[Resistin Program for Diabetes -- Preclinical Studies -- Isis]
>>Published Online July 1, 2004
J. Clin. Invest., doi: 10.1172/JCI200421270
Online First Publication
Role of resistin in diet-induced hepatic insulin resistance
Evan D. Muse 1, Silvana Obici 2, Sanjay Bhanot 3, Brett P Monia 3, Robert A. McKay 3, Michael W. Rajala 4, Philipp E. Scherer 5, Luciano Rossetti 6*
1 Department of Molecular Pharmacology, 2 Department of Medicine, and Diabetes Research and Training Center, Albert Einstein College of Medicine, New York, New York, USA. 3 ISIS Pharmaceuticals, Carlsbad, California, USA. 4 Department of Cell Biology, Albert Einstein College of Medicine, New York, New York, USA. 5 Department of Medicine, and 3Diabetes Research and Training Center, Albert Einstein College of Medicine, New York, New York, USA. 6 Department of Pharmacology and Diabetes Research & Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, New York 10461, USA. Phone: (718) 430-4118; Fax: (718) 430-8557
* Address correspondence to: E-mail: rossetti@aecom.yu.edu.
Received for publication May 25, 2004, and accepted in revised form April 14, 2004
Abstract
Resistin is an adipose-derived hormone postulated to link adiposity to insulin resistance. To determine whether resistin plays a causative role in the development of diet-induced insulin resistance, we lowered circulating resistin levels in mice by use of a specific antisense oligodeoxynucleotide (ASO) directed against resistin mRNA and assessed in vivo insulin action by the insulin-clamp technique. After 3 weeks on a high-fat (HF) diet, mice displayed severe insulin resistance associated with an approximately 80% increase in plasma resistin levels. In particular, the rate of endogenous glucose production (GP) increased more than twofold compared with that in mice fed a standard chow. Treatment with the resistin ASO for 1 week normalized the plasma resistin levels and completely reversed the hepatic insulin resistance. Importantly, in this group of mice, the acute infusion of purified recombinant mouse resistin, designed to acutely elevate the levels of circulating resistin up to those observed in the HF-fed mice, was sufficient to reconstitute hepatic insulin resistance. These results provide strong support for a physiological role of resistin in the development of hepatic insulin resistance in this model.<<
>>Published Online July 1, 2004
J. Clin. Invest., doi: 10.1172/JCI200420785
Online First Publication
Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistance in normal rats
Hiroaki Satoh 1, M.T. Audrey Nguyen 1, Philip D.G. Miles 2, Takeshi Imamura 1, Isao Usui 1, Jerrold M. Olefsky 3*
1 Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA. 2 Department of Surgery, University of California, San Diego, San Diego, California, USA. 3 Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0673, USA. Phone: (858) 534-6651; Fax: (858) 534-6653
* Address correspondence to: E-mail: jolefsky@ucsd.edu.
Received for publication December 11, 2003, and accepted in revised form April 14, 2004
Abstract
We investigated the chronic in vivo effect of resistin on insulin sensitivity and glucose metabolism by overexpressing resistin protein in male Wistar rats using intravenous administration of an adenovirus encoding mouse resistin. After 7 days of elevated resistin levels, at a supraphysiological concentration, the animals displayed glucose intolerance and hyperinsulinemia during glucose tolerance tests, and insulin tolerance tests demonstrated an impaired glucose-lowering effect of insulin. The glucose clamp studies were performed at submaximal (4 mU/kg/min) and maximal (25 mU/kg/min) insulin infusion rates and demonstrated the presence of insulin resistance induced by elevated resistin levels. Indeed, the insulin-stimulated glucose infusion rate was decreased by 12-31%; suppression of hepatic glucose output was attenuated by 28-55%; and insulin suppression of circulating FFA levels was inhibited by 7%. Insulin receptor substrate-1 and -2 phosphorylation and Akt activation were impaired in muscle and adipose tissue. Interestingly, activation of AMP-activated protein kinase in skeletal muscle, liver, and adipose tissue was also significantly downregulated. Together, these results indicate that chronic "hyper-resistinemia" leads to whole-body insulin resistance involving impaired insulin signaling in skeletal muscle, liver, and adipose tissue, resulting in glucose intolerance, hyperinsulinemia, and hypertriglyceridemia. Thus elevated resistin levels in normal rats fed a regular chow diet produce many of the features of human syndrome X.<<
Cheers, Tuck |
