The Effect of Brown Adipose Tissue Activation on Insulin Sensitivity in Humans

NCT01791114 | Completed

• 1 other identifier: 11-193
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

Recent findings document the presence of active brown adipose tissue (BAT) in humans. Cold exposure via adrenergic stimulation activates BAT, which combusts significant amounts of blood glucose and free fatty acid (FFA) to produce heat. Animal studies suggest that BAT activation improves insulin sensitivity. However, the effect of cold-induced BAT activation on insulin sensitivity and glucose kinetics in humans remains unknown. The investigators' central hypothesis is that cold-induced BAT activation increases whole body insulin sensitivity in humans via augmented plasma glucose and FFA clearance. The specific aims of this study are to define the effects of prolonged (8h) cold exposure BAT activation on: insulin sensitivity (Aim 1); lipolysis and plasma glucose and FFA kinetics (Aim 2); on thermoregulation (Aim 3). Moreover, the investigators plan to investigate for alternative ways, which can activate BAT including cold water ingestion, a single meal ingestion, and a single bout of moderate intensity exercise (Aim 4). For the cold exposure study, subjects will complete 3 trials: a) 8hrs of cold exposure at their individually determined shivering threshold; b) 8hrs of cold exposure at their individually determined shivering threshold plus propranolol; c) 8hrs in thermoneutral conditions (26 - 28°C). For the rest of the arms of subjects will complete two trials: cold or tepid water ingestion, a single meal ingestion or no food ingestion, and a single bout of moderate intensity exercise or no exercise.To study the above aims, the investigators will use positron emission tomography - computed tomography, hyperinsulinemic euglycemic clamp, infusion of stable isotopes, and tissue biopsies. The findings will illuminate the role of BAT on plasma substrate regulation and insulin sensitivity and may aid in the development of lifestyle recommendations and pharmacotherapy for the prevention and treatment of diabetes and insulin resistance.

Conditions

Insulin Sensitivity; Obesity

Keywords

Insulin sensitivity; Diabetes Prevention; Obesity; Brown adipose tissue

Outcome Measures

Primary Outcomes (1)

• Insulin Sensitivity

  Insulin sensitivity will be measured using the euglycemic hyperinsulinemic insulin clamp method

  After 8hrs of cold exposure or thermoneutral conditions

Secondary Outcomes (1)

• Metabolic profile

  During the 8hr trial or on the following day

Other Outcomes (2)

• Substrate kinetics

  During the 8hr study

• Thermoregulation

  During the first 5-6 hrs of the cold exposure study

Study Arms (4)

Cold water consumption

EXPERIMENTAL

Subjects will participate in two trials as part of this protocol: a) cold water (4 °C) consumption and b) tepid (36 °C) water consumption

Other: Cold water consumption; Other: Tepid water consumption

Meal consumption

EXPERIMENTAL

Subjects will participate in two trials as part of this protocol: a) High calorie meal consumption and two weeks later b) no meal consumption.

Other: Thermoneutral Conditions; Other: Meal consumption

Cold exposure

EXPERIMENTAL

Participants will complete three studies: a) cold exposure study (above their individually determined shivering threshold \~ 16°C); b) Cold exposure plus 0.5mg/kg up to 40mg propranolol at the beginning of the metabolic study and again after 4-6 hrs; c) thermoneutral conditions (26 - 28°C).

Other: Cold exposure; Other: Cold exposure plus propranolol; Other: Thermoneutral Conditions

Exercise

EXPERIMENTAL

Subjects between 18 and 35 years old will be asked to participate in two trials: a) Exercise, i.e. four times for 10 min- at 85% VO2max (maximal oxygen consumption). with 15-min breaks between each bout b) and two weeks later rest.

