Associations of diabetes mellitus, insulin, leptin, and ghrelin with gastroesophageal reflux and Barrett's esophagus

Abstract

Background & aims: Insulin and leptin have proliferative and anti-apoptotic effects. Ghrelin promotes gastric emptying and secretion of growth hormone and inhibits inflammation. We assessed whether diabetes mellitus and serum levels of insulin, leptin, and ghrelin are associated with gastroesophageal reflux disease (GERD) and Barrett's esophagus.

Methods: We conducted a case-control study in 822 men undergoing colorectal cancer screening who were recruited to also undergo upper endoscopy. We identified 70 with Barrett's esophagus; 80 additional men with Barrett's esophagus were recruited shortly after their clinical diagnoses. Serum levels of insulin, leptin, and ghrelin were assayed in all 104 fasting men with Barrett's esophagus without diabetes and 271 without diabetes or Barrett's esophagus. Logistic regression was used to estimate the effects of diabetes and levels of insulin, leptin, and ghrelin on GERD and Barrett's esophagus.

Results: Among men with GERD, diabetes was inversely associated with Barrett's esophagus (adjusted odds ratio [OR] = 0.383; 95% confidence interval [CI]: 0.179-0.821). Among nondiabetics, hyperinsulinemia was positively associated with Barrett's esophagus, but the association was attenuated by adjustment for leptin and ghrelin. Leptin was positively associated with Barrett's esophagus, adjusting for obesity, GERD, and levels of insulin and ghrelin (OR for 3(rd) vs 1(st) tertile = 3.25; 95% CI: 1.29-8.17); this association was stronger in men with GERD (P = .01 for OR heterogeneity). Ghrelin was positively associated with Barrett's esophagus (OR for an increment of 400 pg/mL = 1.39; 95% CI: 1.09-1.76), but inversely associated with GERD (OR for 3(rd) vs 1(st) tertile = 0.364; 95% CI: 0.195-0.680).

Conclusions: Based on a case-control study, leptin was associated with Barrett's esophagus, particularly in men with GERD. Serum insulin level was associated with Barrett's esophagus, but might be mediated by leptin. Serum ghrelin was inversely associated with GERD, as hypothesized, but positively associated with Barrett's esophagus, contrary to our hypothesis. Additional studies are needed in men and women to replicate these findings.

Keywords: BE; Barrett's esophagus; CI; CRC; GERD; Gastroesophageal Reflux; Ghrelin; Insulin; LA; Leptin; Los Angeles; OR; PPI; colorectal cancer; confidence interval; gastroesophageal reflux disease; odds ratio; proton pump inhibitor.

Figure 1

Potential mechanisms of association of obesity with BE. Obesity mechanically promotes GERD, which can lead to BE. Obesity also leads to insulin resistance and leptin resistance, manifesting as elevated circulating levels of insulin and leptin. Leptin and/or insulin might promote BE, but could also be confounded by the effects of the other. Additionally, the effects of insulin might be mediated through leptin because hyperinsulinemia promotes leptin secretion. We had also hypothesized that diabetes mellitus would be associated with BE due to long-standing hyperinsulinemia. However, in this study, the effect of insulin appeared to be confounded by leptin and ghrelin, and diabetes appeared to be inversely associated with BE. Ghrelin promotes gastric emptying, and so could inhibit GERD. Ghrelin also promotes secretion of growth hormone, which might promote healing of erosive esophagitis with Barrett's metaplasia, either directly, or mediated through local production of insulin-like growth factor-1 (IGF-1).