Lipoprotein profiles across a spectrum of insulin signaling.

Background: Obesity and type 2 diabetes (T2D) are associated with insulin resistance (IR), a risk factor for atherosclerotic cardiovascular disease (ASCVD). In these conditions, IR affects only a subset of insulin signaling pathways, with preserved insulin signaling in others (termed "pathway-selective IR"). Consequently, individuals with obesity and T2D develop both hypertriglyceridemia from excess insulin signaling and hyperglycemia from insufficient insulin signaling.

Objective: As IR involves biology mediated by both increased and decreased insulin signaling, we created a conceptual rare disease model to better understand whether ASCVD risk in states of IR is predominately driven by excessive insulin action, insufficient insulin action, or a combination of both.

Methods: We compared nuclear magnetic resonance lipoprotein profiles (markers of ASCVD risk) in 14 patients (86% female, age 39 ± 17 years) with type B IR (TBIR), a disorder where autoantibodies against the insulin receptor block all insulin signaling (low insulin signaling), which is restored in remission (normal insulin signaling). Age and sex- matched patients with lipodystrophy were included to represent high insulin signaling.

Results: Across the spectrum of insulin signaling, from lowest (TBIR active) to intermediate (TBIR remission) to highest (lipodystrophy), there were increases in all triglyceride-rich lipoprotein parameters. We also observed a shift toward smaller high-density lipoprotein (HDL) particles, with reciprocal decreases in large HDL-Ps and increases in small HDL-Ps across groups.

Conclusion: Excess insulin signaling contributes to a proatherogenic lipoprotein profile. Interventions that downregulate or rebalance insulin signaling may offer cardiovascular benefits for individuals with severe (lipodystrophy) and mild (obesity and T2D) forms of pathway-selective IR.