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

Study Overview
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Brief Summary
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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
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Insulin Sensitivity, Obesity

Intervention / Treatment
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* Other: Cold exposure
* Other: Cold exposure plus propranolol
* Other: Thermoneutral Conditions
* Other: Cold water consumption
* Other: Tepid water consumption
* Other: Exercise
* Other: Meal consumption


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cold water consumption<br>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<br>* Subjects will be asked to consume cold water (4 °C,10 ml/ kg body weight within 10 minutes)<br>Other: Tepid water consumption<br>* Subjects will be asked to consume cold water (36 C,10 ml/ kg body weight within 10 minutes)<br>|
| Experimental: Meal consumption<br>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<br>* Subjects will be exposed to thermoneutral conditions (26 - 28°C)<br>Other: Meal consumption<br>* Subjects will be asked to consume a high calorie meal (12 kcal/kg, 50% carbohydrates, 30% fat, and 20% protein) within 15 minutes.<br>|
| Experimental: Cold exposure<br>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<br>* 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).<br>Other: Cold exposure plus propranolol<br>* 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.<br>Other: Thermoneutral Conditions<br>* Subjects will be exposed to thermoneutral conditions (26 - 28°C)<br>|
| Experimental: Exercise<br>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<br>* Subjects will be exposed to thermoneutral conditions (26 - 28°C)<br>Other: Exercise<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | Insulin sensitivity will be measured using the euglycemic hyperinsulinemic insulin clamp method | After 8hrs of cold exposure or thermoneutral conditions | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | During the 8hr trial or on the following day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin sensitivity, Diabetes Prevention, Obesity, Brown adipose tissue