Genetic Evidence for Distinct Biological Mechanisms That Link Adiposity to Type 2 Diabetes: Toward Precision Medicine

Angela Abraham, Madeleine Cule, Marjola Thanaj, Nicolas Basty, M. Amin Hashemloo, Elena P. Sorokin, Brandon Whitcher, Stephen Burgess, Jimmy D. Bell, Naveed Sattar, E. Louise Thomas, Hanieh Yaghootkar

Research output: Contribution to journalArticlepeer-review

Abstract

We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We used MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated with lower risk (favorable adiposity). We then characterized each cluster based on various biomarkers, metabolites, and MRI-based measures of fat distribution and muscle quality. Analyzing the metabolic signatures of these clusters revealed two primary mechanisms connecting higher adiposity to reduced type 2 diabetes risk. The first involves higher adiposity in subcutaneous tissues (abdomen and thigh), lower liver fat, improved insulin sensitivity, and decreased risk of cardiometabolic diseases and diabetes complications. The second mechanism is characterized by increased body size and enhanced muscle quality, with no impact on cardiometabolic outcomes. Furthermore, our findings unveil diverse mechanisms linking higher adiposity to higher disease risk, such as cholesterol pathways or inflammation. These results reinforce the existence of adiposity-related mechanisms that may act as protective factors against type 2 diabetes and its complications, especially when accompanied by reduced ectopic liver fat.

Original languageEnglish
Pages (from-to)1012-1025
Number of pages14
JournalDiabetes
Volume73
Issue number6
DOIs
Publication statusPublished - Jun 2024
Externally publishedYes

Fingerprint

Dive into the research topics of 'Genetic Evidence for Distinct Biological Mechanisms That Link Adiposity to Type 2 Diabetes: Toward Precision Medicine'. Together they form a unique fingerprint.

Cite this