Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant

Abstract

Gunawardana SC, Piston DW. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am J Physiol Endocrinol Metab 308: E1043-E1055, 2015. First published April 21, 2015; doi:10.1152/ajpendo.00570.2014.-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 longlasting 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 insulinlike 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. type 1 diabetes; brown adipose tissue; insulin independent; transplantation; insulin-like growth factor I TYPE 1 DIABETES (T1D) is characterized by autoimmune-mediated destruction of pancreatic ␤-cells, resulting in absolute deficiency of insulin and loss of glycemic control. Treatments for T1D, despite having been refined over many years, are geared mainly toward replacing insulin, which involves numerous risks and limitations. Direct insulin replacement via daily injections or insulin pump does not cure the disease and requires life-long repeated administration. In addition to the inconvenience, direct insulin therapy requires careful monitoring of dosage and blood glucose levels and can lead to potentially fatal hypoglycemic episodes. Pancreas transplantation, the only available treatment with a good chance of long-term insulin independence, requires invasive surgery and life-long immunosuppressive therapy. Islet transplantation, although less invasive, is limited by the availability of donor tissue and the need for immunosuppression, and patients often return to insulin dependence in the long...

Brown and Beige Adipose Tissues in Health and Disease

“…Interestingly, BAT and beige fat are also able to regulate glucose and lipid metabolism by a body weight-independent mechanism. Adoptive transplantation of BAT grafts normalizes hyperglycemia and substantially improves glucose intolerance in recipient mice with either streptozotocin-induced or genetic type 1 diabetes (105, 106). BAT transplantation also attenuates insulin resistance in recipient mice with high fat diet (HFD)-induced obesity (287).…”

“…Given their small mass relative to WAT, brown and beige fat is unlikely to be an important source of circulating leptin and adiponectin in humans. Additionally, brown and beige adipocytes secrete several specific adipokines, including neuregulin 4, IGF-1, FGF21, and interleukin (IL) 6 (62, 87, 105, 149, 287, 324). Neuregulin 4 suppresses hepatic lipogenesis as an endocrine hormone (324).…”

Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging

“…BAT also plays a role in whole body metabolism, assisting with glucose homeostasis and insulin sensitivity (13,40). For example, a model of diabetic mice received BAT transplants, resulting in an insulin-independent reversal of type 1 diabetes (22). Additionally, active BAT in mice can clear 75% of the glucose and 50% of the triglycerides from circulation (5).…”

Brown Adipose Tissue Regulates Small Artery Function Through NADPH Oxidase 4–Derived Hydrogen Peroxide and Redox-Sensitive Protein Kinase G-1α

“…Furthermore, transplantation of BAT into the visceral cavity corrects the metabolic phenotype of rodents with diabetes mellitus and metabolic syndrome, and transplantation of BAT has been suggested to be of future importance in metabolic diseases. [65][66][67] Based on the novel results of our study, BAT clearly demonstrates a redox-sensitive vasoprotective effect, and as such exposing small arteries to BAT, or increased browning of PVAT, may be an interesting strategy to improve vascular function in pathological conditions.…”