The Effect of Brown Adipose Tissue Activation on Insulin Sensitivity in Humans
Condition: Insulin Sensitivity; Obesity
MeSH terms: Insulin Resistance; Hypersensitivity
Study type: Interventional

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.
    


Intervention name(s): Cold exposure; Cold exposure plus propranolol; Thermoneutral Conditions; Cold water consumption; Tepid water consumption; Exercise; Meal consumption
Intervention type(s): Other; Other; Other; Other; Other; Other; Other
Intervention description(s): 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).; 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.; Subjects will be exposed to thermoneutral conditions (26 - 28°C); Subjects will be asked to consume cold water (4 °C,10 ml/ kg body weight within 10 minutes); Subjects will be asked to consume cold water (36 C,10 ml/ kg body weight within 10 minutes); 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; Subjects will be asked to consume a high calorie meal (12 kcal/kg, 50% carbohydrates, 30% fat, and 20% protein) within 15 minutes.
Intervention MeSH terms: Propranolol
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Insulin sensitivity; Diabetes Prevention; Obesity; Brown adipose tissue