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Horm Metab Res 2010; 42(10): 731-735
DOI: 10.1055/s-0030-1261929
Animals, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Combination Therapy with Nateglinide and Vildagliptin Improves Postprandial Metabolic Derangements in Zucker Fatty Rats

K. Miura1 , Y. Kitahara1 , S. Yamagishi2
  • 1Pharmaceutical Research Laboratories, Ajinomoto, Kawasaki, Japan
  • 2Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
Further Information

Publication History

received 05.04.2010

accepted 21.06.2010

Publication Date:
12 July 2010 (online)

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Abstract

Postprandial metabolic derangements are one of the risk factors of cardiovascular disease in humans. Insulin resistance and/or impaired early-phase insulin secretion are major determinants of postprandial metabolic derangements. In this study, we investigated the potential utility of combination therapy with vildagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor and nateglinide, a rapid-onset/short-duration insulinotropic agent, for the treatment of postprandial metabolic derangements in Zucker Fatty (ZF) rats, an animal model of obesity with insulin resistance. ZF rats fed twice daily with or without high fat diet (HFD) were given vehicle, 50 mg/kg of nateglinide, 10 mg/kg of vildagliptin, or both for 6 weeks. Combination therapy with nateglinide and vildagliptin for 2 weeks ameliorated postprandial hyperglycemia, hypertriglyceridemia, and elevation of free fatty acid in ZF rats fed with HFD. 6-week treatment with nateglinide and vildagliptin not only increased hepatic levels of phosphorylated forkhead box protein 1A (FOXO1A), but also reduced triglyceride contents in the liver. Combination therapy also prevented the loss of pancreatic islet mass in ZF rats fed with HFD. These observations demonstrate that combination therapy with nateglinide and vildagliptin may improve postprandial metabolic derangements probably by ameliorating early phase of insulin secretion and hepatic insulin resistance, respectively, in ZF rats fed with HFD. Since combination therapy with nateglinide and vildagliptin restored the decrease in pancreatic beta cell mass, our present findings suggest that combination therapy could be a promising therapeutic strategy for postprandial dysmetabolism associated with obese and insulin resistance.

Key words

insulin resistance - postprandial metabolic derangements - vildagliptin - nateglinide

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Correspondence

S. YamagishiMD, PhD 

Department of Pathophysiology

and Therapeutics of Diabetic

Vascular Complications

Kurume University School of

Medicine

67 Asahi-machi

830-0011 Kurume

Japan

Phone: +81/942/31 7873

Fax: +81/942/31 7873

Email: shoichi@med.kurume-u.ac.jp