Racial Differences in Vagal Control of Glucose Homeostasis, Chronic Study

Investigators will test the hypothesis that chronic restoration of parasympathetic nervous
system (PNS) activity with a central acetylcholinesterase inhibitor improves insulin
sensitivity and reduces adipose tissue oxidation in obese African American women (AAW)
compared to white women (WW). A cross-over study will be performed in matched cohorts of AAW
and white women subjected to chronic central acetylcholinesterase inhibition with galantamine
versus placebo, given orally over a 4-week period. Insulin sensitivity will be measured using
the gold standard hyperinsulinemic-euglycemic clamp. Adipose tissue will be obtained through
subcutaneous fat biopsies where F2-isoprostanes will be quantified.

Inclusion Criteria

- Female

- African American or white (race will be self-defined, but only subjects who report
both parents of the same race will be included)

- 18-60 years old

- BMI 30-45 Kg/m2

- Not pregnant or breastfeeding

Exclusion Criteria

- Pregnant or breastfeeding

- Diabetes diagnosis (defined by the American Diabetes Association (ADA) criteria)38

- Cardiovascular disease such as myocardial infarction within 6 months prior to
enrollment, presence of angina pectoris, significant arrhythmia, congestive heart
failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, mitral
valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy.

- Arrhythmia (first-, second-, and third-degree AV block)

- Significant weight change >5% in the past 3 months

- Impaired hepatic function (AST and/or ALT >1.5X upper limit of normal range)

- Impaired renal function (eGFR <60ml/min)

- Users of strong inhibitors of CYP3A4 or CYP2D6

- Users of other acetylcholinesterase inhibitors such as pyridostigmine or bethanechol

- History of alcohol or drug abuse

- Mental conditions rendering the subject unable to understand the nature, scope, and
possible consequences of the study

- Inability to comply with the protocol, e.g., uncooperative attitude, inability to
return for follow-up visits, and unlikelihood of completing the study

- Steroid use within 6 weeks prior to study entry

- Any underlying or acute disease requiring regular medication which could possibly pose
a threat to the subject or make implementation of the protocol or interpretation of
the study results difficult

- Discretion of the investigator