title: Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes.
abstract: The treatment of type 2 diabetes with full peroxisome proliferator-activated receptor gamma (PPARγ) agonists improves insulin sensitivity, but is associated with weight gain, heart failure, peripheral oedema and bone loss. Endotrophin, the C-terminal fragment of the α3 chain of procollagen type VI (also called Pro-C6), is involved in both adipose tissue matrix remodelling and metabolic control. We established a serum assay for endotrophin to assess if this novel adipokine could identify type 2 diabetic patients who respond optimally to PPARγ agonists, improving the risk-to-benefit ratio.
  
  
  
  The BALLET trial (NCT00515632) compared the glucose-lowering effects and safety of the partial PPARγ agonist balaglitazone with those of pioglitazone in individuals with type 2 diabetes on stable insulin therapy. The per protocol population (n = 297) was stratified into tertiles based on baseline endotrophin levels. Participants were followed-up after 26 weeks, after which correlational analysis was carried out between endotrophin levels and measures of glucose control. This is a secondary post hoc analysis.
  
  
  
  Endotrophin was significantly associated with therapeutic response to balaglitazone and pioglitazone. At week 26, only individuals in the upper two tertiles showed significant reductions in HbA1cand fasting serum glucose compared with baseline. The OR for a 1% and a 0.5% reduction in HbA1cfor individuals in the upper two tertiles were 3.83 (95% CI 1.62, 9.04) p < 0.01, and 3.85 (95% CI 1.94, 7.61) p < 0.001, respectively. Endotrophin levels correlated with adipose tissue mass, insulin resistance and fatty liver index. Notably, PPARγ-associated adverse effects, such as moderate-to-severe lower extremity oedema, only occurred in the lower tertile.
  
  
  
  Elevated endotrophin serum levels predict response to two insulin sensitisers and reduce the risk of associated adverse effects, thereby, identifying patients with type 2 diabetes who may profit from PPARγ agonist treatment.
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark. mk@nordicbioscience.com.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Henriksen
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark.
authors.forename: Federica
authors.initials: F
authors.lastname: Genovese
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Leeming
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark.
authors.forename: Mette J
authors.initials: MJ
authors.lastname: Nielsen
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark.
authors.forename: Bente J
authors.initials: BJ
authors.lastname: Riis
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark.|Center for Clinical and Basic Research (CCBR), Ballerup, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark.
authors.forename: Inger
authors.initials: I
authors.lastname: Byrjalsen
authors.affiliation: Institute of Translational Immunology and Research Center of Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany.|Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects; D024142:Collagen Type VI / Q000097:blood* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000819:agonists*; D010446:Peptide Fragments / Q000097:blood*; D000077205:Pioglitazone; D011799:Quinazolines / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D024142:Collagen Type VI; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D010446:Peptide Fragments; D011799:Quinazolines; D045162:Thiazolidinediones; C584135:endotrophin; C497232:balaglitazone; D000077205:Pioglitazone
keywords: Balaglitazone; Efficacy; PPARγ; Safety; Type 2 diabetes