title: Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant.
abstract: Traditional therapies for type 1 diabetes (T1D) involve insulin replacement or islet/pancreas transplantation and have numerous limitations. Our previous work demonstrated the ability of embryonic brown adipose tissue (BAT) transplants to establish normoglycemia without insulin in chemically induced models of insulin-deficient diabetes. The current study sought to extend the technique to an autoimmune-mediated T1D model and document the underlying mechanisms. In nonobese diabetic (NOD) mice, BAT transplants result in complete reversal of T1D associated with rapid and long-lasting euglycemia. In addition, BAT transplants placed prior to the onset of diabetes on NOD mice can prevent or significantly delay the onset of diabetes. As with streptozotocin (STZ)-diabetic models, euglycemia is independent of insulin and strongly correlates with decrease of inflammation and increase of adipokines. Plasma insulin-like growth factor-I (IGF-I) is the first hormone to increase following BAT transplants. Adipose tissue of transplant recipients consistently express IGF-I compared with little or no expression in controls, and plasma IGF-I levels show a direct negative correlation with glucose, glucagon, and inflammatory cytokines. Adipogenic and anti-inflammatory properties of IGF-I may stimulate regeneration of new healthy white adipose tissue, which in turn secretes hypoglycemic adipokines that substitute for insulin. IGF-I can also directly decrease blood glucose through activating insulin receptor. These data demonstrate the potential for insulin-independent reversal of autoimmune-induced T1D with BAT transplants and implicate IGF-I as a likely mediator in the resulting equilibrium.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee subhadra.gunawardana@vanderbilt.edu.
authors.forename: Subhadra C
authors.initials: SC
authors.lastname: Gunawardana
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: David W
authors.initials: DW
authors.lastname: Piston
mesh_terms: D002001:Adipose Tissue, Brown / Q000196:embryology / Q000637:transplantation*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D004622:Embryo, Mammalian; D005260:Female; D016332:Fetal Tissue Transplantation; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011247:Pregnancy
chemical_list: D001786:Blood Glucose; D007328:Insulin; D007334:Insulin-Like Growth Factor I
keywords: brown adipose tissue; insulin independent; insulin-like growth factor I; transplantation; type 1 diabetes