Insulin-Independent Reversal of Type-1 Diabetes Following Transplantation of Adult Brown Adipose Tissue Supplemented With IGF-1

Background. As our previous publications show, it is feasible to reverse type 1 diabetes (T1D) without insulin in multiple mouse models, through transplantation of embryonic brown adipose tissue (BAT) in the subcutaneous space. Embryonic BAT transplants result in rapid and long-lasting euglycemia accompanied by decreased inflammation and regenerated healthy white adipose tissue, with no detectable increase in insulin. To translate this approach to human patients, it is necessary to establish practical alternatives for embryonic tissue. Adult adipose tissue transplants or BAT-derived stem cell lines alone fail to reverse T1D. A likely reason is transplant failure resulting from lack of growth factors abundant in embryonic tissue. Adding growth factors may enable transplants to survive and vascularize as well as stimulate adipogenesis and decrease inflammation in the surrounding host tissue. Previous data points to insulin like growth factor 1 (IGF-1) as the most likely candidate. Embryonic BAT abundantly expresses IGF-1, and embryonic BAT transplant recipients exhibit increased plasma levels of IGF-1. Therefore, we tested the ability of temporary administration of exogenous IGF-1 to enable adult BAT transplants to correct T1D. Methods. Fresh BAT from healthy adult CB7BL/6 donors were transplanted in the subcutaneous space of hyperglycemic nonobese diabetic recipients. Exogenous IGF-1 was administered daily for a week following transplant, at 100 mu g/kg SC. Results. Adult BAT transplants with IGF-1 supplementation produced rapid long-lasting euglycemia at a 57% success rate, in contrast with no recovery in the control groups who received adult BAT alone, IGF-1 alone, or no treatment. Conclusions. Temporary supplementation with IGF-1 enables adult BAT transplants to correct T1D phenotypes independent of insulin, providing a possible route to translate this treatment to human patients.