Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes

The treatment of type 2 diabetes with full peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists improves insulin sensitivity, but is associated with weight gain, heart failure, peripheral oedema and bone loss. Endotrophin, the C-terminal fragment of the alpha 3 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 PPAR gamma agonists, improving the risk-to-benefit ratio. The BALLET trial (NCT00515632) compared the glucose-lowering effects and safety of the partial PPAR gamma 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 HbA(1c) and fasting serum glucose compared with baseline. The OR for a 1% and a 0.5% reduction in HbA(1c) for 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, PPAR gamma-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 PPAR gamma agonist treatment.