Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments

doi:10.1016/j.bbrc.2004.09.021

Biochemical and Biophysical Research Communications

Volume 324, Issue 1, 5 November 2004, Pages 92-97

https://doi.org/10.1016/j.bbrc.2004.09.021 Get rights and content

Abstract

Dipeptidyl peptidase-IV (DPP-IV) regulates metabolism by degrading incretins involved in nutritional regulation. Metformin and pioglitazone improve insulin sensitivity whereas glyburide promotes insulin secretion. Zucker diabetic rats were treated with these antidiabetic agents for 2 weeks and DPP-IV activity and expression were determined. Serum DPP-IV activity increased whereas tissue activity decreased as the rats aged. Treatment of rats with metformin, pioglitazone, and glyburide did not alter DPP-IV mRNA expression in liver or kidney. Metformin and pioglitazone significantly (P < 0.05) reduced serum DPP-IV activity and glycosylated hemoglobin. Glyburide did not lower DPP-IV activity or glycosylated hemoglobin. Regression analysis showed serum DPP-IV activity correlated with glycosylated hemoglobin (r = 0.92) and glucagon-like peptide-1 levels (r = −0.49). Metformin, pioglitazone, and glyburide had no effect on serum DPP-IV activity in vitro, indicating these are not competitive DPP-IV inhibitors. We propose the in vivo inhibitory effects observed with metformin and pioglitazone on serum DPP-IV activity results from reduced DPP-IV secretion.

Section snippets

Chemicals

Metformin (1,1-dimethylbiguanide hydrochloride, Catalog # D5035) and glyburide (Catalog # G-0639) were obtained from Sigma (St. Louis, MO 63178) and pioglitazone, GW7845, and LAF237 were from GlaxoSmithKline chemical storage.

In vivo studies

Animals. All studies were conducted using age- and weight-matched male ZDF fa/fa rats (Genetic Models, Indianapolis, IN) or db/db mice (Jackson Labs) housed at 72 °F and 50% relative humidity with a 12 h light/dark cycle. Rats were fed PMI 5008 Formulab Diet (PMI Nutrition

Effects of treatment on serum DPP-IV activity, glucose, glycosylated hemoglobin, GLP-1, and insulin levels

ZDF rats represent an animal model of non-insulin-dependent diabetes that are characterized by profound insulin resistance, insulin hypersecretion, and obesity. To investigate whether altered glycemic control affects DPP-IV activity in vivo, ZDF rats at 6.5 and 8.5 weeks of age were treated with vehicle, glyburide, metformin or pioglitazone for 2 weeks. DPP-IV activity, glycosylated hemoglobin and glucose levels were 218%, 52%, and 84% greater (P < 0.05), respectively, in serum from the older

Discussion

While Mannucci et al. [11] reported that metformin inhibits serum DPP-IV in vitro, Yasuda et al. [12] and Hinke et al. [13] reported that metformin is not a competitive inhibitor of DPP-IV. Our results also demonstrate metformin and piogitazone are not competitive inhibitors of DPP-IV activity in vitro. Moreover, we show pioglitazone or metformin treatment lowered serum DPP-IV activity and glucose levels, whereas glyburide was ineffective. Although DPP-IV activity was reduced in serum after

Acknowledgments

We thank Jane Binz, Daphne Clancy, John Hughes, Shelby Martenson, and Tracy Brainard for technical support.

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Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments

Abstract

Section snippets

Chemicals

In vivo studies

Effects of treatment on serum DPP-IV activity, glucose, glycosylated hemoglobin, GLP-1, and insulin levels

Discussion

Acknowledgments

An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)

J. Biol. Chem.

PPAR gamma/RXR as a molecular target for diabetes

Receptors Channels

Glibenclamide: an old drug with a novel mechanism of action?

Acta Diabetol.

The role of ion channels in insulin secretion

J. Cell. Biochem.

Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects

J. Clin. Endocrinol. Metab.

Effect of metformin on patients with impaired glucose tolerance

Diabet. Med.

Natural substrates of dipeptidyl peptidase IV

Adv. Exp. Med. Biol.

Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes

Expert Opin. Invest. Drugs

Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26

Proc. Natl. Acad. Sci. USA

Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide

Diabetes

Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects

Diabetes Care

Enhanced secretion of glucagon-like peptide 1 by biguanide compounds

Biochem. Biophys. Res. Commun.