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

Rutgers University39 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Interventions

Cold exposureOTHER

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 propranololOTHER

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 ConditionsOTHER

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

Cold water consumptionOTHER

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

Tepid water consumptionOTHER

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

ExerciseOTHER

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

Meal consumptionOTHER

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

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Insulin Sensitivity

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

Time frame: After 8hrs of cold exposure or thermoneutral conditions

Secondary Outcomes

Metabolic profile

Evaluation of metabolic profile will include measurement of various metabolites (glucose, triglycerides, very low-density (VLDL)-triglycerides, non-esterified fatty acids, lipoproteins, apo-B) and hormones (leptin, adiponectin, insulin, ghrelin).

Time frame: During the 8hr trial or on the following day