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Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

Lookup NU author(s): Professor Brian Walker

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Abstract

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1./. mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.


Publication metadata

Author(s): Chapagain A, Caton PW, Kieswich J, Andrikopoulos P, Nayuni N, Long JH, Harwood SM, Webster SP, Raftery MJ, Thiemermann C, Walker BR, Seckl JR, Corder R, Yaqoob MM

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2014

Volume: 111

Issue: 10

Pages: 3817-3822

Print publication date: 11/03/2014

Online publication date: 25/02/2014

Acceptance date: 29/01/2014

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: https://doi.org/10.1073/pnas.1312436111

DOI: 10.1073/pnas.1312436111

PubMed id: 24569863


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