Adiponectin release from adipocytes is stimulated by the thiazolidinedione (TZD) class of PPARγ agonists in a time-dependent fashion, with an increase within 10 days followed by a more robust effect within 3 weeks. Our previous work suggested that adiponectin exerts its metabolic effects in part by enhancing the deacylation of the sphingolipid ceramide, a lipotoxic metabolite stimulated by exposure to saturated fats or inflammatory mediators. Adiponectin receptors in fact display potent ceramidase activity. Ceramides and diacylglycerols correlate with impaired insulin action. The effects of 10 and 21 days’ pioglitazone (Pio; 45 mg/day) treatment on insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp studies in n=26 type 2 diabetic subjects (Diabetes. 62:1843, 2013). Total and high molecular weight (HMW) adiponectin levels in plasma were determined using a commercial sandwich ELISA kit. Sphingolipids in adipose tissue and plasma were quantified by liquid chromatography-tandem mass spectrometry. Improved hepatic and peripheral insulin sensitivity was seen after 21 days, but not 10 days, of Pio, and were highly correlated with an increased ratio of HMW adiponectin/total levels (r2=0.90). Variable responses in both total and HMW adiponectin defined subjects as Responders (R;≥1.5-fold increase with Pio) vs. Non-responders (NR; no change). Sphingosine-1P, a beneficial conversion product from ceramides, increased 2-fold and Sphinganine-1P increased 2.5-fold in R relative to NR and placebo (p=0.0286). Pio induced decreases in dihydroceramides and increases in lactosylceramides as a function of time and adiponectin levels, the functional significance of which needs to be further explored. This study suggests the insulin-sensitizing properties of TZDs critically depend on elevating circulating adiponectin levels, with an associated lowering of certain ceramide species involved in insulin resistance and inflammation.
R. Gordillo: None. K. Zhang: None. P.E. Scherer: None.