ABSTRACT
BACKGROUND: Gastrointestinal dysfunction is very common in diabetic patients. We assessed the changes in the colonic enteric nervous system using colectomy specimens and intestinal biopsies from diabetic subjects and age-matched controls. METHODS: In control and diabetic colons, we determined the total ganglion area (hematoxylin-eosin staining), changes in neuronal markers-protein gene product 9.5, peripherin, neuronal nitric oxide synthase (nNOS), neuropeptide Y (NPY), choline acetyl transferase (ChAT) and vasoactive intestinal peptide (by immunostaining), apoptosis (cleaved caspase-3 staining) and reduced glutathione levels. Superoxide dismutase mRNA was determined in enteric ganglia isolated by laser capture micro dissection. Isometric muscle recording was used to assess contraction and relaxation responses of colonic circular muscle strips. Apoptosis in enteric neurons under hyperglycemia in vitro was determined by cleaved caspase-3 Western blotting and protective effects of lipoic acid were evaluated. KEY RESULTS: Diabetic subjects had higher incidence of lower gastrointestinal symptoms like constipation and diarrhea at baseline prior to surgery. Diabetic ganglia displayed significant decrease in ganglion size due to enhanced apoptosis and loss of peripherin, nNOS, NPY, and ChAT neurons. Reduced glutathione levels in the diabetic colon (HbA1C > 7%) were significantly less than the control, indicating increased oxidative stress. Colonic circular muscle strips from diabetic subjects showed impaired contraction and relaxation responses compared with the healthy controls. Hyperglycemia-induced cleaved caspase-3 in enteric neurons was reversed by lipoic acid. CONCLUSIONS & INFERENCES: Our data demonstrate loss of enteric neurons in the colon due to increased oxidative stress and apoptosis which may cause the motility disturbances seen in human diabetes. Antioxidants may be of therapeutic value for preventing motility disorders in diabetes.
Subject(s)
Apoptosis , Colon/innervation , Colon/physiopathology , Diabetes Complications/complications , Enteric Nervous System/pathology , Gastrointestinal Diseases/etiology , Oxidative Stress/physiology , Aged , Animals , Antioxidants/pharmacology , Apoptosis/drug effects , Biopsy , Case-Control Studies , Cell Line , Disease Models, Animal , Electric Stimulation , Enteric Nervous System/drug effects , Enteric Nervous System/physiopathology , Female , Gastrointestinal Diseases/pathology , Gastrointestinal Diseases/physiopathology , Humans , Male , Mice , Middle Aged , Muscle Contraction/physiology , Muscle Relaxation/physiology , Phosphatidylinositol 3-Kinases/physiology , Reactive Oxygen Species/metabolism , Signal Transduction/physiology , Thioctic Acid/pharmacologyABSTRACT
Diabetes is associated with several changes in gastrointestinal (GI) motility and associated symptoms such as nausea, bloating, abdominal pain, diarrhoea and constipation. The pathogenesis of altered GI functions in diabetes is multifactorial and the role of the enteric nervous system (ENS) in this respect has gained significant importance. In this review, we summarize the research carried out on diabetes-related changes in the ENS. Changes in the inhibitory and excitatory enteric neurons are described highlighting the role of loss of inhibitory neurons in early diabetic enteric neuropathy. The functional consequences of these neuronal changes result in altered gastric emptying, diarrhoea or constipation. Diabetes can also affect GI motility through changes in intestinal smooth muscle or alterations in extrinsic neuronal control. Hyperglycaemia and oxidative stress play an important role in the pathophysiology of these ENS changes. Antioxidants to prevent or treat diabetic GI motility problems have therapeutic potential. Recent research on the nerve-immune interactions demonstrates inflammation-associated neurodegeneration which can lead to motility related problems in diabetes.
