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This Article Full Text Full Text (PDF) All Versions of this Article: EJE-09-0547v1 161/6/877    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by McKillop, A. M Articles by Flatt, P. R PubMed PubMed Citation Articles by McKillop, A. M Articles by Flatt, P. R

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation

School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK¹ Endocrinology and Diabetes, Altnagelvin Hospital, Londonderry, Northern Ireland, UK² School of Biological Sciences, Queens University Belfast, Belfast, Northern Ireland, UK³ Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, Northern Ireland, UK

(Correspondence should be addressed to A M McKillop; Email: am.mckillop{at}ulster.ac.uk)

Background: Nateglinide restores early-phase insulin secretion to feeding and reduces postprandial hyperglycaemia in type 2 diabetes. This study evaluated the effects of nateglinide on dipeptidyl peptidase-IV (DPP-IV) activity and glucose-dependent insulinotropic polypeptide (GIP) degradation.

Research design and methods: Blood samples were collected from type 2 diabetic subjects (n=10, fasting glucose 9.36±1.2 mmol/l) following administration of oral nateglinide (120 mg) 10 min prior to a 75 g oral glucose load in a randomised crossover design.

Results: Plasma glucose reached 18.2±1.7 and 16.7±1.7 mmol/l at 90 min in control and placebo groups (P<0.001). These effects were accompanied by prompt 32% inhibition of DPP-IV activity after 10 min (19.9±1.6 nmol/ml per min, P<0.05), reaching a minimum of 1.9±0.1 nmol/ml per min at 120 min (P<0.001) after nateglinide. Insulin and C-peptide levels increased significantly compared with placebo, to peak after 90 min at 637.6±163.9 pmol/l (P<0.05) and 11.8±1.4 mg/l (P<0.01) respectively. DPP-IV-mediated degradation of GIP was significantly less in patients receiving nateglinide compared with placebo. Inhibition of DPP-IV activity corresponded with a time- and concentration-dependent inhibitory effect of nateglinide on DPP-IV-mediated truncation of GIP(1–42) to GIP(3–42) in vitro. Comparison of in vitro inhibition of DPP-IV by nateglinide and vildagliptin revealed IC₅₀ values of 17.1 and 2.1 µM respectively.

Conclusions: Although considerably less potent than specified DPP-IV inhibitors, the possibility that some of the beneficial actions of nateglinide are indirectly mediated through DPP-IV inhibition and increased bioavailability of GIP and other incretins merits consideration.