Thyroid Hormones Homeostasis and Energy Metabolism Changes During Stimulation of Endogenously Secreted Bile Acids (BAs)

NCT00706381 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: 08016508-DK-0165
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

Postprandial thermogenesis, or thermic effect of food are terms that describe the increase in utilization of energy by the human body following a meal. The mechanisms involved in this process are believed to differ according to the type of food consumed, whether fat, protein or carbohydrate. 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.

Conditions

Healthy Volunteers

Keywords

Deiodinase; Bile Acids; Cholecystokinin; Thyroid Hormones; Energy Expenditure; Healthy Volunteer

Outcome Measures

Primary Outcomes (2)

• Energy Expenditure

  Energy expenditure is measured over 6 hours in a respiratory chamber for each intervention and placebo.

  6 hours

• Bile Acid

  Bile acid is measured at 0, 60, 90 and 360 minutes during a 6 hour stay in in a respiratory chamber for each intervention and placebo. The mean of these 4 values is then calculated.

  6 hours

Study Arms (4)

1: Carb meal, fat meal, sincalide, placebo, urso

EXPERIMENTAL

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

Drug: Sincalide; Drug: Ursodiol; Procedure: Fat Meal; Procedure: Carb meal; Drug: Placebo

2: Fat meal, carb meal, sincalide, placebo, urso

EXPERIMENTAL

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

Drug: Sincalide; Drug: Ursodiol; Procedure: Fat Meal; Procedure: Carb meal; Drug: Placebo

3: Carb meal, fat meal, placebo, sincalide, urso

EXPERIMENTAL

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

Drug: Sincalide; Drug: Ursodiol; Procedure: Fat Meal; Procedure: Carb meal; Drug: Placebo

4: Fat meal, carb meal, placebo, sincalide, urso

EXPERIMENTAL

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

Drug: Sincalide; Drug: Ursodiol; Procedure: Fat Meal; Procedure: Carb meal; Drug: Placebo

Interventions

Sincalide DRUG

1: Carb meal, fat meal, sincalide, placebo, urso; 2: Fat meal, carb meal, sincalide, placebo, urso; 3: Carb meal, fat meal, placebo, sincalide, urso; 4: Fat meal, carb meal, placebo, sincalide, urso

Ursodiol DRUG

1: Carb meal, fat meal, sincalide, placebo, urso; 2: Fat meal, carb meal, sincalide, placebo, urso; 3: Carb meal, fat meal, placebo, sincalide, urso; 4: Fat meal, carb meal, placebo, sincalide, urso

Fat Meal PROCEDURE

600 calorie meal containing 72% fat, 8% protein, and 20% carbohydrate

1: Carb meal, fat meal, sincalide, placebo, urso; 2: Fat meal, carb meal, sincalide, placebo, urso; 3: Carb meal, fat meal, placebo, sincalide, urso; 4: Fat meal, carb meal, placebo, sincalide, urso

Carb meal PROCEDURE

600 calorie meal containing 100% carbohydrate

1: Carb meal, fat meal, sincalide, placebo, urso; 2: Fat meal, carb meal, sincalide, placebo, urso; 3: Carb meal, fat meal, placebo, sincalide, urso; 4: Fat meal, carb meal, placebo, sincalide, urso

Placebo DRUG

IV and/or oral placebo

1: Carb meal, fat meal, sincalide, placebo, urso; 2: Fat meal, carb meal, sincalide, placebo, urso; 3: Carb meal, fat meal, placebo, sincalide, urso; 4: Fat meal, carb meal, placebo, sincalide, urso

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than or equal to18 years, male or female
• Written informed consent

You may not qualify if:

• Hypo- or hyperthyroidism (history or serum thyroid-stimulating hormone (TSH) greater than 5.0 or less than 0.4 miU/L)
• 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

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• 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.

  PMID: 17122359 BACKGROUND

• 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.

  PMID: 17167472 BACKGROUND

• 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.

  PMID: 17372316 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

Sincalide; Ursodeoxycholic Acid

Intervention Hierarchy (Ancestors)

Cholecystokinin; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Deoxycholic Acid; Cholic Acids; Bile Acids and Salts; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Cholanes

Results Point of Contact

• Title: Kong Chen, Ph.D.
• Organization: NIDDK

chenkong@niddk.nih.gov

301-451-1636

Study Officials

• Kong Y Chen, Ph.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 26, 2008
• First Posted: June 27, 2008
• Study Start: June 23, 2008
• Primary Completion: August 21, 2012
• Study Completion: August 21, 2012
• Last Updated: July 22, 2020
• Results First Posted: July 22, 2020

Record last verified: 2017-08-04

Locations

US (1)