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

NCT ID: NCT01791114

Last Updated: 2021-03-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 39 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-01-31
• Study Completion Date: 2018-12-30

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Cold water consumption

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

Group Type: EXPERIMENTAL

Cold water consumption

Intervention Type: OTHER

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

Tepid water consumption

Intervention Type: OTHER

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

Meal consumption

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

Group Type: EXPERIMENTAL

Thermoneutral Conditions

Intervention Type: OTHER

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

Meal consumption

Intervention Type: OTHER

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

Cold exposure

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).

Group Type: EXPERIMENTAL

Cold exposure

Intervention Type: 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 plus propranolol

Intervention Type: 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.

Thermoneutral Conditions

Intervention Type: OTHER

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

Exercise

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.

Group Type: EXPERIMENTAL

Thermoneutral Conditions

Intervention Type: OTHER

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

Exercise

Intervention Type: 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

Interventions

Cold exposure

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).

Intervention Type: OTHER

Cold exposure plus propranolol

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.

Intervention Type: OTHER

Thermoneutral Conditions

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

Intervention Type: OTHER

Cold water consumption

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

Intervention Type: OTHER

Tepid water consumption

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

Intervention Type: OTHER

Exercise

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

Intervention Type: OTHER

Meal consumption

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

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• men or women
• 18-75 years old
• BMI 20-40 kg/m2

Exclusion Criteria

• 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
• pacemaker or other implanted electromedical device
• alcohol and drug abuse
• tobacco use
• impaired cognition
• asthma
• chronic obstructive pulmonary disease (COPD) or other reactive airway diseases

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Rutgers University

OTHER

Sponsor Role: lead

Responsible Party

Labros Sidossis, Ph.D.

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Labros Sidossis, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Texas Medical Branch at Galveston

Locations

University of Texas Medical Branch at Galveston

Galveston, Texas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 27148068 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25056438 (View on PubMed)

Other Identifiers

11-193

Identifier Type: -

Identifier Source: org_study_id