Hypoglycemia Associated Autonomic Failure in Type 1 Diabetes Mellitus (DM)

Hypoglycemia Associated Autonomic Failure in Type 1 DM, SSRI and Exercise

Exercise is a cornerstone of diabetes management. It helps reduce blood pressure, promote weight loss, lower insulin resistance and improve glucose and lipid (triglyceride and HDL-cholesterol) profiles. Unfortunately, the benefits of exercise are often not embraced by diabetic individuals because of the fear of low blood sugar (hypoglycemia). My laboratory has demonstrated that Autonomic nervous system (ANS) counterregulatory failure plays an important role in exercise associated hypoglycemia in Type 1 DM. ANS responses are significantly reduced in Type 1 DM and are further blunted by antecedent episodes of hypoglycemia. Furthermore, there is a large sexual dimorphism of reduced ANS responses during submaximal exercise in both Type 1 DM and healthy individuals that is unexplained. Accumulating data are demonstrating that serotonergic pathways can regulate ANS discharge. Generally, serotonergic pathways are inhibitory but both single and longer term administration of selective serotonin reuptake inhibitors (SSRI's) such as Prozac has been demonstrated to increase basal epinephrine levels and enhance baroreflex control of Sympathetic nervous system (SNS) activity. What is unknown is whether fluoxetine can also enhance SNS responses and also override the large ANS sexual dimorphism present during sub maximal exercise. Therefore, the purpose of this study is to determine if the SSRI fluoxetine (Prozac) can improve SNS responses during exercise.

Study Overview

• Status: Recruiting
• Conditions: Type 1 Diabetes; Hypoglycemia Associated Autonomic Failure
• Intervention / Treatment: Drug: Fluoxetine; Drug: Placebo control

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Maka Siamashvili, MD; Phone Number: 410-706-5623; Email: msiamashvili@som.umaryland.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Recruiting
      • University of Maryland, Baltimore
      • Contact: Maka Siamashvili, MD; Phone Number: 410-706-5623
      • Principal Investigator: Stephen N. Davis, MBBS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 32 (16 males, 16 females) Healthy controls aged 18-45 yr.
• 32 (16 males, 16 females) Type 1 diabetic patients aged 18-45 yr.
• HbA1c 6-10.0%
• Has been diagnosed Type 1 DM
• No clinically diagnosed diabetic tissue complications (i.e. history of retinopathy, neuropathy, stasis ulcers, etc)
• Body mass index < 40kg • m-2

Exclusion Criteria:

• Pregnant women
• Subjects unable to give voluntary informed consent
• Subjects on anticoagulant drugs, anemic or with known bleeding diatheses
• Subjects taking any of the following medications will be excluded: Non-selective Beta Blockers, Sedative-Hypnotics, Anticonvulsants, Antiparkinsonian drugs, Antipsychotics, Antidepressants, Mood stabilizers, CNS Stimulants, Opioids, Hallucinogens
• Subjects with a recent medical illness
• Subjects with a history of hypertension, heart disease, cerebrovascular incidents
• Current tobacco use

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
Active Comparator: Trial 1-SSRI; 90 minute exercise baseline with 6 weeks treatment with SSRI (Prozac). Repeat 90 minute exercise after 6 week treatment.	Drug: Fluoxetine; 20 mg week 1, 40 mg week 2, 60 mg week 3, 80 mg week 4-6; Other Names: Prozac
Placebo Comparator: Trial 2-Placebo; 90 minute exercise at baseline with 6 weeks treatment with placebo. Repeat 90 minute exercise after 6 weeks treatment of placebo.	Drug: Placebo control; 20 mg Week 1, 40 mg Week 2, 60 mg Week 3, 80 mg Week 4-6

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Catecholamines	This change in catecholamines will be compared to another 90 minute experimental period after 8 weeks administration of SSRI or placebo.	During 90 minute experimental period

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Stephen N. Davis, MBBS, University of Maryland, Baltimore

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: August 17, 2012
• First Submitted That Met QC Criteria: August 21, 2012
• First Posted (Estimated): August 24, 2012

Study Record Updates

• Last Update Posted (Estimated): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: diabetes; exercise; SSRIs
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Autonomic Nervous System Diseases; Primary Dysautonomias; Diabetes Mellitus, Type 1; Hypoglycemia; Pure Autonomic Failure; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Selective Serotonin Reuptake Inhibitors; Fluoxetine
• Other Study ID Numbers: HP-00044537; SSRI and Exercise