The effect of a diiodothyronine mimetic on insulin sensitivity in male cardiometabolic patients: a double-blind randomized controlled trial
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 the...
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| Veröffentlicht in: | PloS one 2014-02, Vol.9 (2), p.e86890-e86890 |
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| creator | van der Valk, Fleur Hassing, Carlijne Visser, Maartje Thakkar, Purav Mohanan, Anookh Pathak, Kaushal Dutt, Chaitanya Chauthaiwale, Vijay Ackermans, Mariette Nederveen, Aart Serlie, Mireille Nieuwdorp, Max Stroes, Erik |
| description | 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.
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.
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.
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.
clinicaltrials.gov NCT01408667. |
| doi_str_mv | 10.1371/journal.pone.0086890 |
| format | Article |
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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.
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.
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.
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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.
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.
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.
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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van der Valk, Fleur</au><au>Hassing, Carlijne</au><au>Visser, Maartje</au><au>Thakkar, Purav</au><au>Mohanan, Anookh</au><au>Pathak, Kaushal</au><au>Dutt, Chaitanya</au><au>Chauthaiwale, Vijay</au><au>Ackermans, Mariette</au><au>Nederveen, Aart</au><au>Serlie, Mireille</au><au>Nieuwdorp, Max</au><au>Stroes, Erik</au><au>Atkin, Stephen L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The effect of a diiodothyronine mimetic on insulin sensitivity in male cardiometabolic patients: a double-blind randomized controlled trial</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-02-21</date><risdate>2014</risdate><volume>9</volume><issue>2</issue><spage>e86890</spage><epage>e86890</epage><pages>e86890-e86890</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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.
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.
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.
clinicaltrials.gov NCT01408667.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24586256</pmid><doi>10.1371/journal.pone.0086890</doi><tpages>e86890</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-02, Vol.9 (2), p.e86890-e86890 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1500940083 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Analysis Biology Blood pressure Brain cancer Clinical trials Diabetes Diabetes mellitus Diabetes therapy Diiodothyronines - pharmacology Double-blind studies Drug dosages Endocrinology Fatty acids Glucose Glucose Clamp Technique Health risks Heart Homeostasis Hormones Humans Hypertriglyceridemia India Insulin Insulin resistance Insulin Resistance - physiology Laboratories Lipids Lipolysis Magnetic resonance Magnetic Resonance Spectroscopy Male Medicine Metabolic syndrome Metabolic Syndrome - metabolism Middle Aged Muscles Netherlands Nuclear magnetic resonance spectroscopy Obesity Patients Pharmaceuticals Randomization Rodents Sensitivity Spectroscopy Statistics, Nonparametric Studies Thyroid Thyroid gland Thyroid hormones Thyronines - pharmacology Triglycerides |
| title | The effect of a diiodothyronine mimetic on insulin sensitivity in male cardiometabolic patients: a double-blind randomized controlled trial |
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