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

You S, Anitha M, deSouza SM, Jia D, Lu X, Kozlowski M, Olson DE, Srinivasan S, Thulé PM - Mol Ther Methods Clin Dev (2015)

Bottom Line: 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.We conclude that in addition to normalizing oxidative metabolism in diabetic rodents, HIGT is sufficient to prevent the development of diabetic gastroenteropathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolism & Lipids, Atlanta VA Medical Center, Emory University, School of Medicine , Atlanta, Georgia, USA ; Diabetes Center, Institute of Metabolism & Endocrinology, Second Xiangya Hospital, Central South University , Changsha, China ; Key Laboratory of Diabetes Immunology, National Clinical Research Center for Metabolic Diseases, Ministry of Education , Changsha, China.

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.

No MeSH data available.


Related in: MedlinePlus

Abundance of stimulatory (ACh) and inhibitory (NADPH oxidase) staining nuclei were assessed in colonic segments from control, DM, and HIGT-treated mice. (a) There was no difference in the number of nuclei of stimulatory (ACh) neurons across conditions. (b) The number of inhibitory (NADPH oxidase) neurons was diminished among DM animals, and this diminution was abrogated among HIGT treated animals. *P < 0.05 versus Con; #P < 0.05 versus DM, n = 6–10. Con, control nondiabetic mice; DM, diabetic mice; HIGT, hepatic insulin gene therapy.
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fig6: Abundance of stimulatory (ACh) and inhibitory (NADPH oxidase) staining nuclei were assessed in colonic segments from control, DM, and HIGT-treated mice. (a) There was no difference in the number of nuclei of stimulatory (ACh) neurons across conditions. (b) The number of inhibitory (NADPH oxidase) neurons was diminished among DM animals, and this diminution was abrogated among HIGT treated animals. *P < 0.05 versus Con; #P < 0.05 versus DM, n = 6–10. Con, control nondiabetic mice; DM, diabetic mice; HIGT, hepatic insulin gene therapy.

Mentions: Sustained EFS-induced colonic smooth muscle contraction combined with impaired relaxation suggested a selective impairment of inhibitory neurons with relative sparing of stimulatory neurons. We observed no difference in the number of nuclei staining for ACh, i.e., stimulatory neurons within the colon (Figure 6a). In contrast, the number of NADPH diaphorase staining nuclei, i.e., inhibitory neurons, was diminished among DM mice (Figure 6b). This deficit in inhibitory neurons was prevented by HIGT treatment.


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

You S, Anitha M, deSouza SM, Jia D, Lu X, Kozlowski M, Olson DE, Srinivasan S, Thulé PM - Mol Ther Methods Clin Dev (2015)

Abundance of stimulatory (ACh) and inhibitory (NADPH oxidase) staining nuclei were assessed in colonic segments from control, DM, and HIGT-treated mice. (a) There was no difference in the number of nuclei of stimulatory (ACh) neurons across conditions. (b) The number of inhibitory (NADPH oxidase) neurons was diminished among DM animals, and this diminution was abrogated among HIGT treated animals. *P < 0.05 versus Con; #P < 0.05 versus DM, n = 6–10. Con, control nondiabetic mice; DM, diabetic mice; HIGT, hepatic insulin gene therapy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557470&req=5

fig6: Abundance of stimulatory (ACh) and inhibitory (NADPH oxidase) staining nuclei were assessed in colonic segments from control, DM, and HIGT-treated mice. (a) There was no difference in the number of nuclei of stimulatory (ACh) neurons across conditions. (b) The number of inhibitory (NADPH oxidase) neurons was diminished among DM animals, and this diminution was abrogated among HIGT treated animals. *P < 0.05 versus Con; #P < 0.05 versus DM, n = 6–10. Con, control nondiabetic mice; DM, diabetic mice; HIGT, hepatic insulin gene therapy.
Mentions: Sustained EFS-induced colonic smooth muscle contraction combined with impaired relaxation suggested a selective impairment of inhibitory neurons with relative sparing of stimulatory neurons. We observed no difference in the number of nuclei staining for ACh, i.e., stimulatory neurons within the colon (Figure 6a). In contrast, the number of NADPH diaphorase staining nuclei, i.e., inhibitory neurons, was diminished among DM mice (Figure 6b). This deficit in inhibitory neurons was prevented by HIGT treatment.

Bottom Line: 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.We conclude that in addition to normalizing oxidative metabolism in diabetic rodents, HIGT is sufficient to prevent the development of diabetic gastroenteropathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolism & Lipids, Atlanta VA Medical Center, Emory University, School of Medicine , Atlanta, Georgia, USA ; Diabetes Center, Institute of Metabolism & Endocrinology, Second Xiangya Hospital, Central South University , Changsha, China ; Key Laboratory of Diabetes Immunology, National Clinical Research Center for Metabolic Diseases, Ministry of Education , Changsha, China.

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.

No MeSH data available.


Related in: MedlinePlus