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

Abstract

Aims/hypothesis 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. Methods 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. Results 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, PPARγ-associated adverse effects, such as moderate-to-severe lower extremity oedema, only occurred in the lower tertile. Conclusions/interpretation 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.

Endotrophin, a multifaceted player in metabolic dysregulation and cancer progression, is a predictive biomarker for the response to PPARγ agonist treatment

“…Indeed, these findings indicate that circulating endotrophin may be a useful additional indicator for the diagnosis of diabetes. In the present study, however, the most relevant observation relates to the fact that plasma endotrophin (most likely deriving from adipose tissue) can serve as a predictive biomarker for the response of diabetic individuals to TZD exposure [26]. In the upper two tertiles of endotrophin levels, the authors observe a more drastic reduction in fasting glucose and HbA 1c levels after TZD exposure than in individuals within the lowest tertile.…”

“…In this issue of Diabetologia , Karsdal and colleagues [26] provide a novel clinical assay in which they measure circulating endotrophin, a C-terminal cleavage fragment generated from the α3 chain of collagen VI. To date, very little is known about critical markers that may be available to identify drug response rates to TZDs.…”

“…Specifically, the relationship between the response to TZDs and the level of ECM components is not well understood. In the present study [26], the authors divided participants into tertiles based on plasma endotrophin levels. They showed that serum endotrophin levels were positively associated with fasting glucose levels, as well as with HOMA-IR, triacylglycerol, adiposity and indices of fatty liver.…”

“…This suggests that individuals with circulating endotrophin levels higher than 6.3 ng/ml are more responsive to TZDs (at least for the two compounds used here, pioglitazone and balaglitazone), while patients whose plasma endotrophin level is relatively lower at baseline do not respond well to these TZDs and may be better candidates for other glucose-lowering agents. In addition, in terms of adverse effects of the glitazone-based compounds, the incidence rate of peripheral oedema (considered a severe adverse effect [SAE]) was also related to endotrophin tertiles [26]. Thus endotrophin levels may serve as a predictable indicator of at least some of the side effects of TZDs.…”

“…Subsequent larger scale studies are required to provide further insights into possible associations between endotrophin levels and some of these other adverse events of TZDs. Nevertheless, Karsdal and colleagues [26] provide an exciting new biomarker to allow for a more customisable choice of insulin-sensitising regimen for optimal results in individual patients with type 2 diabetes.…”