Alteration in Gastric Ghrelin Expression in a Mouse Model of Type 2 Diabetes Mellitus

Background Ghrelin, produced and secreted in the stomach, stimulates appetite by acting on the hypothalamus and inhibits insulin secretion, leading to hyperglycemia. Ghrelin is also associated with obesity and insulin resistance in type 2 diabetes mellitus (T2DM). Beyond metabolic regulation, ghrelin is linked to autophagy and oxidative stress, leading to many chronic inflammatory diseases. However, few studies have focused on the local mechanisms of ghrelin secretion in a diabetic stomach. We aimed to investigate ghrelin expression in the gastric mucosa using a mouse model of T2DM. Methods At five weeks of age, male C57BL/6J mice (Japan SLC, Hamamatsu, Japan) were randomly assigned to two major groups: a T2DM (DM) group and an age-matched control (CON) group. The DM group was fed a high-fat diet from six weeks of age, and the CON group was fed a normal diet. At week four, the DM mice received intraperitoneal injections of streptozotocin (STZ). Gastric mucosa samples were collected at 11 weeks and 13 weeks of age, and ghrelin mRNA expression was analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Only samples that met the quality criteria (A260/A280 = 1.8-2.0 and RNA integrity number (RIN) > 7) were included in the RT-qPCR analysis, resulting in n = 4 (11 weeks) and n = 5 (13 weeks) per group. The sample size was determined based on feasibility and reference to similar studies. All experimental procedures were approved by the Institutional Animal Care and Welfare Committee of Tokyo Medical and Dental University, Tokyo, Japan (approval no.: A2022-090A). Results The DM group showed significantly higher body weight and blood glucose levels than the CON group. Ghrelin mRNA expression significantly increased in the 13-week-old DM group compared to the CON group. No significant difference was observed at 11 weeks. Conclusions Immunostaining and RT-qPCR analyses revealed elevated gastric ghrelin levels in T2DM mice. This first demonstration of ghrelin upregulation in the diabetic gastric mucosa emphasizes the importance of assessing local gastric expression, which has been largely overlooked compared with circulating levels. These findings suggest a compensatory role of gastric ghrelin in endocrine regulation and may provide translational insights that could contribute to the development of novel therapeutic approaches for diabetes.