Genetic Study links High Insulin to Lower Lp(a) Levels, Offers New Insights into Type 2 Diabetes Risk

"These findings indicate that hyperinsulinemia, commonly associated with type 2 diabetes (T2D), may partly explain why lower Lp(a) concentrations are linked to a higher risk of developing T2D," the researchers wrote.

Commenting on the clinical implications, the authors underscore two key points. First, the connection between Lp(a) and diabetes is complex; Lp(a) is likely not an independent risk factor for diabetes outside the context of existing hyperinsulinemia and insulin resistance. Second, while reducing Lp(a) through therapy might be linked to increased diabetes risk, this does not necessarily translate into adverse outcomes. Therapies to improve insulin resistance and glycemic control, which may raise Lp(a) levels, generally offer significant cardiometabolic benefits. The overall positive impact on patient survival from effective glycemic control suggests that the benefits of such therapies outweigh the risks associated with increased Lp(a).

Several observational studies have suggested an inverse relationship between circulating Lp(a) levels and the risk of type 2 diabetes. However, recent MR studies have shown inconsistent support for this association. In vitro research indicates that elevated insulin concentrations may lower Lp(a) levels by influencing the synthesis of apolipoprotein(a) [apo(a)]. Considering this, Mateusz Lejawa, Medical University of Silesia, Katowice, Poland, and colleagues aimed to explore the relationship between genetically predicted insulin concentrations and Lp(a) levels, which might help clarify why low Lp(a) levels are associated with higher risk of T2D.

For this purpose, the researchers identified independent genetic variants strongly linked to fasting insulin levels through meta-analyses of genome-wide association studies (GWAS) involving European populations (N = 151,013). Summary-level data for Lp(a) in individuals of European ancestry were obtained from a GWAS conducted within the UK Biobank (N = 361,194). Two-sample summary-level Mendelian randomization (MR) was performed using the inverse-variance weighted (IVW) method.

To ensure robustness, several sensitivity analyses were employed, including MR-Egger, the weighted median (WME) method, MR pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out analysis, and MR Steiger.

The study led to the following findings:

• Genetically predicted fasting insulin levels were negatively associated with Lp(a) levels (β = − 0.15, SE = 0.05).
• The sensitivity analysis revealed that WME (β = − 0.26, SE = 0.07), but not MR‒Egger (β = − 0.22, SE = 0.13), supported a causal relationship between genetically predisposed insulin levels and Lp(a).

The analysis suggests higher serum insulin levels may lower Lp(a) concentrations. However, limitations include reliance on summary-level data, exclusion of diabetic patients, lack of subgroup analyses, and focus on individuals of European descent. Further research is needed to explore indirect effects and generalizability across diverse populations.

"Our findings indicate that hyperinsulinemia, commonly seen in type 2 diabetes (T2D), may partly account for the observed inverse relationship between low Lp(a) levels and elevated T2D risk. Further research is required to confirm this link and elucidate the precise mechanisms underlying this association," the researchers concluded.

Reference:

Lejawa, M., Goławski, M., Fronczek, M. et al. Causal associations between insulin and Lp(a) levels in Caucasian population: a Mendelian randomization study. Cardiovasc Diabetol 23, 316 (2024). https://doi.org/10.1186/s12933-024-02389-7