title: 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.
authors.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.
authors.forename: Shuo
authors.initials: S
authors.lastname: You
authors.affiliation: Department of Internal Medicine, Division of Digestive Diseases, Atlanta VA Medical Center, Emory University, School of Medicine , Atlanta, Georgia, USA.
authors.forename: Mallappa
authors.initials: M
authors.lastname: Anitha
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolism & Lipids, Atlanta VA Medical Center, Emory University, School of Medicine , Atlanta, Georgia, USA.
authors.forename: Sean Md
authors.initials: SM
authors.lastname: deSouza
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolism & Lipids, Atlanta VA Medical Center, Emory University, School of Medicine , Atlanta, Georgia, USA.
authors.forename: Dingwu
authors.initials: D
authors.lastname: Jia
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolism & Lipids, Atlanta VA Medical Center, Emory University, School of Medicine , Atlanta, Georgia, USA.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Pathology and Laboratory Medicine, Translational Research Program, Center for Cellular Immunotherapy, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Kozlowski
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolism & Lipids, Atlanta VA Medical Center, Emory University, School of Medicine , Atlanta, Georgia, USA.
authors.forename: Darin E
authors.initials: DE
authors.lastname: Olson
authors.affiliation: Department of Internal Medicine, Division of Digestive Diseases, Atlanta VA Medical Center, Emory University, School of Medicine , Atlanta, Georgia, USA.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolism & Lipids, Atlanta VA Medical Center, Emory University, School of Medicine , Atlanta, Georgia, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Thulé