1653-P: Brown Adipocyte–Secreted Factors for Treating Type 1 Diabetes Mellitus

Abstract

Hyperglycemia during type 1 Diabetes (T1D) is driven not only by a lack of insulin secretion due to autoimmune destruction of the pancreatic β-cells, but also by hypersecretion of glucagon from pancreatic α-cells. Insulin therapy can replace the lack of insulin secretion, but there is no effective therapeutic tool to counter the hyperglucagonemia. Brown adipose tissue (BAT) has gained attention for treating metabolic diseases due to its role as an endocrine organ and its effect on whole-body energy metabolism. Subcutaneous transplantation of embryonic BAT into T1D mouse models reverses hyperglycemia, independent of insulin but accompanied by reduced plasma glucagon levels, which suggests that lowering plasma glucagon plays a central role in restoring euglycemia. However, the molecular mechanism(s) underlying this action remain unclear. Towards discovering these mechanisms, we have examined the effects of secretions from immortalized brown adipocytes (imBAT) on pancreatic α-cells and mouse models of T1D. We show that the large molecule fraction (>100kDa) of imBAT-secreted factors suppresses glucagon secretion from both mouse and human pancreatic α-cells. Live cell fluorescence imaging shows that this fraction inhibits both intracellular Ca2+ and cAMP activities, and these inhibitions are ameliorated by blocking the insulin receptor, suggesting that imBAT-secreted factors act, at least in part, through these receptors. Injecting this imBAT-secreted fraction into the NOD mouse model reverses hyperglycemia (242 ± 47.4 to 146 ± 24.7mg/dL, n=8), suppresses hyperglucagonemia (77.6 ± 55.4 to 10.7 ± 4.75pg/mL, n=8), improves glucose tolerance (n=3), and increases thermogenic activity and differentiation of endogenous BAT (n=7). Our data provide insights into the mechanisms of long-term recovery of euglycemia by BAT transplants, and further fractionation experiments to isolate active factors are ongoing. Disclosure J.Lee: None. D.W.Piston: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2305-06050); National Institutes of Health (R01DK123301, P30DK020579)