title: Decreased circulating BMP-9 levels in patients with Type 2 diabetes is a signature of insulin resistance.
abstract: Bone morphogenetic protein 9 (BMP-9) has been demonstrated to improve glucose homoeostasis in diabetic mice. However, no report has demonstrated the relationship of circulating BMP-9 levels with insulin resistance (IR) or Type 2 diabetes mellitus (T2DM) in humans. The objective of the present study was to investigate the relationship between BMP-9 and IR in cross-sectional and interventional studies. Circulating BMP-9 levels were analysed by ELISA in 280 well-characterized individuals. Two-hour oral glucose tolerance test (OGTT) and euglycaemic-hyperinsulinaemic clamp (EHC) were performed in 20 healthy subjects. Acute IR was induced by lipid infusion for 4 h in 20 healthy volunteers. Real-time (RT)-PCR and Western blotting were used to assess mRNA and protein expression of BMP-9. The effect of a glucagon-like peptide-1 (GLP-1) receptor agonist (PEX168) on circulating BMP-9 was investigated in a 24-week treatment trial. Circulating BMP-9 levels were significantly higher in healthy subjects than in newly diagnosed patients with T2DM. Circulating BMP-9 negatively correlated with HbA1c, fasting blood glucose (FBG), OGTT, the area under the curve for glucose (AUCglucose) and homoeostasis model assessment of insulin resistance (HOMA-IR). Multivariate regression analyses showed that BMP-9 levels were independently associated with non-esterified fatty acid (NEFA) and AUCglucoseBoth hyperinsulinaemia and lipid infusion decreased circulating BMP-9 levels. BMP-9 mRNA and protein expressions were significantly decreased in muscle and adipose tissues of T2DM patients. In the placebo treated group, BMP-9 levels continued to decline over time, whereas in the PEX 168 treated groups BMP-9 levels remained stable. Our data suggest that BMP-9 is likely to play an important role in IR in humans.
authors.affiliation: The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Luo
authors.affiliation: The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400010, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Mengliu
authors.initials: M
authors.lastname: Yang
authors.affiliation: The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China.
authors.forename: Huaming
authors.initials: H
authors.lastname: Mou
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Chenrongrong
authors.initials: C
authors.lastname: Cai
authors.affiliation: Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, U.S.A.
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.affiliation: The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China xianxiangzh@163.com) gangyiyang@163.com.|Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Gangyi
authors.initials: G
authors.lastname: Yang
authors.affiliation: The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China xianxiangzh@163.com) gangyiyang@163.com.
authors.forename: Xianxiang
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005230:Fatty Acids, Nonesterified; D005260:Female; D005951:Glucose Tolerance Test; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000097:blood*; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism; D010455:Peptides; D011092:Polyethylene Glycols
chemical_list: D015415:Biomarkers; D005230:Fatty Acids, Nonesterified; C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D010455:Peptides; C000601947:polyethylene glycol loxenatide; D011092:Polyethylene Glycols
keywords: Type 2 diabetes mellitus; bone morphogenetic protein 9 (BMP-9); insulin resistance