A New Treatment Strategy for Diabetic Dyslipidemia?

Abstract

The increased cardiovascular disease (CVD) risk associated with type 2 diabetes (T2D) is likely due in part to diabetic dyslipidemia—a condition characterized by elevated plasma levels of triglyceride‐rich lipoproteins (TRLs), smaller denser LDL particles, and decreased HDL cholesterol (1,2). Lifestyle modifications and statins are first-line interventions for CVD risk reduction in individuals with T2D, but such individuals remain at considerable risk for cardiovascular events (3). This residual CVD risk appears to be linked to abnormal metabolism of TRLs (3)—chylomicrons, VLDL, and their respective remnant lipoprotein particles (RLPs), many of which are present as intermediate-density lipoproteins (4). Thus, there is a need for developing effective and safe alternative approaches/medications to prevent and reduce diabetic dyslipidemia. In this issue of Diabetes , Roger et al. (5) report a potential new therapeutic strategy to simultaneously reduce LDL and VLDL levels by using a hybrid compound that demonstrates dual inhibition of cannabinoid-1 receptor (CB1R) and inducible nitric oxide synthase (iNOS) in a mouse model. The elevated TRLs in T2D are generally attributed to hepatic overproduction of apolipoprotein B (APOB)-containing VLDL, increased intestinal secretion of APOB48 (a truncated form of APOB100 in chylomicrons and their remnants), and dysregulated clearance of TRLs (1,2,6,7), as shown by Fig. 1. Insulin resistance and the resulting elevated fatty acids are believed to be responsible for the abnormal TRL metabolism in T2D (1,2,7). For example, inhibition of the transcription factor FoxO1 by insulin-induced Akt activation represses expression of microsomal triglyceride transfer …