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 to effectively deliver insulin to the brain. Clinical studies demonstrated improvement of cognitive function and memory in healthy and cognitively impaired people. Our goal is to determine the acute effects of intranasal insulin on regional perfusion and cognition in older diabetic adults. We propose a pilot study to examine the effects 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.
Aim 1 : We will 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 effects on intranasal insulin vs. placebo on dynamic autoregulation based on measurements of beat-to-beat pressure-flow velocity relationship.
Aim 2 : We will determine whether intranasal insulin improves cognitive functioning including attention, memory and executive function in older diabetic 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 diabetic people 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 clinical management of large population of older adults with T2DM.

Public Health Relevance

Diabetes mellitus is a major risk factor for both large and small vessel atherosclerosis, strokes, and vascular dementia. This pilot study aims to determine the efficacy of intranasal insulin to improve cerebral vasoreactivity and to explore the effects on cognitive function in older diabetic adults. If proven effective, intranasal insulin may become a new preventive and therapeutic target for treatment of cerebromicrovascular disease in older diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK084463-02
Application #
8049733
Study Section
Special Emphasis Panel (ZRG1-EMNR-K (90))
Program Officer
Jones, Teresa L Z
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2011
Total Cost
$213,797
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Chung, Chen-Chih; Pimentel Maldonado, Daniela A; Jor'dan, Azizah J et al. (2018) Lower cerebral vasoreactivity as a predictor of gait speed decline in type 2 diabetes mellitus. J Neurol 265:2267-2276
Dai, Weiying; Duan, Wenna; Alfaro, Freddy J et al. (2017) The resting perfusion pattern associates with functional decline in type 2 diabetes. Neurobiol Aging 60:192-202
Novak, Vera; Gomez, Federico; Dias, Alexandre Campos et al. (2017) Diabetes-Related Cognitive Decline, a Global Health Issue, and New Treatments Approaches. Int J Priv Health Inf Manag 5:58-70
Dubey, Prachi; Lioutas, Vasileios-Arsenios; Bhadelia, Rafeeque et al. (2016) Quantitative microstructural deficits in chronic phase of stroke with small volume infarcts: A diffusion tensor 3-D tractographic analysis. Magn Reson Imaging 34:662-7
Alfaro, Freddy J; Lioutas, Vasileios-Arsenios; Pimentel, Daniela A et al. (2016) Cognitive decline in metabolic syndrome is linked to microstructural white matter abnormalities. J Neurol 263:2505-2514
Lioutas, Vasileios-Arsenios; Novak, Vera (2016) Intranasal insulin neuroprotection in ischemic stroke. Neural Regen Res 11:400-1
Lioutas, Vasileios-Arsenios; Alfaro-Martinez, Freddy; Bedoya, Francisco et al. (2015) Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke. Transl Stroke Res 6:264-75
Chung, Chen-Chih; Pimentel, Daniela; Jor'dan, Azizah J et al. (2015) Inflammation-associated declines in cerebral vasoreactivity and cognition in type 2 diabetes. Neurology 85:450-8
Zhang, Hui; Hao, Ying; Manor, Bradley et al. (2015) Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes 64:1025-34
Jor'dan, Azizah J; Manor, Brad; Novak, Vera (2014) Slow gait speed - an indicator of lower cerebral vasoreactivity in type 2 diabetes mellitus. Front Aging Neurosci 6:135

Showing the most recent 10 out of 20 publications