: a membrane-anchored complex, which is involved in transmembrane signalling independent of its enzymatic activity, and a circulating soluble protein with preserved enzymatic activity.1 DPP-4 has mainly been nvestigated as the enzyme responsible for inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) These two gastrointestinal hormones, which are mainly secreted after meals, enhance glucose-dependent insulin secretion.

13 GLP-1 and GIP also stimulate (3-cell proliferation, promote resistance to apoptosis and ncrease (3-cell survival, thus increasing (3-cell mass and function in the long term.1 Furthermore, GLP-1 inhibits glucagon secretion and reduces food intake through the inhibition of gastric emptying and through a direct hypothalamic effect.1 All of these actions of GIP and GLP-1 contribute to the physiological regulation of glucose homeostatis, particularly in the post-prandial state

Type 2 diabetes is associated with a reduction of meal-induced active GLP-1 levels.4,5 In type 2 diabetic patients, active GIP levels are not different from those of healthy controls,6 but the sensitivity of insulin secretion to this hormone is reduced.6,7 In vivo, both GLP-1 and GIP are rapidly inactivated through the cleavage of the N-terminal fraction of the peptide, mainly by DPP-4.1 Chronic exposure to elevated glucose concentrations induces DPP-4 expression in vitro8 and is associated with ncreased circulating enzyme activity in type 2 diabetic patients;9,10 however, DPP-4 plasma activity is not increased in type 2 diabetic patients with mild hyperglycaemia.9 The impairment of GLP-1 response to meals in type 2 diabetes is more probably due to reduced secretion rather than to increased degradation, although the induction of DPP-4 activity by high glucose levels could contribute to a further derangement in patients with very poor metabolic control

Dipeptidyl Peptidase-4 as a Therapeutic Target in Type 2 Diabetes
The inhibition of DDP-4 is an interesting target for the treatment of type 2 diabetes. Among currently available hypoglycaemic drugs, only metformin has been shown to inhibit DPP-4 activity;11,12 however, metformin is a weak DPP-4 inhibitor, capable of determining only a small increase of post-prandial GLP-1 levels.11 The effect of metformin on DPP-4 contributes only marginally to the hypoglycaemic action of the drug, which is mainly determined by the inhibition of hepatic gluconeogenesis and the stimulation of insulin-induced glucose uptake in skeletal muscles

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