Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and GIP degradation.
, Duffy N
, Lindsay J
, Green B
, Patterson S
, O'Harte F
, Bell P
, Flatt P
A McKillop, School of Biomedical Sciences, University of Ulster, Coleraine, United Kingdom.
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 (120mg) 10 min prior to a 75g oral glucose load in a randomised cross-over design. Results: Plasma glucose reached 18.2 +/- 1.7 mmol/l 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/min, P<0.05), reaching a minimum of 1.9 +/- 0.1 nmol/ml/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 +/- 163.9pmol/l (P<0.05) and 11.8 +/- 1.4mg/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) <italic>in vitro</italic>. Comparison of <italic>in vitro</italic> inhibition of DPP-IV by nateglinide and vildagliptin revealed IC<sub>50</sub> values of 17.1 muM and 2.1 muM, respectively. Conclusions: Although considerably less potent than specified DPP-IV inhibitors, the possibility that some of the beneficial actions of nateglinide are mediated indirectly through DPP-IV inhibition and increased bioavailability of GIP and other incretins merits consideration.
PMID: 19755410 [PubMed - as supplied by publisher]