Hypoglycemia and Autonomic Nervous System Function-B (HypoANS-B)

Hypoglycemia and Autonomic Nervous System Function

This study tests the hypothesis that, compared to prior normal blood sugar, prior low blood sugar impairs cardiovascular autonomic function. The proposed studies will also test the hypothesis that the effects of prior low blood sugar on cardiovascular autonomic function are blocked by administration of a mineralocorticoid receptor antagonist.

Study Overview

• Status: Active, not recruiting
• Conditions: Healthy; Hypoglycemia
• Intervention / Treatment: Drug: Spironolactone; Other: Hypoglycemic Hyperinsulinemic Clamp; Drug: Placebo; Other: Euglycemic Hyperinsulinemic Clamp

Detailed Description

This study involves three interventions, which are performed in random order. Each intervention involves a 3-day inpatient visit. There is a space of 1-3 months between interventions. The three interventions are: 1) placebo with a hyperinsulinemic euglycemic clamp, 2) spironolactone with a hyperinsulinemic hypoglycemic clamp, or 3) placebo with a hyperinsulinemic hypoglycemic clamp. Each 3-day inpatient visit includes the following. On Day 1, autonomic testing is performed. Autonomic testing includes assessment of Baroreflex Sensitivity (BRS). BRS is assessed using the Modified Oxford procedure, which involves sequential administration of nitroprusside and phenylephrine while measuring heart rate and beat to beat blood pressure with a finapress and assessing Muscle Sympathetic Nerve Activity (MSNA). MSNA is measured using microelectrodes placed near the peroneal nerve. On Day 2, hyperinsulinemic clamps are performed with pre-treatment with either placebo or spironolactone. Modified Oxford Procedures are performed prior to and during each clamp on Day 2. On Day 3, the autonomic testing performed on Day 1 is repeated..

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy volunteers
• Males and females age 18 to 55 years

Exclusion Criteria:

• Pregnancy
• Lactation
• Clinically evident coronary artery, cerebrovascular, or peripheral vascular disease, or presence of systemic illness that might affect autonomic function. Such illnesses include diabetes mellitus, congestive heart failure, hypertension, renal, pulmonary, hepatic disease, anemia, malignancies, untreated thyroid disease, and alcoholism.
• Current major depressive illness
• In all subjects, any individuals on oral, injected, inhaled or topical corticosteroids within the last year or oral contraceptives within the past 3 months will be excluded.
• Use of medications other than thyroxine
• Known hypersensitivity to nitroglycerin, nitroprusside and/or phenylephrine.
• Blood pressure > 140/90 mmHg
• Creatinine > 1.5 mg/dL
• Serum potassium >5.2 mmol/L
• Estimated GFR < 50 mL/min
• Use of Viagra, Cialis, and similar drugs within 72 hours of admission.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Hypoglycemia and Spironolactone; Participants undergo two 120-minute hypoglycemic hyperinsulinemic clamp procedures (50 mg/dL) - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Participants receive two doses of 100 mg of spironolactone - one dose 12 hours and one dose 3 hours before the first clamp starts. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.	Drug: Spironolactone; Participants will receive spironolactone 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment.; Other: Hypoglycemic Hyperinsulinemic Clamp; Participants undergo two 120-minute hypoglycemic (50 mg/dL) hyperinsulinemic clamps - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.; Other Names: Hypoglycemic Hyperinsulinemic Clamp Procedure
ACTIVE_COMPARATOR: Hypoglycemia and Placebo; Participants undergo two 120-minute hypoglycemic hyperinsulinemic clamp procedures (50 mg/dL) - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Participants receive two doses of placebo - one dose 12 hours and one dose 3 hours before the first clamp starts. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.	Other: Hypoglycemic Hyperinsulinemic Clamp; Participants undergo two 120-minute hypoglycemic (50 mg/dL) hyperinsulinemic clamps - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.; Other Names: Hypoglycemic Hyperinsulinemic Clamp Procedure; Drug: Placebo; Participants will receive placebo 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment.
PLACEBO_COMPARATOR: Euglycemia and Placebo; Participants undergo two 120-minute euglycemic hyperinsulinemic clamp procedures (90 mg/dL) - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Participants receive two doses of placebo - one dose 12 hours and one dose 3 hours before the first clamp starts. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.	Drug: Placebo; Participants will receive placebo 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment.; Other: Euglycemic Hyperinsulinemic Clamp; Participants undergo two 120-minute euglycemic (90 mg/dL) hyperinsulinemic clamps - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit.Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.; Other Names: Euglycemic Hyperinsulinemic Clamp Procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baroreflex Sensitivity assessed on Day 3	Comparison of Day 3 baroreflex sensitivity (milliseconds/mm Hg) assessed during Hypoglycemic hyperinsulinemic clamp + Placebo treatment as compared to Hypoglycemic hyperinsulinemic clamp + Spironolactone treatment.	Baroreflex sensitivity is assessed on the 3rd day of each treatment (i.e. about 16 hours after completion of the hyperinsulinemic clamp)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle sympathetic nerve activity assessed on Day 3	Comparison of Day 3 muscle sympathetic nerve activity (bursts/min) assessed during hypoglycemic hyperinsulinemic clamp + placebo treatment as compared to hypoglycemic hyperinsulinemic clamp + spironolactone treatment.	Muscle sympathetic nerve activity is assessed on the 3rd day of each treatment (i.e. about 16 hours after completion of the hyperinsulinemic clamp)

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Beth Israel Deaconess Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 17, 2013
• Primary Completion (ANTICIPATED): January 4, 2024
• Study Completion (ANTICIPATED): January 4, 2024

Study Registration Dates

• First Submitted: January 30, 2018
• First Submitted That Met QC Criteria: February 9, 2018
• First Posted (ACTUAL): February 12, 2018

Study Record Updates

• Last Update Posted (ACTUAL): July 20, 2022
• Last Update Submitted That Met QC Criteria: July 18, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hypoglycemia; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Hypoglycemic Agents; Spironolactone
• Other Study ID Numbers: 2004P001233-B; K24HL103845 (NIH); UL1TR001102 (NIH); R01HL109634 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data collected will comply with the NIH requirements for timely release and data sharing. Data will be shared in the form of publications and presentations in scientific forums. As the NIH has noted, the investigators reserve the right to keep the data restricted in order to perform the initial analyses for this grant proposal and will continue to use the data for further, but not prolonged, exclusive use. Of note, the sharing of this data will be limited by at least the following issues, some unique to this proposal and some not unique. Some of the data obtained in this study is defined to be sensitive in nature, which may restrict its ability to be shared. Data may only be shared with the approval of our IRB and is limited by HIPPA and any other regulations that may be promulgated during the course of this proposal.
• IPD Sharing Time Frame: Data will be shared after completion of study and initial publications which we anticipate to be within 18 months of the final participant completing the study protocol.
• IPD Sharing Access Criteria: Access to data must be approved by the IRB at our institution.

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.: Yes