Other: Thermoneutral Conditions; Other: Exercise

Interventions

Cold exposure OTHER

For the cold exposure trial, the subjects will follow an individualized cold exposure protocol maximize the elicited non-shivering thermogenesis. Subjects will be wearing liquid conditioned garments (Polar Products Inc, Stow, OH). The temperature will initially be set at 18°C, then decreased at 1 degree celsius intervals thought the air- conditioned temperature control bath until subjects report shivering. Electromyography (EMG; Delsys, Bagnoli 8, Boston, MA) will be performed continuously to verify shivering muscle activity. Upon shivering, the temperature will be increased by 1degree Celsius intervals until shivering resides. Subjects' core temperature will be measured at 10-second intervals with the use of a telemetric pill (Core Temp Inc., Palmetto, FL).

Cold exposure

Cold exposure plus propranolol OTHER

For the cold exposure plus propanol trial, temperature will be titrated as previously described. The non-selective beta-adrenergic antagonist propranolol (0.5mg/kg and up to 40) will be given orally before the beginning of the study and again after 4-6 hours. In case participant's heart rate after propranolol administration decreases below 50 beats per min or systolic blood pressure below 90 mmHg second dose of propranolol will not be administered. Heart rate and blood pressure will be monitored continuously throughout the study. Propranolol doses up to 80 mg have been shown to significantly reduce fludeoxyglucose (FDG) uptake in brown fat in clinical patients.

Cold exposure

Thermoneutral Conditions OTHER

Subjects will be exposed to thermoneutral conditions (26 - 28°C)

Cold exposure; Exercise; Meal consumption

Cold water consumption OTHER

Subjects will be asked to consume cold water (4 °C,10 ml/ kg body weight within 10 minutes)

Cold water consumption

Tepid water consumption OTHER

Subjects will be asked to consume cold water (36 C,10 ml/ kg body weight within 10 minutes)

Cold water consumption

Exercise OTHER

Subject will be asked to complete four bouts of exercise for 10 min- at 85% of their maximal oxygen consumption (VO2max) with 15-min breaks between each bout

Exercise

Meal consumption OTHER

Subjects will be asked to consume a high calorie meal (12 kcal/kg, 50% carbohydrates, 30% fat, and 20% protein) within 15 minutes.

Meal consumption

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• men or women
• years old
• BMI 20-40 kg/m2

You may not qualify if:

• taking diabetes medications
• liver/renal/endocrine/heart disease
• obstructive disease of the gastrointestinal tract
• impaired gag reflex or swallowing disorder
• history of GI surgery or fenilization of esophagus
• GI hypomotility disorder
• cancer
• thyroid or hormone replacement treatment
• beta-blockers
• anabolic or corticosteroids the last 6 mo
• pregnant/lactating women
• individuals that are likely to need PET/CT in the near future for medical reasons
• bleeding disorders/ anemia
• positive hepatitis or HIV screening
• weight less than 36 kg

Sponsors & Collaborators

• Rutgers University: lead

Study Sites (1)

University of Texas Medical Branch at Galveston

Galveston, Texas, 77555, United States

Location

Related Publications (2)

• Chondronikola M, Volpi E, Borsheim E, Chao T, Porter C, Annamalai P, Yfanti C, Labbe SM, Hurren NM, Malagaris I, Cesani F, Sidossis LS. Brown Adipose Tissue Is Linked to a Distinct Thermoregulatory Response to Mild Cold in People. Front Physiol. 2016 Apr 19;7:129. doi: 10.3389/fphys.2016.00129. eCollection 2016.

  PMID: 27148068 DERIVED

• Chondronikola M, Volpi E, Borsheim E, Porter C, Annamalai P, Enerback S, Lidell ME, Saraf MK, Labbe SM, Hurren NM, Yfanti C, Chao T, Andersen CR, Cesani F, Hawkins H, Sidossis LS. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes. 2014 Dec;63(12):4089-99. doi: 10.2337/db14-0746. Epub 2014 Jul 23.

  PMID: 25056438 DERIVED

MeSH Terms

Conditions

Insulin Resistance; Obesity

Interventions

Propranolol; Exercise

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Labros Sidossis, PhD

  The University of Texas Medical Branch, Galveston

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 11, 2013
• First Posted: February 13, 2013
• Study Start: January 1, 2012
• Primary Completion: December 30, 2018
• Study Completion: December 30, 2018
• Last Updated: March 16, 2021

Record last verified: 2019-01

Locations

US (1)