Endocrinology, Diabetes and Hypertension

P. Reed Larsen, M.D.

Clinical Research. Dr. Larsen’s clinical interests are in the effects of pregnancy on thyroid hormone requirements, the evaluation of patients with thyroid nodules, and the factors regulating the peripheral production of T3 in humans. He shares these interests with several members of the Thyroid Section, including Dr. Erik Alexander, Dr. Ellen Marqusee, and Dr. Brian Kim. The details of the thyroid function in pregnancy and nodule studies are described by Dr. Alexander. Dr. Kim’s interests include not only thyroid nodules but also regulation of the peripheral production of T3 (see Dr. Kim’s training description).

Basic Research.  Dr. Larsen has a broad interest in the molecular mechanisms underlying the regulation of thyroid hormone activation and inactivation. Most of these studies involve evaluation of deiodinase function from biochemical studies of the deiodinase enzymes themselves, analysis of the effects of interacting proteins, the role of ubiquitination or other proteolytic mechanisms in the control of deiodinase levels, the modeling of the human D1 and D2 activation processes in determining T3 production rates in an in vitro system, the effects of intracellular D2 activation in human skeletal muscle on intermediary metabolism in these cells, identifying factors regulating the control of the inactivating enzyme, the Type 3 iodothyronine deiodinase, in various cells, the role of dimerization in deiodinase function, structure/function studies of potential dimerization domains, and factors determining the subcellular localizations of the three iodothyronine deiodinases. Interested trainees will work at the bench under close supervision by Drs. Larsen and Bianco.

1. Bianco AC, Salvatore D, Gereben B, Berry M, Larsen PR.  Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.  Endocrine Reviews 2002; 23:38-89. 
2. Baqui M, Botero D, Gereben B, Curcio C, Harney JW, Salvatore D, Sorimachi K, Larsen PR, Bianco AC.  Human type 3 iodothyronine selenodeiodinase is located in the plasma membrane and undergoes rapid internalization to endosomes.  J. Biol Chem 2003; 278:1206-1211.
3. Callebaut I, Curcio-Morelli C, Mornon JP, Gereben B, Huang S, Castro B, Fonseca TL, Harney JW, Larsen PR, Bianco AC. The iodothyronine selenodeiodinases are thioredoxin-fold family proteins containing a glycoside hydrolase clan GH-A-like structure.  J Biol Chem 2003; 278:36887-96. 
4. Carvalho-Bianco SD, Kim BW, Zhang JX, Harney JW, Ribeiro RS, Gereben B, Bianco AC, Mende U, Larsen PR. Chronic cardiac-specific thyrotoxicosis increases myocardial beta-adrenergic responsiveness.  Mol Endocrinology 2004; 18:1840-9.
5. Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR.  Timing and magnitude of increases in  levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004; 351:241-9.
6. Canani LH, Capp C, Dora JM, Meyer EL, Wagner MS, Harney JW, Larsen PR, Gross JL, Bianco AC, Maia AL. The type 2 deiodinase A/G (Thyr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with type 2 diabetes mellitus.  J Clin Endocrinol Metab 2005; 90:3472-8. 
7. Maia AM, Kim BW, Huang SA, Harney JW, Larsen PR.  Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans.  J Clin Invest, 2005; 115:2524-2533.
8. Huang SA, Mulcahey MA, Crescenzi A, Chung M, Kim BW, Barnes C, Kuijt W, Turano H, Harney J, Larsen PR.  TGF-b promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 iodothyronine deiodinase.  Molecular Endo, 2005; 19(12):3126-36. 
9. Christoffolete MA, Ribeiro R, Singru P, Fekete C, da Silva WS, Gordon DF, Huang SA, Crescenzi A, Harney JW, Ridgway EC, Larsen PR, Lechan RM, Bianco AC.  Atypical expression of type 2 iodothyronine deiodinase in thyrotrophs explains the thyroxine-mediated pituitary thyrotropin feedback mechanism.  Endocrinology, 2006; 147(4):1735-1743. 

 Contact Information:
(617) 525-5150
plarsen@partners.org