Clinical trial NCT01206322: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 2 Diabetes Mellitus
Keywords: diabetes, blood flow, brain perfusion, cognitive function
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: Boston University
name: Joslin Diabetes Center
name: Peking University
name: University of Washington
name: University of Arkansas
name: VA Boston Healthcare System
name: University of Massachusetts, Worcester
name: Wake Forest University
First posted: 2010-09-21
Enrollment: 30
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: Cognitive Outcome: Brief Visuospatial Spatial Memory Test -Total Recall (Unit T Score)
timeFrame: Acute changes within 2 hours
measure: Perfusion Outcome: Right Insular Cortex Perfusion (ml/100g/Min/mmHg)
timeFrame: Acute changes within 2 hours
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School
name: Vera Novak, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.