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

IF 2.7 4区医学 Q3 ENDOCRINOLOGY & METABOLISM

Canadian Journal of Diabetes Pub Date : 2026-08-01 Epub Date: 2026-03-06 DOI:10.1016/j.jcjd.2026.03.001

Yuchao Wu BSc, Habiba Hashemy MD, Andrew D. Paterson MD, PhD, Satya Dash MD, PhD, FRCPC

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引用次数: 0

Abstract

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.

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胰岛素对葡萄糖和2型糖尿病的反应及其对心脏代谢疾病的影响：一项性别分层孟德尔随机研究，以评估潜在的因果关系

背景：高胰岛素血症与肥胖、2型糖尿病（T2D）和心脏病（心脏代谢疾病，CMD）有关。我们之前的性别联合孟德尔随机化（MR）研究表明，口服葡萄糖摄入后30分钟胰岛素反应增加，调整血糖（校正胰岛素反应，CIR）可能会适度增加体重指数（BMI），但可以预防T2D和血脂异常。方法：考虑到脂肪分布的性别差异，我们使用欧洲血统中最大的全基因组关联研究的汇总统计数据，进行了性别分层MR，以评估CIR对肥胖和CMD的潜在因果影响。Bonferroni调整p值≤0.003被认为是显著的，名义显著性≤0.05。结果:方差倒数加权(IVWMR)先生认为,增加背景可能会增加腿部脂肪比例女性(女性:β= 0.311±0.10,P = 0.002,男性:β= 0.253±0.12,P = 0.035),减少甘油三酸酯(男性:β= -0.046±0.015,P = 0.002;女性:β= -0.077±0.023,P = 9.17 4 x打败)和预防2型糖尿病患者(男性:或者0.471,95%可信区间0.327 - -0.676,P = 4.64 x的纯;女性:或0.511,95%可信区间0.372 - -0.701,P = 3.31 x的纯)。在Bonferroni校正后，我们没有发现证据表明增加的CIR可以调节身体质量指数、腰臀比、高密度脂蛋白胆固醇或冠状动脉疾病。逆IVWMR显示T2D仅在男性中降低CIR （OR为0.613-0.927，P=5.47 × 10-3）。结论：增加的CIR可能对两性的T2D和血脂有有益的影响，但对肥胖和CMD没有有害的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Canadian Journal of Diabetes ENDOCRINOLOGY & METABOLISM-

CiteScore

4.80

自引率

4.00%

发文量

130

审稿时长

54 days

期刊介绍： The Canadian Journal of Diabetes is Canada''s only diabetes-oriented, peer-reviewed, interdisciplinary journal for diabetes health-care professionals. Published bimonthly, the Canadian Journal of Diabetes contains original articles; reviews; case reports; shorter articles such as Perspectives in Practice, Practical Diabetes and Innovations in Diabetes Care; Diabetes Dilemmas and Letters to the Editor.