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Adenovirus-mediated chronic “hyper-resistinemia” leads to in vivo insulin resistance in normal rats
Hiroaki Satoh, … , Isao Usui, Jerrold M. Olefsky
Hiroaki Satoh, … , Isao Usui, Jerrold M. Olefsky
Published July 15, 2004
Citation Information: J Clin Invest. 2004;114(2):224-231. https://doi.org/10.1172/JCI20785.
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Article Metabolism Article has an altmetric score of 3

Adenovirus-mediated chronic “hyper-resistinemia” leads to in vivo insulin resistance in normal rats

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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.

Authors

Hiroaki Satoh, M.T. Audrey Nguyen, Philip D.G. Miles, Takeshi Imamura, Isao Usui, Jerrold M. Olefsky

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Figure 1

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Adenoviral transduction of mouse resistin expression. (A) Structure of A...
Adenoviral transduction of mouse resistin expression. (A) Structure of Adv encoding mouse resistin. δE1 and δE3 indicate deletion of early genes 1 and 3. Arrows indicate direction of gene transcription in the construct. (B) Analysis of Adv-infected rat liver for lacZ expression. Rats were injected with Adv-lacZ and euthanized on day 7 after injection, and liver tissue was evaluated for lacZ expression with the X-gal histochemical stain (left panel). Control liver did not stain with X-gal (right panel). (C and D) Western blot analysis of plasma resistin protein levels in male Wistar rats injected with Adv-resistin. (C) Plasma resistin protein level on day 7 after Adv injection. (D) Representative time course of the appearance and disappearance of resistin of adenoviral origin in the plasma of rats injected with Adv-resistin. Plasma samples were collected on the indicated day after injection (above lanes). After separation of 1 μl of the plasma samples by SDS-PAGE, proteins were transferred to PVDF membrane, and resistin was detected using a polyclonal Ab against mouse resistin.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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