Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, blood flow, brain perfusion, cognitive function
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.
Interventions
DRUGPlacebo
The acute effects of intranasal sterile saline.
DRUGIntranasal insulin
The acute effects of a single 40-IU dose of intranasal insulin
Sponsors
Boston University
Joslin Diabetes Center
Peking University
University of Washington
University of Arkansas
VA Boston Healthcare System
University of Massachusetts, Worcester
Wake Forest University
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive Outcome: Brief Visuospatial Spatial Memory Test -Total Recall (Unit T Score) | Acute changes within 2 hours | 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) | Acute changes within 2 hours | 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). |
Countries
United States
Participant flow
Pre-assignment details
Thirty consented subjects, 15 type 2 diabetic and 14 controls completed the protocol. One control was excluded after starting the study. Screened participants that did not start study: 27 were excluded after screening visit, 7 withdrew consent. Enrollment Table list the characteristics of 29 participants who completed the protocol.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Comparisons of acute effects of intranasal insulin or placebo on cerebral blood flow and cognition.
Intranasal insulin: The acute effects of a single 40-IU dose of intranasal insulin vs. placebo ( sterilesaline) in type 2 diabetes and the non-diabetic control group.Each participant received a single dose of insulin and a single dose of placebo on 2 consequent days in random order. | 14 |
| Diabetics Comparisons of acute effects of intranasal insulin or placebo on cerebral blood flow and cognition.
Intranasal insulin: The acute effects of a single 40-IU dose of intranasal insulin vs. placebo ( sterilesaline) in type 2 diabetes and the non-diabetic control group.Each participant received a single dose of insulin and a single dose of placebo on 2 consequent days in random order. | 15 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Healthy | Diabetics | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 3 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 12 Participants | 21 Participants |
| Age, Continuous | 60.1 years STANDARD_DEVIATION 9.9 | 62.0 years STANDARD_DEVIATION 7.9 | 61.1 years STANDARD_DEVIATION 8.81 |
| Region of Enrollment United States | 14 participants | 15 participants | 29 participants |
| Sex: Female, Male Female | 10 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Male | 4 Participants | 8 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 0 / 15 | 0 / 15 | 1 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
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.
Time frame: Acute changes within 2 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetes Group: Placebo | Cognitive Outcome: Brief Visuospatial Spatial Memory Test -Total Recall (Unit T Score) | 39.46 T-score | Standard Deviation 8.86 |
| Diabetes Group: Insulin | Cognitive Outcome: Brief Visuospatial Spatial Memory Test -Total Recall (Unit T Score) | 41.23 T-score | Standard Deviation 9.85 |
| Control Group: Placebo | Cognitive Outcome: Brief Visuospatial Spatial Memory Test -Total Recall (Unit T Score) | 43.1 T-score | Standard Deviation 17.29 |
| Control Group: Insulin | Cognitive Outcome: Brief Visuospatial Spatial Memory Test -Total Recall (Unit T Score) | 50.9 T-score | Standard Deviation 9.66 |
Primary
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).
Time frame: Acute changes within 2 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetes Group: Placebo | Perfusion Outcome: Right Insular Cortex Perfusion (ml/100g/Min/mmHg) | 39.2 ml/100g/min/mmHg | Standard Deviation 3.3 |
| Diabetes Group: Insulin | Perfusion Outcome: Right Insular Cortex Perfusion (ml/100g/Min/mmHg) | 46.4 ml/100g/min/mmHg | Standard Deviation 3.6 |
| Control Group: Placebo | Perfusion Outcome: Right Insular Cortex Perfusion (ml/100g/Min/mmHg) | 40.3 ml/100g/min/mmHg | Standard Deviation 2.4 |
| Control Group: Insulin | Perfusion Outcome: Right Insular Cortex Perfusion (ml/100g/Min/mmHg) | 36.9 ml/100g/min/mmHg | Standard Deviation 2.5 |