title: Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans.
abstract: In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kozi
authors.initials: K
authors.lastname: Hosoya
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Minakuchi
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Fujimura
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Motoaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yoshifuji
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Futatsugi
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shinozuka
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Washida
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanda
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Tokuyama
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000368:Aged; D000450:Aldosterone / Q000097:blood / Q000378:metabolism*; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000378:metabolism; D005260:Female; D005919:Glomerular Filtration Rate; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009392:Nephrectomy; D018384:Oxidative Stress / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000503:physiopathology*; D012083:Renin / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology* / Q000627:therapeutic use; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000450:Aldosterone; D000581:Amidohydrolases; D001120:Arginine; D019405:Cytochrome P-450 CYP11B2; D017874:Immediate-Early Proteins; D000451:Mineralocorticoid Receptor Antagonists; D017346:Protein Serine-Threonine Kinases; D018161:Receptors, Mineralocorticoid; D012083:Renin; D013148:Spironolactone; D000099184:Serum-Glucocorticoid Regulated Kinases; C487735:dimethylarginine; C059999:dimethylargininase