Racial Differences in Vagal Control of Glucose Homeostasis (RDVCGH)

The investigators will test the hypothesis that acute central acetylcholinesterase inhibition will restore PNS activity and reduce oxidation in AAW compared to whites.

Study Overview

• Status: Completed
• Conditions: Obesity
• Intervention / Treatment: Drug: Galantamine; Drug: Placebo Oral Capsule; Drug: Intralipid; Drug: Heparin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Galantamine 16 mg then placebo; Galantamine 16 mg po one time dose then placebo on 2nd visit	Drug: Galantamine; 16 mg po prior to the infusion of intralipid; Other Names: Razadyne; Drug: Placebo Oral Capsule; Placebo oral capsule prior to the infusion of intralipid/heparin; Drug: Intralipid; Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine; Other Names: I.V. Fat Emulsion; Drug: Heparin; heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine
Placebo Comparator: Placebo then Galantamine 16 mg; Placebo capsule po one time dose then Galantamine 16 mg on 2nd visit	Drug: Galantamine; 16 mg po prior to the infusion of intralipid; Other Names: Razadyne; Drug: Placebo Oral Capsule; Placebo oral capsule prior to the infusion of intralipid/heparin; Drug: Intralipid; Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine; Other Names: I.V. Fat Emulsion; Drug: Heparin; heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Oxidative Stress: Baseline to 2 Hours	Measure F-2 isoprostanes as a marker of oxidation	Baseline to 2 hours
Change in Oxidative Stress: Baseline to 4 Hours	Measure F-2 isoprostanes as a marker of oxidation	Baseline to 4 hours

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: Doris Duke Charitable Foundation
• Investigators: Principal Investigator: Cyndya Shibao, MD, Vanderbilt University Medical Center, Clinical Pharmacology

Publications and helpful links

General Publications

• Parsa D, Aden LA, Pitzer A, Ding T, Yu C, Diedrich A, Milne GL, Kirabo A, Shibao CA. Enhanced parasympathetic cholinergic activity with galantamine inhibited lipid-induced oxidative stress in obese African Americans. Mol Med. 2022 Jun 3;28(1):60. doi: 10.1186/s10020-022-00486-5.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Actual): October 5, 2017
• Study Completion (Actual): October 5, 2017

Study Registration Dates

• First Submitted: January 28, 2015
• First Submitted That Met QC Criteria: February 17, 2015
• First Posted (Estimate): February 18, 2015

Study Record Updates

• Last Update Posted (Actual): March 19, 2019
• Last Update Submitted That Met QC Criteria: February 28, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Pharmaceutical Solutions; Nootropic Agents; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Cholinesterase Inhibitors; Parasympathomimetics; Heparin; Soybean oil, phospholipid emulsion; Galantamine
• Other Study ID Numbers: 141552

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No