Thyroid Hormones Homeostasis and Energy Metabolism Changes During Stimulation of Endogenously Secreted Bile Acids (BAs)
NCT ID: NCT00706381
Last Updated: 2020-07-22
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
31 participants
INTERVENTIONAL
2008-06-23
2012-08-21
Brief Summary
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The bile acids (BAs), unique substances secreted by the gall bladder into the gut after a meal, play an important role in the absorption of fat and the management of cholesterol stores in the body. Recent studies suggest that BAs may also serve as regulators of energy expenditure (consumption) in the cells of our body by increasing the production of T3, an active form of thyroid hormone. T3 in turn is believed to increase the efficiency with which our bodies burn calories thereby generating heat. Although this process has been shown to be effective in rodents who demonstrated weight loss after treatment, the role of BAs in humans is poorly understood. Thus we do not know whether endogenous (produced by the body) or exogenous (taken as medication) BAs play a significant role in the maintenance of body weight. We hypothesize that, similarly to rodents, humans will respond to BAs by increasing energy expenditure via the production of the active form of thyroid hormone.
This randomized, cross-over study will look at changes in thyroid hormones and energy consumption in response to stimuli of endogenous BA secretion including dietary content, and to the intake of pharmacological doses of bile acids.
Following a two-day period of equilibration diet, 30 healthy volunteers will be randomly assigned to receive either a high-fat or high-carbohydrate isocaloric meal followed by a 6-hour metabolic chamber stay; the next day they will be crossed-over to the alternate intervention. During the following three days, the study subjects will again be randomized to receive either an intravenous injection of sincalide (the C-terminal octapeptide fragment of cholecystokinin) 0.04 mcg/kg or placebo and P.O. placebo, or I.V. placebo and 15 mg/kg of BA (ursodiol) with similar metabolic chamber stays and cross-over design.
The data gathered from this study will provide greater insight into the physiological and molecular mechanism(s) regulating the relation between endogenous bile acid secretion and energy metabolism in response to meals, as well as the role of BAs per se on energy metabolism.
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Detailed Description
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The bile acids (BAs), unique substances secreted by the gall bladder into the gut after a meal, play an important role in the absorption of fat and the management of cholesterol stores in the body. Recent studies suggest that BAs may also serve as regulators of energy expenditure (consumption) in the cells of our body by increasing the production of T3, an active form of thyroid hormone. T3 in turn is believed to increase the efficiency with which our bodies burn calories thereby generating heat. Although this process has been shown to be effective in rodents who demonstrated weight loss after treatment, the role of BAs in humans is poorly understood. Thus we do not know whether endogenous (produced by the body) or exogenous (taken as medication) BAs play a significant role in the maintenance of body weight. We hypothesize that, similarly to rodents, humans will respond to BAs by increasing energy expenditure via the production of the active form of thyroid hormone.
This randomized, cross-over study will look at changes in thyroid hormones and energy consumption in response to stimuli of endogenous BA secretion including dietary content, and to the intake of pharmacological doses of bile acids.
Following a two-day period of equilibration diet, 30 healthy volunteers will be randomly assigned to receive either a high-fat or high-carbohydrate isocaloric meal followed by a 6-hour metabolic chamber stay; the next day they will be crossed-over to the alternate intervention. During the following three days, the study subjects will again be randomized to receive either an intravenous injection of sincalide (the C-terminal octapeptide fragment of cholecystokinin) 0.04 mcg/kg or placebo and P.O. placebo, or I.V. placebo and 15 mg/kg of BA (ursodiol) with similar metabolic chamber stays and cross-over design.
The following parameters will be recorded and compared to placebo:
Energy expenditure
Substrate utilization
Spontaneous movements
Skin and core temperature
Serial changes in circulating thyroid hormones
Serial changes in bile acid serum concentrations
The data gathered from this study will provide greater insight into the physiological and molecular mechanism(s) regulating the relation between endogenous bile acid secretion and energy metabolism in response to meals, as well as the role of BAs per se on energy metabolism.
