title: Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia.
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.
authors.affiliation: Centre of Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Ananda
authors.initials: A
authors.lastname: Chapagain
authors.forename: Paul W
authors.initials: PW
authors.lastname: Caton
authors.forename: Julius
authors.initials: J
authors.lastname: Kieswich
authors.forename: Petros
authors.initials: P
authors.lastname: Andrikopoulos
authors.forename: Nanda
authors.initials: N
authors.lastname: Nayuni
authors.forename: Jamie H
authors.initials: JH
authors.lastname: Long
authors.forename: Steven M
authors.initials: SM
authors.lastname: Harwood
authors.forename: Scott P
authors.initials: SP
authors.lastname: Webster
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Raftery
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: Roger
authors.initials: R
authors.lastname: Corder
authors.forename: Muhammad Magdi
authors.initials: MM
authors.lastname: Yaqoob
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose; D002229:Carbenoxolone / Q000008:administration & dosage / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005938:Glucocorticoids / Q000378:metabolism; D015151:Immunoblotting; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D014511:Uremia / Q000201:enzymology* / Q000209:etiology
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D005938:Glucocorticoids; D007328:Insulin; D012333:RNA, Messenger; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D002229:Carbenoxolone; D003345:Corticosterone