Gastrointestinal Consequences of Type 2 Diabetes Mellitus and Impaired Glycemic Homeostasis: A Mendelian Randomization Study

OBJECTIVE We conducted a Mendelian randomization (MR) study to examine the associations of type 2 diabetes and glycemic traits with gastrointestinal diseases (GDs). RESEARCH DESIGN AND METHODS Uncorrelated genetic variants associated with type 2 diabetes (n = 231), fasting insulin (n = 38), fasting glucose (n = 71), and hemoglobin A1c (n = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with 23 common GDs were obtained from the FinnGen and UK Biobank studies and other large consortia. RESULTS Genetic liability to type 2 diabetes was associated with the risk of 12 GDs. Per 1-unit increase in the log-transformed odds ratio (OR) of type 2 diabetes, the OR was 1.06 (95% CI, 1.03–1.09) for gastroesophageal reflux disease, 1.12 (95% CI, 1.07–1.17) for gastric ulcer, 1.11 (95% CI, 1.03–1.20) for acute gastritis, 1.07 (95% CI, 1.01–1.13) for chronic gastritis, 1.08 (95% CI, 1.03–1.12) for irritable bowel syndrome, 1.04 (95% CI, 1.01–1.07) for diverticular disease, 1.08 (95% CI, 1.02–1.14) for acute pancreatitis, 1.09 (95% CI, 1.05–1.12) for cholelithiasis, 1.09 (95% CI, 1.05–1.13) for cholelithiasis with cholecystitis, 1.29 (95% CI, 1.17–1.43) for nonalcoholic fatty liver disease, 1.12 (95% CI, 1.03–1.21) for liver cirrhosis, and 0.93 (95% CI, 0.89–0.97) for ulcerative colitis. Genetically predicted higher levels of fasting insulin and glucose were associated with six and one GDs, respectively. CONCLUSIONS Associations were found between genetic liability to type 2 diabetes and an increased risk of a broad range of GDs, highlighting the importance of GD prevention in patients with type 2 diabetes.