Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress

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.

Antidiabetic and anti-oxidant activities of the methanol leaf extract of <i>Vernonia amygdalina</i> in alloxan-induced diabetes in Wistar rats

“…Research data indicate that in diabetic patients, the gastric cells are subject to oxidative stress (Lomax, Sharkey & Furness 2010). Excessive production of glucose-derived free radicals in diabetes then causes damage to cellular proteins, lipids and eventually cell death as free radicals react with lipids causing peroxidation, leading to the release of products such as malondialdehyde (MDA), hydrogen peroxide and hydroxyl radicals (Pompella et al 1991), resulting in damages to the gastric mucosa (Chandrasekharan et al 2011). …”

Mechanisms and factors associated with gastrointestinal symptoms in patients with diabetes mellitus

“…É responsável por várias complicações, tanto do DMT1 como do DMT2, entre as quais a neuropatia diabética e o acometimento do TGI. A disfunção do trato digestório no DM é secundária ao controle inadequado da glicemia e a consequente neuropatia autonômica diabética, que exerce grande influência nas funções motora e sensorial do trato digestório, desde o estômago até a porção terminal 12 . A angiopatia diabética e as complicações vasculares também são secundárias à hiperglicemia crônica e se relacionam com a patogênese da isquemia intestinal e a função nervosa e muscular alteradas da gastroenteropatia diabética 14,42 .…”

“…É comprovada pelas alterações associadas entre mudanças agudas nos níveis da glicemia e motilidade 12,31,43 . Variações agudas na glicose sérica, mesmo nos limites das taxas normais, podem ter grande influência na função motora e sensitiva do trato digestório 17,42 .…”

“…Também ativa as vias de estresse oxidativo Diabetes melito e sintomas gastrointestinais -Rodrigues ML & Motta ME (desequilíbrio entre sistemas pró e antioxidantes), o que acarreta apoptose de neurônios entéricos e mudança no seu código químico, resultando em alterações da motilidade 12 . Estudo demonstrou que o aumento do estresse oxidativo no estômago e no fígado de animais de laboratório é influenciado pelo tempo de DM e pelo aumento da glicemia 1 .…”

“…Em decorrência do comprometimento do tubo digestório, com danos no sistema nervoso entérico (SNE), pacientes portadores de DM podem apresentar quadros específicos de distúrbios de motilidade, alguns de grande relevância clínica, como gastroparesia diabética, constipação e diarreia 10,12 . Dessa forma, a enteropatia diabética reflete comprometimento autonômico generalizado 11,13,14 .…”