Diabetic gastrointestinal motility disorders and the role of enteric nervous system: current status and future directions

Abstract

Background: Gastrointestinal manifestations of diabetes are common and a source of significant discomfort and disability. Diabetes affects almost every part of gastrointestinal tract from the esophagus to the rectum and causes a variety of symptoms including heartburn, nausea, vomiting, abdominal pain, diarrhea and constipation. Understanding the underlying mechanisms of diabetic gastroenteropathy is important to guide development of therapies for this common problem. Over recent years, the data regarding the pathophysiology of diabetic gastroenteropathy is expanding. In addition to autonomic neuropathy causing gastrointestinal disturbances the role of enteric nervous system is becoming more evident.

Purpose: In this review, we summarize the reported alterations in enteric nervous system including enteric neurons, interstitial cells of Cajal and neurotransmission in diabetic animal models and patients. We also review the possible underlying mechanisms of these alterations, with focus on oxidative stress, growth factors and diabetes induced changes in gastrointestinal smooth muscle. Finally, we will discuss recent advances and potential areas for future research related to diabetes and the ENS such as gut microbiota, micro-RNAs and changes in the microvasculature and endothelial dysfunction.

Keywords: diabetes; enteric nervous system; enteric neurons; interstitial cells of Cajal; oxidative stress; smooth muscle.

Figure 1. Effects of diabetes on motility in various parts of gastrointestinal tract

Diabetes affects almost all parts of GI tract. It can reduced the motility of esophagus and reduce the basal tone of LES. Gastroparesis and impaired gastric fundal relaxation are well known effects of diabetes on stomach. Both diarrhea and constipation are reported as GI manifestations of diabetes. GERD: gastroesophageal reflux disorder. LES: lower esophageal sphincter.

Figure 2. Potential mechanisms involving the ENS in impaired gastrointestinal motility in DM

Mechanism of diabetes induced gastrointestinal enteric neuropathy is complex and multifactorial. Autonomic neuropathy can affect both afferent and efferent connections between enteric nervous system and central nervous system. Reduced number of enteric neurons is caused by increased oxidative stress and increased apoptosis. The number of interstitial cells of Cajal in is also reduced, possibly due to lack of growth factors. There myopathic changes in smooth muscle and decreased contractility due to impaired signaling pathways. Diabetes induced changes in gut microbiota can modulate the CNS-gut interaction. ICC: interstitial cells of Cajal, SCF: stem cell factor, MLC: myosine light chain, DM: diabetes mellitus, CNS: central nervous system.