Diabetes in relation to Barrett’s esophagus and adenocarcinomas of the esophagus: A pooled study from the International Barrett’s and Esophageal Adenocarcinoma Consortium

Abstract

Background Diabetes is positively associated with various cancers, but its relationship with tumors of the esophagus/esophagogastric junction remains unclear. Methods Data were harmonized across 13 studies in the International Barrett’s and Esophageal Adenocarcinoma Consortium, comprising 2309 esophageal adenocarcinoma (EA) cases, 1938 esophagogastric junction adenocarcinoma (EGJA) cases, 1728 Barrett's esophagus (BE) cases, and 16,354 controls. Logistic regression was used to estimate study‐specific odds ratios (ORs) and 95% CIs for self‐reported diabetes in association with EA, EGJA, and BE. Adjusted ORs were then combined using random‐effects meta‐analysis. Results Diabetes was associated with a 34% increased risk of EA (OR, 1.34; 95% CI, 1.00‐1.80; I2 = 48.8% [where 0% indicates no heterogeneity, and larger values indicate increasing heterogeneity between studies]), 27% for EGJA (OR, 1.27; 95% CI, 1.05‐1.55; I2 = 0.0%), and 30% for EA/EGJA combined (OR, 1.30; 95% CI, 1.06‐1.58; I2 = 34.9%). Regurgitation symptoms modified the diabetes‐EA/EGJA association (P for interaction = .04) with a 63% increased risk among participants with regurgitation (OR, 1.63; 95% CI, 1.19‐2.22), but not among those without regurgitation (OR, 1.03; 95% CI, 0.74‐1.43). No consistent association was found between diabetes and BE. Conclusions Diabetes was associated with increased EA and EGJA risk, which was confined to individuals with regurgitation symptoms. Lack of an association between diabetes and BE suggests that diabetes may influence progression of BE to cancer.

Circulating Levels of Inflammatory and Metabolic Biomarkers and Risk of Esophageal Adenocarcinoma and Barrett Esophagus: Systematic Review and Meta-analysis

“…The carcinogenic mechanisms associated with elevated leptin levels may include enhanced cell proliferation, changes in the regulation of certain cell signaling pathways, and promotion of inflammation and angiogenesis (41)(42)(43). Our metaanalysis of three prospective studies found that elevated glucose levels were associated with a modestly (12%) increased risk of esophageal adenocarcinoma, which was in line with a recent pooled study of 13 population-based studies showing a 30% increased risk of esophageal adenocarcinoma or esophagogastric junctional adenocarcinoma in patients with diabetes (44). A stronger association between insulin levels and Barrett esophagus risk was indicated, but the evidence was mainly based on cross-sectional studies and the association was attenuated after adjustment for leptin (26).…”

Visceral Obesity, Metabolic Syndrome, and Esophageal Adenocarcinoma

“…Hyperinsulinemia and insulin resistance increase the risk of BE among individuals without diabetes, an effect which is mediated at least in part by leptin, and hence due to increased adiposity (95). The association between type T2DM and EAC and BE is inconsistent however (102), as BE risk does not correlate with serum insulin levels among patients with established T2DM (95,103). This may reflect uncoupling of peripheral insulin resistance and insulin secretion among patients with advanced metabolic disease, reflective of β-cell dysfunction among patients with severe or longstanding T2DM, and suggests that insulin itself may not be direct driver of the inflammation-metaplasia-dysplasia sequence in EAC.…”

GWAS identifies genetic clusters of cardiometabolic risk factors in continental Africans

“…highlighted key pleiotropic signals via their powerful reverse regression approach. However, functional work is needed to better understand the utility of the ve novel lead loci found via META-SCOPA and the MAGMA tissue and gene-set analyses results, as they are associated with well-known metabolic pathways/diseases (e.g., diabetes) and tissues such as the human histone acetyltransferase/MSL complex 20,21 , the esophagus gastroesophageal junction and the esophagus muscularis 22 .…”