期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 10, 页码 3817-3822出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1312436111
关键词
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资金
- Barts and the London National Institute of Health Research Cardiovascular Biomedical Research Unit
- European Foundation for the Study of Diabetes/Lilly research fellowship
- Wellcome Trust
- British Heart Foundation Centre of Research Excellence
- British Heart Foundation [RG/11/4/28734] Funding Source: researchfish
- Medical Research Council [MR/K026992/1] Funding Source: researchfish
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. 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta HSD1) 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 11 beta HSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11 beta HSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11 beta HSD 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, 11 beta HSD1(-/-) mice and rats treated with a specific 11 beta HSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11 beta HSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11 beta HSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.
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