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Enhancement of Cerebral Vasoreactivity and Cognition by Intranasal Insulin in Type 2 Diabetes

Primary Purpose

Type 2 Diabetes Mellitus

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Intranasal insulin
Placebo
Sponsored by
Beth Israel Deaconess Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Type 2 Diabetes Mellitus focused on measuring diabetes, blood flow, brain perfusion, cognitive function

Eligibility Criteria

50 Years - 85 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Diabetes group:

  • 30 men and women aged >50 years old diagnosed with T2DM and treated > 5 years with oral agents
  • Diabetes severity will be assessed from diabetes duration, hemoglobin A1C, and fasting glucose levels.

Control group:

  • 30 healthy men and women aged >50 years selected to have the same age and sex distributions as the diabetic subjects
  • Normotensive, not treated for any systemic disease, and have normal fasting blood glucose.

Exclusion Criteria:

  • Type 1 Diabetes Mellitus
  • History of severe hypoglycemia or hypoglycemic episode during home baseline monitoring
  • Positive stress test for CAD or other ischemic conditions
  • Carotid stenosis > 50% by medical history
  • History of a clinically documented stroke
  • Treatment with any medications administered intranasally including intranasal steroids
  • Any previous adverse or allergic reactions to insulin
  • Acute or unstable medical condition including Myocardial infarction or major illness and surgery within six months
  • Liver or renal failure or transplant
  • Uncontrolled hypertension (systolic BP >180 and/or diastolic BP >100 mm Hg or subjects taking more than 3 antihypertensive medications)
  • Seizure disorders
  • Malignant tumors
  • Clinical dementia (by history) or inability to follow details of the protocol(MMSE (Mini Mental Status Exam) score (≥3 points below the Comparative Normal Value for the subject's age group and education level, or ≤ 24)
  • Current recreational drug or alcohol abuse
  • Morbid obesity (BMI >40)
  • Inability to obtain permission for participation from the primary care physician
  • Transcranial Doppler (TCD) exclusion criterion - poor insonation window and TCD signal
  • MR exclusion criteria - any metal or bioimplants not compatible with 3 Tesla MRI and claustrophobia
  • Clinically significant and movement limiting hip, knee and/or back disorders or injury, and rheumatoid arthritis

Sites / Locations

  • Beth Israel Deaconess Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Insulin vs. placebo

Healthy vs. Diabetic

Arm Description

Comparisons of acute effects of intranasal insulin or placebo (saline) on cerebral blood flow and cognition in healthy controls and type 2 diabetes.

Comparisons of acute effects of intranasal insulin or placebo (saline) on cerebral blood flow and cognition in healthy controls and type 2 diabetes.

Outcomes

Primary Outcome Measures

Cognitive Outcome: Brief Visuospatial Spatial Memory Test -Total Recall (Unit T Score)
To determine the acute effects of a single 40-IU dose of intranasal insulin vs. placebo on cognition and regional perfusion and vasoreactivity to CO2 challenge measured by 3-D continuous arterial spin labeling (CASL) MRI at 3 Tesla in the control and diabetic groups. Cognitive outcome: Brief Visuospatial Spatial Memory test -Total Recall (unit T Score). Perfusion outcome: Regional vasoreactivity (ml/100g/min/mmHg). Each participant received a single dose of intranasal insulin (INI) or placebo on day 2 and a single dose dose of insulin or placebo on day 3 in a random order. Acute effects on baseline perfusion, regional vasoreactivity and cognition were determined within 2 hours after administration of insulin or placebo.
Perfusion Outcome: Right Insular Cortex Perfusion (ml/100g/Min/mmHg)
To determine the acute effects of a single 40-IU dose of intranasal insulin vs. placebo on cognition and regional perfusion and vasoreactivity to CO2 challenge measured by 3-D continuous arterial spin labeling (CASL) MRI at 3 Tesla in the control and diabetic groups. Cognitive outcome: Brief Visuospatial Spatial Memory test -Total Recall (unit T Score). Perfusion outcome: Regional vasoreactivity (ml/100g/min/mmHg).

