Multi-Organ Fibrosis and Risk of Type 2 Diabetes: Genetic and Observational Evidence Highlighting a Causal Role of Pancreatic Fibrosis
Year: 2025
Type: other
Abstract: Pancreatic fibrosis has been proposed as a contributor to type 2 diabetes (T2D), by impairing islet function, but whether it plays a causal role remains unclear. We investigate this question using two complementary approaches. First, we performed a computed tomography-based retrospective case-control study (T2D cases: n=58; controls: n=58) assessing extracellular volume fraction (fECV) as a marker of fibrosis in the pancreas, liver, and myocardium. Greater pancreatic fibrosis was associated with T2D (adjusted odds ratio [OR] per one standard deviation [SD] increase:1.64; 95% confidence interval [CI]:1.00–2.68), independent of age, sex, body mass index, liver fibrosis, and myocardial fibrosis. Second, we conducted a Mendelian randomization analysis using genome-wide association study (GWAS) data on multi-organ fibrosis derived from magnetic resonance imaging in the UK Biobank (n=43,881), along with T2D GWAS data from the DIAGRAM consortium (242,283 T2D cases and 1,569,734 controls). Genetically predicted pancreatic fibrosis levels were associated with an increased T2D risk (OR per one-SD increase:1.43; 95%CI:1.09–1.89), while liver and myocardial fibrosis levels showed no associations. These findings support a potential causal and organ-specific role of pancreatic fibrosis in the pathogenesis of T2D, highlighting pancreatic fibrosis as a mechanistically plausible and potentially targetable target in diabetes prevention.
Authors: Masato Uchida, Hajime Yamazaki, Sihao Han, Brian Z. Huang, Shoko Ariyoshi, Yoji Hirayama, Sho Matsushita, Ryosuke Horitani, Róbert Wagner, Martin Heni
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4416865515