THU335 Hyperinsulinemia Is Associated With An Atherogenic Lipoprotein Profile In Humans With Selective Insulin Resistance And An Atheroprotective Profile In Humans With Non-selective Insulin Resistance

Disclosure: D. Walzer: None. M. Lightbourne: None. M. Walter: None. Y. Dai: None. R.D. Shamburek: None. R.J. Brown: None. Insulin resistance (IR), a major risk factor for cardiovascular disease (CVD), leads to hyperglycemia and dyslipidemia. In obesity-associated IR, dyslipidemia attributed to increased stimulation of hepatic lipogenesis by insulin, whereas IR in glucoregulatory pathways leads to hyperglycemia. This dichotomy in insulin signaling pathways is termed selective IR. Lipodystrophy syndromes (LD) are rare conditions of severe, selective IR in which, like obesity, hyperinsulinemia with excess insulin receptor signaling is thought to cause high triglycerides (TG) & low HDL. By contrast, in the rare condition of insulin receptor pathogenic variants (INSR) (nonselective IR) lack of insulin signaling through its receptor despite hyperinsulinemia leads to low TG and high HDL. Rodents with hepatic INSR k/o have an atherogenic lipid profile, but the lipoprotein profile in humans with INSR is unknown. Factors influencing atherogenicity of lipoprotein particles, including cholesteryl ester transfer protein (CETP) activity and adiponectin, have not been explored in these human models of severe selective vs. non-selective IR. We characterized atherogenicity of lipoprotein particles and factors influencing these particles in subjects with LD matched 2:1 with subjects with INSR based on age and sex. All subjects had fasting lipoprotein profiles by NMR spectroscopy, apolipoproteins AI (ApoI) and B (ApoB), total adiponectin by ELISA, and CETP activity by fluorometric assay. Subjects with LD (N=24, 75% female; 8 generalized, 16 partial) had a more atherogenic lipoprotein profile vs INSR (N=12, 50% female; 6 homozygous, 6 heterozygous), with 45-fold higher large TRLP, 20-fold higher medium TRLP, 15-fold higher very small TRLP (representing IDL), 3-fold higher small LDLP, 4-fold lower large HDLP, 1.7—fold higher ApoB, and 1.4—fold lower ApoAI (p <0.05 for all). CETP activity was comparable in INSR and LD. Adiponectin was 5.9- fold lower in LD vs INSR (p <0.0001). Among all subjects, adiponectin was positively associated with HDL-C, large HDLP, HDL size, and ApoA-I (p=0.001), and negatively correlated with TRLP number & size, small LDLP, and very small TRLP (p<0.0001). Selective IR in LD is associated with an atherogenic lipoprotein particle profile. By contrast, non-selective IR in INSR is associated with an atheroprotective profile, which differs from rodent models. These divergent lipid phenotypes are not explained by different CETP activity. Although preclinical studies suggest that adiponectin promotes a favorable lipoprotein profile consistent with our observed associations, a causal link in humans is not supported by Mendelian randomization studies or rare ADIPOQ gene deletions. Overall, these findings suggest a key role of selective insulin resistance in the development of an atherogenic lipid profile. Further studies are needed to see if this profile leads to increased CVD risk. Presentation: Thursday, June 15, 2023