Role of Mfge8 in the reduced contractility of diabetic gastroparesis

Abstract

Coordinated gastric contractility is imperative for ideal digestion and absorption of nutrients. This is impaired during diabetic gastroparesis, a disorder characterized by abnormal gastric smooth muscle contractions leading to delayed gastric emptying. The objective of this research was to further the understanding of the gastric smooth muscle contraction regulatory mechanisms and how these cascades are affected by diabetes. In addition to its anti-inflammatory properties, it has been shown that milk fat globule-epidermal growth factor 8 (Mfge8) binding to ɑ8β1 integrin decreases murine gastric contractile activity by reducing the inhibitory phosphorylation of MLCP, resulting in MLCP activation and reduced myosin phosphorylation. Additionally, Mfge8 is elevated in human serum from type 2 diabetic individuals compared to non-diabetic individuals. It is hypothesized that elevated levels of Mfge8 in smooth muscle tissue will lead to decreased contractility strength, a phenomenon that would resemble gastroparesis secondary to diabetes. We analyzed the contractility and Mfge8 expression of human gastric antrum smooth muscles from obese diabetic and obese non-diabetic individuals who elected to undergo sleeve gastrectomy surgery for weight loss. Short strips of gastric muscle were stimulated to contract with serial concentrations of carbachol and contractile activity was measured with AcqKnowledge software. Mfge8 protein expression was then analyzed using a Wes Simple western instrument. We report that human gastric antrum smooth muscle tissue levels of Mfge8 are elevated in diabetic obese individuals (n=22) compared to non-diabetic obese individuals (n=37, P=0.004). However, we show that the contractile activity of antrum smooth muscle from diabetic obese individuals (n=38) is not dependent on Mfge8 levels and is not significantly different from the contractility of non-diabetic obese individuals (n=38). The rate of contraction, rate of relaxation, and overall tension ( P=0.40) produced by the muscle tissues from the two groups did not significantly differ from each other. It is possible that Mfge8 was not elevated enough to cause reduced contractility, or that those with elevated Mfge8 had not yet developed symptoms of gastroparesis. Mfge8 may serve as a biomarker for diabetic gastroparesis in the future, and additional research is required to determine the pathologic significance of elevated Mfge8 levels in obese diabetic human gastric antrum smooth muscle. This research was supported by a National Institute of Diabetes and Digestive and Kidney Diseases Diabetic Complications Consortium (DiaComp, http://www.diacomp.org ) Grant DK076169, a Takeda Pharmaceuticals Innovation Center Grant to BP, and a UNRSOM Office of Medical Research Grant FD110-PG08935 to DD. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.