Racial Differences in Vagal Control of Glucose Homeostasis

NCT ID: NCT02365285

Last Updated: 2019-03-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 23 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-03-31
• Study Completion Date: 2017-10-05

Brief Summary

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

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.

Conditions

Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Galantamine 16 mg then placebo

Galantamine 16 mg po one time dose then placebo on 2nd visit

Group Type: EXPERIMENTAL

Galantamine

Intervention Type: DRUG

16 mg po prior to the infusion of intralipid

Placebo Oral Capsule

Intervention Type: DRUG

Placebo oral capsule prior to the infusion of intralipid/heparin

Intralipid

Intervention Type: DRUG

Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine

Heparin

Intervention Type: DRUG

heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine

Placebo then Galantamine 16 mg

Placebo capsule po one time dose then Galantamine 16 mg on 2nd visit

Group Type: PLACEBO_COMPARATOR

Galantamine

Intervention Type: DRUG

16 mg po prior to the infusion of intralipid

Placebo Oral Capsule

Intervention Type: DRUG

Placebo oral capsule prior to the infusion of intralipid/heparin

Intralipid

Intervention Type: DRUG

Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine

Heparin

Intervention Type: DRUG

heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine

Interventions

Galantamine

16 mg po prior to the infusion of intralipid

Intervention Type: DRUG

Placebo Oral Capsule

Placebo oral capsule prior to the infusion of intralipid/heparin

Intervention Type: DRUG

Intralipid

Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine

Intervention Type: DRUG

Heparin

heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine

Intervention Type: DRUG

Other Intervention Names

Razadyne; I.V. Fat Emulsion

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Doris Duke Charitable Foundation

OTHER

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Cyndya Shibao

Medical Doctor, Assistant Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Cyndya Shibao, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center, Clinical Pharmacology

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 35659521 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

141552

Identifier Type: -

Identifier Source: org_study_id