title: The effect of a diiodothyronine mimetic on insulin sensitivity in male cardiometabolic patients: a double-blind randomized controlled trial.
abstract: OBJECTIVE
  Obesity and its associated cardiometabolic co-morbidities are increasing worldwide. Since thyroid hormone mimetics are capable of uncoupling the beneficial metabolic effects of thyroid hormones from their deleterious effects on heart, bone and muscle, this class of drug is considered as adjacent therapeutics to weight-lowering strategies. This study investigated the safety and efficacy of TRC150094, a thyroid hormone mimetic.
  
  
  METHODS
  This 4-week, randomized, placebo-controlled, double-blind trial was conducted in India and The Netherlands. Forty subjects were randomized at a 1:1 ratio to receive either TRC150094 dosed at 50 mg or placebo once daily for 4 weeks. Hyperinsulinemic euglycemic clamp and (1)H-Magnetic Resonance Spectroscopy (MRS) were performed before and after treatment.
  
  
  RESULTS
  At baseline, subjects were characterized by markedly impaired hepatic and peripheral insulin sensitivity. TRC150094 dosed 50 mg once daily was safe and well tolerated. Hepatic nor peripheral insulin sensitivity improved after TRC150094 treatment, expressed as the suppression of Endogenous Glucose Production from 59.5 to 62.1%; p = 0.477, and the rate of glucose disappearance from 28.8 to 26.4 µmol kg(-1)min(-1), p = 0.185. TRC150094 administration did not result in differences in fasting plasma free fatty acids from 0.51 to 0.51 mmol/L, p = 0.887 or in insulin-mediated suppression of lipolysis from 57 to 54%, p = 0.102. Also, intrahepatic triglyceride content was unaltered.
  
  
  CONCLUSIONS
  Collectively, these data show that, in contrast to the potent metabolic effects in experimental models, TRC150094 at a dose of 50 mg daily does not improve the metabolic homeostasis in subjects at an increased cardiometabolic risk. Further studies are needed to evaluate whether TRC150094 has beneficial effects in patients with more severe metabolic derangement, such as overt diabetes mellitus and hypertriglyceridemia.
  
  
  BACKGROUND
  clinicaltrials.gov NCT01408667.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Fleur
authors.initials: F
authors.lastname: van der Valk
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Carlijne
authors.initials: C
authors.lastname: Hassing
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: Visser
authors.affiliation: Clinical Research Department, Torrent Pharmaceuticals Limited, Village-Bhat, Dist. Gandhinagar, India.
authors.forename: Purav
authors.initials: P
authors.lastname: Thakkar
authors.affiliation: Clinical Research Department, Torrent Pharmaceuticals Limited, Village-Bhat, Dist. Gandhinagar, India.
authors.forename: Anookh
authors.initials: A
authors.lastname: Mohanan
authors.affiliation: Clinical Research Department, Torrent Pharmaceuticals Limited, Village-Bhat, Dist. Gandhinagar, India.
authors.forename: Kaushal
authors.initials: K
authors.lastname: Pathak
authors.affiliation: Clinical Research Department, Torrent Pharmaceuticals Limited, Village-Bhat, Dist. Gandhinagar, India.
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Dutt
authors.affiliation: Clinical Research Department, Torrent Pharmaceuticals Limited, Village-Bhat, Dist. Gandhinagar, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Chauthaiwale
authors.affiliation: Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Mariette
authors.initials: M
authors.lastname: Ackermans
authors.affiliation: Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Aart
authors.initials: A
authors.lastname: Nederveen
authors.affiliation: Department of Endocrinology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Mireille
authors.initials: M
authors.lastname: Serlie
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Max
authors.initials: M
authors.lastname: Nieuwdorp
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Stroes
mesh_terms: D000328:Adult; D004104:Diiodothyronines / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D006801:Humans; D007194:India; D007333:Insulin Resistance / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism*; D008875:Middle Aged; D009426:Netherlands; D018709:Statistics, Nonparametric; D013970:Thyronines / Q000494:pharmacology*
chemical_list: D004104:Diiodothyronines; D013970:Thyronines; C576522:TRC150094