Hepatic insulin gene therapy prevents diabetic enteropathy in STZ-treated CD-1 mice

Abstract

Depending on the population examined, from 6 to 83% of people with diabetes mellitus exhibit symptoms of altered gut motility, manifesting as dysphagia, reflux, early satiety, nausea, abdominal pain, diarrhea, or constipation. Hyperglycemia-induced cell loss within the enteric nervous system has been demonstrated in both diabetic rodents and patients with diabetes. Glycemic control is recommended to prevent diabetic gastroenteropathy but is often difficult to achieve with current treatment modalities. We asked if hepatic insulin gene therapy (HIGT) could inhibit the development of diabetic gastroenteropathy in mice. Bowel length, bowel transit, colonic muscle relaxation, and the numbers of both stimulatory and inhibitory neurons in the colonic myenteric plexus were compared in groups of diabetic mice (DM), control nondiabetic mice (Con), and diabetic mice treated with HIGT (HIGT). Delivery of a metabolically responsive insulin transgene to the liver of STZ-diabetic mice with an adeno-associated virus, sero-type 8 (AAV8) produced near-normal blood sugars for over 1 month and prevented anatomic, functional, and neurohistologic changes observed in diabetic mice. We conclude that in addition to normalizing oxidative metabolism in diabetic rodents, HIGT is sufficient to prevent the development of diabetic gastroenteropathy.

Enteric glial cell activation protects enteric neurons from damage due to diabetes in part via the promotion of neurotrophic factor release

“…Although ENS damage in diabetic animals has been reported in several studies, our results did not show significant changes in PGP9.5‐immunopositive cells in the ilea of rats 1, 4, 8, or 16 weeks after the induction of diabetes. Similar to our results, a previous study demonstrated that a longer period, up to 19 weeks, is necessary to cause total loss of neurons in the ilea of diabetic rats .…”

Resveratrol ameliorates podocyte damage in diabetic mice via SIRT1/PGC‐1α mediated attenuation of mitochondrial oxidative stress

“…A total of 90 pathogen-free healthy male CD-1 mice (weight 20-25 g, age 5 weeks) were purchased from Vital River Laboratory Animal Technology Co., Ltd (Beijing, China), and diabetes model was established in CD-1 mice via the injection of streptozotocin (STZ) as described previously (You et al, 2015). After two weeks of adaptive feeding, the mice were randomly divided into three groups: normal control group (NC group), diabetic group (DM group), and diabetic + RESV group (DR group).…”

Inhibiting Fatty Acid Amide Hydrolase Ameliorates Enteropathy in Diabetic Mice: A Cannabinoid 1 Receptor Mediated Mechanism

“…About 20% of patients affected with longstanding diabetes are at risk of diarrhea or fecal incontinence [ 3 ]. Abnormal GI motility, in combination with irregular secretion and absorption leading to a decline in the contractile functional ability of the gut musculature as a result of loss of cells within the enteric nervous system [ 4 , 5 ], has been implicated as the main causal factor for these conditions [ 6 ]. Other factors such as mucosal inflammation could also contribute to disorders of the GI tract [ 7 ].…”