Selective regulation of cellular and secreted multimeric adiponectin by antidiabetic therapies in humans

• Published in: American journal of physiology: endocrinology and metabolism Vol. 297; no. 3; pp. E767 - E773
• Main Authors: Phillips, Susan A, Kung, Jacqueline, Ciaraldi, Theodore P, Choe, Charles, Christiansen, Louis, Mudaliar, Sunder, Henry, Robert R
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.09.2009
• Subjects: Adiponectin - blood; Adiponectin - chemistry; Adiponectin - metabolism; Adiponectin - secretion; Adipose tissue; Adult; Aged; Cells; Correlation analysis; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Dose-Response Relationship, Drug; Double-Blind Method; Effects; Female; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin; Intracellular Space - drug effects; Intracellular Space - metabolism; Male; Metformin - administration & dosage; Middle Aged; Molecular Weight; Protein Isoforms - blood; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Protein Isoforms - secretion; Protein Multimerization - drug effects; Proteins; Substrate Specificity; Thiazolidinediones - administration & dosage; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use; Tissues; Young Adult
• ISSN: 0193-1849; 1522-1555; 1522-1555
• DOI: 10.1152/ajpendo.00378.2009

1 Veterans Affairs San Diego Healthcare System, San Diego; and Departments of 2 Pediatrics and 3 Medicine, University of California, San Diego, La Jolla, California Submitted 12 June 2009 ; accepted in final form 8 July 2009 Adiponectin, an insulin-sensitizing factor secreted from adipose tissue, is decreased in individuals with type 2 diabetes (T2D) and increased in response to thiazolidinedione (TZD) therapy. Changes in its secretion and assembly into higher-order forms affect insulin sensitivity. To determine the relative potency of TZDs on intra-adipocyte multimerization and secretion of adiponectin, we assessed the impact of in vivo low- or high-dose rosiglitazone treatment alone or combined with metformin in subjects with T2D. T2D subjects received high-dose rosiglitazone (8 mg/day), high-dose metformin (2,000 mg/day), or low-dose combination rosiglitazone-metformin therapy (4 mg + 1,000 mg/day) for 4 mo. All subjects were then switched to high-dose rosiglitazone-metformin combination therapy (8 mg + 2,000 mg/day) for another 4 mo. Low-dose rosiglitazone increased serum adiponectin, whereas the high dose increased both adipocyte content and serum adiponectin levels. TZDs selectively increased the percentage of circulating adiponectin in the potent, high-molecular-weight (HMW) form. No TZD effects were evident on multimer distribution in the cell. Expression of the chaperone protein ERp44, which retains adiponectin within the cell, was decreased by TZD treatment. No changes occurred in Ero1-L expression. Metformin had no effect on any of these measures. Increases in adiponectin correlated with improvements in insulin sensitivity. In vivo, TZDs have apparent dose-dependent effects on cellular and secreted adiponectin. TZD-mediated improvements in whole body insulin sensitivity are associated with increases in circulating but not cellular levels of the HMW adiponectin multimer. Finally, TZDs promote the selective secretion of HMW adiponectin, potentially, in part, through decreasing the expression of the adiponectin-retaining protein ERp44. thiazolidinedione; adipocyte; ERp44; Ero1-L ; chaperone proteins Address for reprint requests and other correspondence: S. A. Phillips, Children's Hospital, 3020 Children's Wy, MC 5103, San Diego, CA 92123 (E-mail: saphillips{at}ucsd.edu )