Insulin Response to Glucose and Type 2 Diabetes and Its Impact on Cardiometabolic Disease: A Sex-stratified Mendelian Randomization Study to Assess Potential Causality.

OBJECTIVES

Hyperinsulinemia is implicated in obesity, type 2 diabetes (T2D), and heart disease (cardiometabolic disease [CMD]). Our previous sex-combined Mendelian randomization (MR) study suggested that increased insulin response 30 minutes after oral glucose ingestion, adjusted for glycemia (corrected insulin response [CIR]), may modestly increase body mass index (BMI) but protect against T2D and dyslipidemia.

METHODS

Given the sex differences in fat distribution, we undertook sex-stratified MR to assess the potential causal effect of CIR on adiposity and CMD using summary statistics from the largest genome-wide association studies of European ancestries. A Bonferroni-adjusted p value of ≤0.003 was considered significant and p≤0.05 nominally significant.

RESULTS

Inverse variance weighted MR (IVWMR) suggested that increased CIR may increase leg fat percentage in females (females: β=0.311±0.10, p=0.002; males: β=0.253±0.12, p=0.035), reduce triglyceride levels (males: β=-0.046±0.015, p=0.002; females: β=-0.077±0.023, p=9.17×10-4), and protect against type 2 diabetes (males: odds ratio [OR] 0.471, 95% confidence interval [CI] 0.327-0.676, p=4.64×10-5; females: OR 0.511, 95% CI 0.372-0.701, p=3.31×10-5). After Bonferroni correction, we found no evidence that increased CIR modulates BMI, waist-to-hip ratio, high-density lipoprotein cholesterol, or coronary artery disease in either sex. Reverse IVWMR indicated that T2D reduced CIR only in males (OR 0.613-0.927, p=5.47×10-3).

CONCLUSIONS

Increased CIR may have beneficial effects on T2D and lipids in both sexes, with no evidence of deleterious effects on adiposity and CMD.