Abstract
Background: Circulating sex hormone–binding globulin (SHBG) is associated with insulin resistance and cardiometabolic disease, yet causality, sex differences and genetic determinants remain unclear. Methods: Bidirectional two-sample Mendelian randomization (MR) analyses were performed to evaluate the associations of SHBG with type 2 diabetes (T2D) and major cardiometabolic outcomes. Associations of measured SHBG levels and a hyaluronan-mediated motility receptor locus–based genetic score (HMMR-GRS) with incident T2D were further evaluated in the UK Biobank participants. Results: Genetically proxied higher SHBG was causally associated with lower risk of T2D and ischemic heart disease, with weaker or null evidence for myocardial infarction, heart failure, stroke, and fatty liver disease–related outcomes. Reverse-direction analyses supported that genetic liability to T2D lowers SHBG levels. In the UK Biobank, higher circulating SHBG showed a robust, graded inverse association with incident T2D, and the association was stronger in women. The HMMR-GRS was strongly associated with higher SHBG and inversely associated with incident T2D in women, with a directionally similar but non-significant trend in men. Conclusions: These findings triangulate genetic and prospective cohort evidence to support SHBG as a causal, bidirectional determinant of T2D risk and highlight the HMMR–SHBG axis as a potential target for risk stratification and prevention.