Secondary Outcome Measures

Full Information

First Posted
August 20, 2010
Last Updated
June 17, 2019
Sponsor
Beth Israel Deaconess Medical Center
Collaborators
Boston University, Joslin Diabetes Center, Peking University, University of Washington, University of Arkansas, VA Boston Healthcare System, University of Massachusetts, Worcester, Wake Forest University
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1. Study Identification

Unique Protocol Identification Number
NCT01206322
Brief Title
Enhancement of Cerebral Vasoreactivity and Cognition by Intranasal Insulin in Type 2 Diabetes
Official Title
Enhancement of Cerebral Vasoreactivity and Cognition by Intranasal Insulin in Type 2 Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Completed
Study Start Date
May 2010 (undefined)
Primary Completion Date
April 2013 (Actual)
Study Completion Date
April 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Beth Israel Deaconess Medical Center
Collaborators
Boston University, Joslin Diabetes Center, Peking University, University of Washington, University of Arkansas, VA Boston Healthcare System, University of Massachusetts, Worcester, Wake Forest University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Our goal is to determine the acute effects of intranasal insulin on regional perfusion and cognition of older adults. We propose a pilot study to examine the effect of a single dose of intranasal insulin on regional vasoreactivity and cognitive functions in 30 subjects with T2DM and 30 healthy controls >50 years old using a double blinded, placebo-controlled, cross-over design. Hypothesis 1: Intranasal insulin improves acutely regional perfusion and vasoreactivity in older patients with T2DM as compared with placebo and compared with the control group. Hypothesis 2: Intranasal insulin improves cognitive functioning including attention, memory and executive function in diabetic patients as compared with placebo and compared with control group.
Detailed Description
Type 2 diabetes mellitus (T2DM) is a major risk factor for vascular dementia. DM alters insulin transport across blood-brain barrier affecting perfusion and neuronal function. Intranasal administration enables effective delivery of insulin to the brain. Clinical studies demonstrated improvement of cognitive function and memory in healthy and cognitively impaired people. Aim 1: To determine the acute effects of a single 40-IU dose of intranasal insulin vs. placebo on regional perfusion and vasoreactivity to CO2 challenge measured by 3-D continuous arterial spin labeling (CASL) MRI at 3 Tesla in the control and diabetic groups. We will use transcranial Doppler to determine the effects on intranasal insulin vs. placebo on cerebral autoregulation based on measurements of beat-to-beat pressure flow velocity relationship. Aim 2: To determine whether intranasal insulin improves cognitive functioning in older T2DM patients as compared with placebo and the control group. This translational study will address an important area about the effects of intranasal insulin on cerebral blood flow regulation and cognition in older diabetics that has not been studied. Intranasal insulin administration may provide a novel therapeutic target for prevention and treatment of microvascular disease and cerebrovascular complications of T2DM. If successful, this approach may have significant impact on the clinical management of large population of older adults with T2DM.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus
Keywords
diabetes, blood flow, brain perfusion, cognitive function

