Racial Differences in Vagal Control of Glucose Homeostasis

Obesity has a greater detrimental impact on the health of African American women (AAW) than
on any other racial or gender group. Nearly 80% of AAW are overweight or obese. Reduced
insulin sensitivity is more prevalent among AAW as compared to white women and men of both
races. This condition puts AAW at increased risk for the development of type 2 diabetes
mellitus. The exact mechanism underlying these pathophysiological differences remains
unknown. The investigators have found that obese AAW have decreased parasympathetic nerve
(PNS) activity compared to whites and recent studies in animal models showed that the PNS
confers protection against oxidative stress. In our AA cohort, PNS activity was directly
correlated with insulin sensitivity in obese AAW even after controlling for differences in
age, blood pressure and visceral adiposity. Equally important, the investigators also showed
that the decrease in insulin sensitivity was associated with increased oxidative stress as
measured by plasma levels of F2-isoprostanes. Taken together these findings lead us to
hypothesize that the decreased PNS activity in obese AAW compared to white women has
deleterious effects on oxidative stress and insulin sensitivity.The investigators will test
the hypothesis that acute central acetylcholinesterase inhibition will restore PNS activity
and reduce oxidation in AAW compared to whites.

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 atrioventricular (AV) block)

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

- Impaired hepatic function (AST and/or Alanine transaminase (ALT) > one and one half
times (1.5X) upper limit of normal range)

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

- Users of strong inhibitors of Cytochrome P450 3A4 (CYP3A4) or cytochrome P450, family
2, subfamily D, polypeptide 6 (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