Fig. 1: Seven potential mechanisms for hyperinsulinemia.

Panel A Forest plot displaying meta-analysis results from five cohorts (UKBB, MVP, ASPREE, MGBB, and FHS) for cluster associations with type 2 diabetes. Data points represent the mean effect size (odds ratio). Error bars indicate 95% confidence intervals (CIs) calculated using logistic regression models. All statistical tests were two-sided, with a significance threshold set at α = 0.0008, based on a Bonferroni adjustment for multiple comparisons. The dotted vertical line at 1 represents the null effect (no association). Panel B Each cluster is represented by a set of loci and a set of traits; The loci and traits represented in the plots are the top-weighted for better visualization; clusters might have more variants and traits. Loci with a number after the period “.xx” represents that there was more than one SNP at that locus. The green bars represent the weights with which each variant contributes to each cluster. In the case of traits, the color of the bars represents the direction of the effect that was found in each cluster, red for positive association and blue for negative association. Purple lines distinguished diabetogenic hyperinsulinemia clusters; increased fasting insulin, reduced glycemia, and preserved insulin secretion. Yellow lines distinguish clusters of non-diabetogenic hyperinsulinemia; increased fasting insulin due to a strong effect on body fat distribution, liver, lipid, and inflammatory processes. VAT visceral adipose tissue, SAT subcutaneous adipose tissue, 2hrG glucose at 2 hours after an oral glucose tolerance test, LEP leptin, HDL high-density lipoprotein, LVEDV left ventricular end-diastolic volume, WHR waist–hip ratio, PATadjHtWt pericardial adipose tissue adjusted by height to weight ratio, HOMAB Homeostasis Model Assessment of β-cell function, HIPC hip circumference, BFP body fat percentage; VATSAT VAT:SAT ratio, PI proinsulin, CIR corrected insulin response, FG fasting glucose, HBA1C hemoglobin A1C, LDL low-density lipoprotein. Source data are provided as a Source Data file.