Gastric Bypass Surgery May Improve Beta Cell Apoptosis with Ghrelin Overexpression in Patients with BMI ≥ 32.5 kg/m2

Abstract

Roux-en-Y gastric bypass (RYGB) surgery can lead to long-term remission of type 2 diabetes mellitus, depending on changes in weight and circulating levels of gut hormones. The general objectives of this study were to evaluate changes in plasma levels of the ghrelin gene products following RYGB surgery and to determine the role of ghrelin in inhibiting apoptosis of INS-1 cells induced by hyperglycemia. Sixteen obese Chinese patients with type 2 diabetes mellitus who underwent gastric bypass surgery were assessed in this investigation. Blood plasma levels of acylated ghrelin (AG), unacylated ghrelin (UAG), and obestatin (OB) were measured both before and 12months after RYGB surgery. To determine the effect of ghrelin on inhibition of apoptosis, INS-1 cells were cultured in a high glucose concentration and treated with AG, UAG, or OB. Cell viability was assessed using the MTT assay, and apoptosis was evaluated by flow cytometry with Annexin-V FITC/PI double staining and transmission electron microscopy. Intracellular calcium trafficking was assessed using flow cytometry and confocal microscopy. All the data was processed using the SPSS statistical package and expressed as means ± SD, with p < 0.05 considered statistically significant. Fasting and postprandial plasma levels of AG, UAG, and OB were significantly elevated 1year after RYGB surgery. Mean fasting plasma AG, UAG, and OB increased from preoperative levels of 37.0, 462, and 69.4pg/mL, respectively, to 61.4, 804, and 112pg/mL (with p < 0.05) 1year after surgery. Mean 120-min postprandial plasma AG, UAG, and OB increased from preoperative levels of 23.8, 287, and 53.8pg/mL, respectively, to 39.7, 516, and 69.0pg/mL (with p < 0.05) postoperatively. After a 1-week culture of INS-1 beta cell in high glucose, peptide treatment showed increased cell survival by 69% (AG), 60% (UAG), and 73% (OB) and decreased apoptosis by 49% (AG), 37% (UAG), and 38% (OB) compared to cells cultured in high glucose without peptides, respectively (with p < 0.05). Treatment with AG, UAG, and OB inhibited intracellular calcium mobilization and intramitochondrial calcium accumulation in INS-1 cells to protect the cells from hyperglycemia-induced apoptosis. The remission of diabetes following RYGB surgery seems to be associated with increased plasma levels of AG, UAG, and OB. Moreover, the ghrelin gene products probably protect β cells by maintaining calcium homeostasis. Additional mechanisms, currently unclear, are likely to be involved as well.