Lipoprotein profiles across a spectrum of insulin signaling

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.

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 predominantly driven by excessive insulin action, insufficient insulin action, or a combination of both.

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.

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 particles (HDL-Ps), with reciprocal decreases in large HDL-Ps and increases in small HDL-Ps across groups.

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.