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
OTHER
TRIPLE
Study Groups
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1: Carb meal, fat meal, sincalide, placebo, urso
Participants randomized to consume a 100% carbohydrate meal day 1, then a high fat (72% fat, 8% protein, 20% carbohydrate) meal day 2, IV sincalide 0.04mcg/kg + PO placebo day 3, IV placebo + PO placebo day 4, and IV placebo + PO Ursodiol 15mg/kg day 5
Sincalide
Ursodiol
Fat Meal
600 calorie meal containing 72% fat, 8% protein, and 20% carbohydrate
Carb meal
600 calorie meal containing 100% carbohydrate
Placebo
IV and/or oral placebo
2: Fat meal, carb meal, sincalide, placebo, urso
Participants randomized to consume a high fat (72% fat, 8% protein, 20% carbohydrate) meal day 1, then a 100% carbohydrate meal day 2, IV sincalide 0.04mcg/kg + PO placebo day 3, IV placebo + PO placebo day 4, then IV placebo + PO Ursodiol 15mg/kg day 5
Sincalide
Ursodiol
Fat Meal
600 calorie meal containing 72% fat, 8% protein, and 20% carbohydrate
Carb meal
600 calorie meal containing 100% carbohydrate
Placebo
IV and/or oral placebo
3: Carb meal, fat meal, placebo, sincalide, urso
Participants randomized to consume a 100% carbohydrate meal day 1, then a high fat (72% fat, 8% protein, 20% carbohydrate) meal day 2, IV placebo + PO placebo day 3, IV sincalide 0.04mcg/kg + PO placebo day 4, then IV placebo + PO Ursodiol 15mg/kg day 5
Sincalide
Ursodiol
Fat Meal
600 calorie meal containing 72% fat, 8% protein, and 20% carbohydrate
Carb meal
600 calorie meal containing 100% carbohydrate
Placebo
IV and/or oral placebo
4: Fat meal, carb meal, placebo, sincalide, urso
Participants randomized to consume a high fat (72% fat, 8% protein, 20% carbohydrate) meal day 1, then a 100% carbohydrate meal day 2, IV placebo + PO placebo day 3, IV sincalide 0.04mcg/kg + PO placebo day 4, the IV placebo + PO Ursodiol 15mg/kg day 5
Sincalide
Ursodiol
Fat Meal
600 calorie meal containing 72% fat, 8% protein, and 20% carbohydrate
Carb meal
600 calorie meal containing 100% carbohydrate
Placebo
IV and/or oral placebo
Interventions
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Sincalide
Ursodiol
Fat Meal
600 calorie meal containing 72% fat, 8% protein, and 20% carbohydrate
Carb meal
600 calorie meal containing 100% carbohydrate
Placebo
IV and/or oral placebo
Eligibility Criteria
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Inclusion Criteria
Written informed consent
Exclusion Criteria
Blood pressure greater than 140/90 mmHg (26) or receiving antihypertensive therapy
History of cardiovascular disease
BMI less than or equal to 20 or greater than or equal to 27 Kg/m(2)
Diabetes mellitus (fasting serum glucose greater than or equal to 126 mg/dL)
Hyperlipidemia (serum total cholesterol greater than or equal to 240 mg/dL, triglycerides greater than or equal to 220 mg/dL, and/or use of antilipemic therapy)
Liver disease or ALT serum concentrations greater than 1.5 times the upper laboratory reference limit
Hyperbilirubinemia (serum total bilirubin greater than 1.5 mg/dL)
Renal insufficiency or estimated creatinine clearance less than or equal to 50 mL/min (MDRD equation)
Anemia (Hemoglobin concentration less than or equal to 11.1 g/dL females, and 12.7 g/dL males)
History of cholecystectomy or cholelithiasis (by ultrasound at screening).
History of malabsorption, or food allergies/intolerances that would preclude participant from consuming foods required for study
Claustrophobia
History of illicit drug or alcohol abuse within the last 5 years; current use of illicit drugs (by history) or alcohol (CAGE greater than 3)
Psychiatric conditions or behavior that would be incompatible with safe and successful participation in this study
Current use of medications/dietary supplements/alternative therapies known to alter thyroid function, energy expenditure or bile acid secretion
History of weight loss or weight gain of greater than 3 percent body weight over the past 2 months (self-reported)
Pregnancy/breastfeeding/hormonal contraceptive use and childbirth within the last 6 months
Perimenopausal (as self-described within two years from onset of amenorrhea or current complaints of hot flashes)
Current smoker
18 Years
ALL
No
Sponsors
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH
Responsible Party
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Principal Investigators
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Kong Y Chen, Ph.D.
Role: PRINCIPAL_INVESTIGATOR
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Locations
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National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
Countries
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References
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Hill JO. Understanding and addressing the epidemic of obesity: an energy balance perspective. Endocr Rev. 2006 Dec;27(7):750-61. doi: 10.1210/er.2006-0032. Epub 2006 Nov 22.
Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006 Dec 14;444(7121):847-53. doi: 10.1038/nature05483.
Blaak EE, Hul G, Verdich C, Stich V, Martinez JA, Petersen M, Feskens EF, Patel K, Oppert JM, Barbe P, Toubro S, Polak J, Anderson I, Astrup A, Macdonald I, Langin D, Sorensen T, Saris WH; NUGENOB Consortium. Impaired fat-induced thermogenesis in obese subjects: the NUGENOB study. Obesity (Silver Spring). 2007 Mar;15(3):653-63. doi: 10.1038/oby.2007.606.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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NIH Clinical Center Detailed Web Page
Other Identifiers
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08-DK-0165
Identifier Type: OTHER
Identifier Source: secondary_id
080165
Identifier Type: -
Identifier Source: org_study_id
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