Thyroid Hormone Induced Brown Adipose Tissue and Amelioration of Diabetes in a Patient with Extreme Insulin Resistance

Skarulis, Monica C.; Celi, Francesco S.; Mueller, Elisabetta; Zemskova, Marina; Malek, Rana; Hugendubler, Lynne; Cochran, Craig; Solomon, Jeffrey; Chen, Clara; Görden, Phillip

doi:10.1210/jc.2009-0543

Cited by 152 publications

(101 citation statements)

References 22 publications

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“…The importance of BAT in metabolic homeostasis has been reported in a number of studies that consistently demonstrate the ability of BAT to improve glucose homeostasis and energy expenditure and decrease obesity (10,22,23,56,61,62,71,76). Recent studies show promise in adult BAT transplants in alleviating T2D and obesity.…”

Section: Discussionmentioning

confidence: 93%

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

Gunawardana

Piston

2015

American Journal of Physiology-Endocrinology and Metabolism

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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...

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Section: Discussionmentioning

confidence: 93%

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

Gunawardana

Piston

2015

American Journal of Physiology-Endocrinology and Metabolism

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“…This interpretation, in turn, suggests that thyroid hormone treatment should itself induce BAT activation and glucose uptake in STZdiabetic rats, resulting in a decrease of blood glucose. This hypothesis is supported by evidence that thyroid hormone increases basal glucose uptake in various tissues including BAT (52) and that reversal of hypothyroidism dramatically improved glucose homeostasis in a patient with diabetes due to a mutation in the insulin receptor gene, an effect accompanied by enhanced PET-CT uptake in BAT (45).…”

mentioning

confidence: 87%

In uncontrolled diabetes, thyroid hormone and sympathetic activators induce thermogenesis without increasing glucose uptake in brown adipose tissue

Matsen

Thaler

Wisse

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Recent advances in human brown adipose tissue (BAT) imaging technology have renewed interest in the identification of BAT activators for the treatment of obesity and diabetes. In uncontrolled diabetes (uDM), activation of BAT is implicated in glucose lowering mediated by intracerebroventricular (icv) administration of leptin, which normalizes blood glucose levels in streptozotocin (STZ)-induced diabetic rats. The potent effect of icv leptin to increase BAT glucose uptake in STZ-diabetes is accompanied by the return of reduced plasma thyroxine (T4) levels and BAT uncoupling protein-1 (Ucp1) mRNA levels to nondiabetic controls. We therefore sought to determine whether activation of thyroid hormone receptors is sufficient in and of itself to lower blood glucose levels in STZ-diabetes and whether this effect involves activation of BAT. We found that, although systemic administration of the thyroid hormone (TR)␤-selective agonist GC-1 increases energy expenditure and induces further weight loss in STZ-diabetic rats, it neither increased BAT glucose uptake nor attenuated diabetic hyperglycemia. Even when GC-1 was administered in combination with a ␤3-adrenergic receptor agonist to mimic sympathetic nervous system activation, glucose uptake was not increased in STZ-diabetic rats, nor was blood glucose lowered, yet this intervention potently activated BAT. Similar results were observed in animals treated with active thyroid hormone (T3) instead of GC-1. Taken together, our data suggest that neither returning normal plasma thyroid hormone levels nor BAT activation has any impact on diabetic hyperglycemia, and that in BAT, increases of Ucp1 gene expression and glucose uptake are readily dissociated from one another in this setting.thyroid; diabetes; brown adipose tissue; sympathetic nervous system; glucose uptake IN RODENTS, BROWN ADIPOSE TISSUE (BAT) is implicated as a key mediator of both cold-induced (14) and diet-induced thermogenesis (38). Since BAT consumes energy to generate heat, several lines of evidence suggest that, despite its small size, BAT may play a role not only in the control of thermogenesis but in glucose metabolism as well (33). For example, in both cold-exposed humans (34) and rodents (4), BAT exhibits rates of uptake of glucose per gram of tissue that exceed those of insulin-stimulated skeletal muscle (34). Moreover, BAT transplantation improves glucose metabolism and insulin sensitivity in wild-type mice (46) and restores euglycemia to mice with streptozotocin-(STZ)-induced diabetes (20). We recently demonstrated that the effect of centrally administered leptin to normalize blood glucose levels in a rodent model of uncontrolled insulin-deficient diabetes (uDM) occurs via an insulinindependent mechanism characterized by increased rates of tissue glucose uptake in skeletal muscle and BAT (16). Our finding that the decline of circulating thyroxine (T 4 ) hormone levels characteristic of STZ-induced uDM (35, 37) is prevented by intracerebroventricular (icv) leptin treatment suggests that the increase o...

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“…Subcutaneous adipose tissue around the neck demonstrated molecular features of BAT including increased uncoupling protein-1 and type 2 deiodinase expression. Discontinuation of levothyroxine resulted in decreased FDG uptake in the fatty tissue and a diminished volume of BAT depots accompanied by worsening of diabetic control, suggesting a positive thyroid hormone effect on BAT activity and glucose homeostasis (54).…”

Section: Deiodinases and Metabolic Controlmentioning

confidence: 98%

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

Marsili

Zavacki

Harney

et al. 2011

J Endocrinol Invest

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Thyroxine (T4) is a prohormone secreted by the thyroid. T4 has a long half life in circulation and it is tightly regulated to remain constant in a variety of circumstances. However, the availability of iodothyronine selenodeiodinases allow both the initiation or the cessation of thyroid hormone action and can result in surprisingly acute changes in the intracellular concentration of the active hormone T3, in a tissue-specific and chronologically-determined fashion, in spite of the constant circulating levels of the prohormone. This fine-tuning of thyroid hormone signaling is becoming widely appreciated in the context of situations where the rapid modifications in intracellular T3 concentrations are necessary for developmental changes or tissue repair. Given the increasing availability of genetic models of deiodinase deficiency, new insights into the role of these important enzymes are being recognized. In this review, we have incorporated new information regarding the special role played by these enzymes into our current knowledge of thyroid physiology, emphasizing the clinical significance of these new insights.

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Thyroid Hormone Induced Brown Adipose Tissue and Amelioration of Diabetes in a Patient with Extreme Insulin Resistance

Cited by 152 publications

References 22 publications

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

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

In uncontrolled diabetes, thyroid hormone and sympathetic activators induce thermogenesis without increasing glucose uptake in brown adipose tissue

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

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