7. Study Design

Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Insulin vs. placebo
Arm Type
Experimental
Arm Description
Comparisons of acute effects of intranasal insulin or placebo (saline) on cerebral blood flow and cognition in healthy controls and type 2 diabetes.
Arm Title
Healthy vs. Diabetic
Arm Type
Other
Arm Description
Comparisons of acute effects of intranasal insulin or placebo (saline) on cerebral blood flow and cognition in healthy controls and type 2 diabetes.
Intervention Type
Drug
Intervention Name(s)
Intranasal insulin
Other Intervention Name(s)
Novolin R
Intervention Description
The acute effects of a single 40-IU dose of intranasal insulin
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
The acute effects of intranasal sterile saline.
Primary Outcome Measure Information:
Title
Cognitive Outcome: Brief Visuospatial Spatial Memory Test -Total Recall (Unit T Score)
Description
To determine the acute effects of a single 40-IU dose of intranasal insulin vs. placebo on cognition and regional perfusion and vasoreactivity to CO2 challenge measured by 3-D continuous arterial spin labeling (CASL) MRI at 3 Tesla in the control and diabetic groups. Cognitive outcome: Brief Visuospatial Spatial Memory test -Total Recall (unit T Score). Perfusion outcome: Regional vasoreactivity (ml/100g/min/mmHg). Each participant received a single dose of intranasal insulin (INI) or placebo on day 2 and a single dose dose of insulin or placebo on day 3 in a random order. Acute effects on baseline perfusion, regional vasoreactivity and cognition were determined within 2 hours after administration of insulin or placebo.
Time Frame
Acute changes within 2 hours
Title
Perfusion Outcome: Right Insular Cortex Perfusion (ml/100g/Min/mmHg)
Description
To determine the acute effects of a single 40-IU dose of intranasal insulin vs. placebo on cognition and regional perfusion and vasoreactivity to CO2 challenge measured by 3-D continuous arterial spin labeling (CASL) MRI at 3 Tesla in the control and diabetic groups. Cognitive outcome: Brief Visuospatial Spatial Memory test -Total Recall (unit T Score). Perfusion outcome: Regional vasoreactivity (ml/100g/min/mmHg).
Time Frame
Acute changes within 2 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Diabetes group: 30 men and women aged >50 years old diagnosed with T2DM and treated > 5 years with oral agents Diabetes severity will be assessed from diabetes duration, hemoglobin A1C, and fasting glucose levels. Control group: 30 healthy men and women aged >50 years selected to have the same age and sex distributions as the diabetic subjects Normotensive, not treated for any systemic disease, and have normal fasting blood glucose. Exclusion Criteria: Type 1 Diabetes Mellitus History of severe hypoglycemia or hypoglycemic episode during home baseline monitoring Positive stress test for CAD or other ischemic conditions Carotid stenosis > 50% by medical history History of a clinically documented stroke Treatment with any medications administered intranasally including intranasal steroids Any previous adverse or allergic reactions to insulin Acute or unstable medical condition including Myocardial infarction or major illness and surgery within six months Liver or renal failure or transplant Uncontrolled hypertension (systolic BP >180 and/or diastolic BP >100 mm Hg or subjects taking more than 3 antihypertensive medications) Seizure disorders Malignant tumors Clinical dementia (by history) or inability to follow details of the protocol(MMSE (Mini Mental Status Exam) score (≥3 points below the Comparative Normal Value for the subject's age group and education level, or ≤ 24) Current recreational drug or alcohol abuse Morbid obesity (BMI >40) Inability to obtain permission for participation from the primary care physician Transcranial Doppler (TCD) exclusion criterion - poor insonation window and TCD signal MR exclusion criteria - any metal or bioimplants not compatible with 3 Tesla MRI and claustrophobia Clinically significant and movement limiting hip, knee and/or back disorders or injury, and rheumatoid arthritis
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vera Novak, MD PhD
Organizational Affiliation
Beth Israel Deaconess Medical Center, Harvard Medical School
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
24101698
Citation
Novak V, Milberg W, Hao Y, Munshi M, Novak P, Galica A, Manor B, Roberson P, Craft S, Abduljalil A. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care. 2014;37(3):751-9. doi: 10.2337/dc13-1672. Epub 2013 Oct 7.
Results Reference
result
PubMed Identifier
25249577
Citation
Zhang H, Hao Y, Manor B, Novak P, Milberg W, Zhang J, Fang J, Novak V. Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes. 2015 Mar;64(3):1025-34. doi: 10.2337/db14-1000. Epub 2014 Sep 23.
Results Reference
result

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Enhancement of Cerebral Vasoreactivity and Cognition by Intranasal Insulin in Type 2 Diabetes

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