ANGPTL3 as a target for treating lipid disorders in type 2 diabetes patients

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  Fig. 1. Mechanisms leading to diabetic dyslipidemia. Type 2 diabetes mellitus (T2DM) is associated with decreased levels of high-density lipoprotein-cholesterol (HDL-C) and elevated levels of atherosclerosis-inducing lipids or lipoproteins, namely, very-low-density lipoprotein (VLDL), chylomicron (CM), and small dense low-density lipoprotein (sdLDL). Under insulin-resistant conditions, insulin is insufficient to suppress the lipolysis of stored triglycerides (TGs) in adipose tissues, leading to increased levels of circulatory FFAs, which can serve as substrates for hepatic VLDL assembly. In addition, insulin in the liver fails to suppress gluconeogenesis but activates lipogenesis and increases the secretion of hepatic VLDLs, especially VLDL1. The levels of ANGPTL3 are increased under insulin-resistant conditions, which inhibits the activity of LPL and delays the clearance of VLDL. In individuals with T2DM, HDL-C levels tend to decrease, whereas ANGPTL3 inhibitors can regulate HDL function by increasing the activity of EL to preserve HDL composition, resulting in the production of small HDL. Moreover, T2DM not only leads to an increased presence of chylomicrons but also reduces their…