Diabetic Enteropathy: From Molecule to Mechanism-Based Treatment

Abstract

The incidence of the micro- and macrovascular complications of diabetes is rising, mirroring the increase in the worldwide prevalence. Arguably, the most common microvascular complication is neuropathy, leading to deleterious changes in both the structure and function of neurons. Amongst the various neuropathies with the highest symptom burden are those associated with alterations in the enteric nervous system, referred to as diabetic enteropathy. The primary aim of this review is to provide a contemporaneous summary of pathophysiology of diabetic enteropathy thereby allowing a "molecule to mechanism" approach to treatment, which will include 4 distinct aspects. Firstly, the aim is to provide an overview of the diabetes-induced structural remodelling, biochemical dysfunction, immune-mediated alterations, and inflammatory properties of the enteric nervous system and associated structures. Secondly, the aim is to provide a synopsis of the clinical relevance of diabetic enteropathy. Thirdly, the aim is to discuss the various patient-reported outcome measures and the objective modalities for evaluating dysmotility, and finally, the aim is to outline the clinical management and different treatment options that are available. Given the burden of disease that diabetic enteropathy causes, earlier recognition is needed allowing prompt investigation and intervention, which may lead to improvements in quality of life for sufferers.

Figure 1

The enteric nervous system. (a) Cross-sectional view. The enteric nervous system (ENS) is embedded in the wall of the GI tract. The neurons are localized in the myenteric and submucosal plexi and are connected by interneurons (depicted in grey). Extrinsic efferent innervation via autonomic sympathetic (green) and parasympathetic (blue) pathways contributes to the regulation and coordination of GI function. Extrinsic afferent sensory nerves (orange) following either vagal or spinal routes provide the central nervous system with information about GI homeostasis. (b) Longitudinal view illustrating a selection of neuronal subtypes. Secretomotor and vasodilator neurons regulate fluid and molecular exchange between gut lumen, tissue, and vasculature. Peristaltic movements (oral contraction and aboral relaxation of intestinal smooth muscle) are facilitated by intrinsic primary afferent neurons (IPANs) activating ascending and descending interneurons, which then activate upstream excitatory and downstream inhibitory motor neurons, respectively. IPANs may initially be activated, e.g., through mechanoreceptors or by acetylcholine secreted by enteric endocrine cells in the luminal epithelial cell layer upon luminal distension. In addition, ENS includes the innervation of gastroenteropancreatic endocrine cells (not shown) and gut-associated lymphoid tissue, responsible for hormone secretion and transmitter release. Although not equally represented, the juxtapositioned networks of enteric glial cells (EGCs) and interstitial cells of Cajal (ICCs) are present in all layers of the GI wall. Note that the thickness of the different tissue layers is not proportionally represented.

Figure 2

Hyperglycaemia induced intracellular biochemical changes in neurons. (a) Generation of ROS. (b) Consequences of ROS generation. See text and Table 1 for explanation. Abbreviations: 1,3BPG: 1,3-bisphosphoglyceric acid; Acetyl-CoA: acetyl coenzyme A; ADP: adenosine diphosphate; AGE: advanced glycation end products; ATP: adenosine triphosphate; DAG: diacylglycerol; DHAP; dihydroxyacetone phosphate; e⁻: electron; F-1,6-BP: fructose-1,6-bisphosphate; F-6-P: fructose-6-phosphate; FAD: flavin adenine dinucleotide (oxidised); FADH₂: flavin adenine dinucleotide (reduced); GAP: glyceraldehyde 3-phosphate; GAPH: glyceraldehyde 3-phosphate dehydrogenase; GlcN-6-P: glucosamine 6-phosphate; GR: glutathione reductase; GSH: glutathione; GSSG: glutathione disulphide; H⁺: proton; NAD⁺: nicotinamide adenine dinucleotide (oxidised); NADH: nicotinamide adenine dinucleotide (reduced); NADP⁺: nicotinamide adenine dinucleotide phosphate (oxidised); NADPH: nicotinamide adenine dinucleotide phosphate (reduced); O₂: oxygen: O₂^•−: superoxide; P: phosphor group; PARP-1: poly(ADP-ribose) polymerase 1; PKC: protein kinase C; PP: diphosphate; RAGE: receptor for advanced glycation end products; ROS: reactive oxygen species; UDP-GlcNAc: uridine diphosphate N-acetylglucosamine; UTP: uracil triphosphate.