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

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.

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