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

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          Abstract

          OBJECTIVE

          To determine acute effects of intranasal insulin on regional cerebral perfusion and cognition in older adults with type 2 diabetes mellitus (DM).

          RESEARCH DESIGN AND METHODS

          This was a proof-of-concept, randomized, double-blind, placebo-controlled intervention evaluating the effects of a single 40-IU dose of insulin or saline on vasoreactivity and cognition in 15 DM and 14 control subjects. Measurements included regional perfusion, vasodilatation to hypercapnia with 3-Tesla MRI, and neuropsychological evaluation.

          RESULTS

          Intranasal insulin administration was well tolerated and did not affect systemic glucose levels. No serious adverse events were reported. Across all subjects, intranasal insulin improved visuospatial memory ( P ≤ 0.05). In the DM group, an increase of perfusion after insulin administration was greater in the insular cortex compared with the control group ( P = 0.0003). Cognitive performance after insulin administration was related to regional vasoreactivity. Improvements of visuospatial memory after insulin administration in the DM group ( R 2 adjusted = 0.44, P = 0.0098) and in the verbal fluency test in the control group ( R 2 adjusted = 0.64, P = 0.0087) were correlated with vasodilatation in the middle cerebral artery territory.

          CONCLUSIONS

          Intranasal insulin administration appears safe, does not affect systemic glucose control, and may provide acute improvements of cognitive function in patients with type 2 DM, potentially through vasoreactivity mechanisms. Intranasal insulin-induced changes in cognitive function may be related to vasodilatation in the anterior brain regions, such as insular cortex that regulates attention-related task performance. Larger studies are warranted to identify long-term effects and predictors of positive cognitive response to intranasal insulin therapy.

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          Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration.

          R Thorne, G Pronk, V. Padmanabhan … (2004)
          We investigated the CNS delivery of insulin-like growth factor-I (IGF-I), a 7.65 kDa protein neurotrophic factor, following intranasal administration and the possible pathways and mechanisms underlying transport from the nasal passages to the CNS. Anesthetized adult male Sprague-Dawley rats were given [125I]-IGF-I intranasally or intravenously and then killed by perfusion-fixation within 30 min. Other animals were killed following cisternal puncture and withdrawal of cerebrospinal fluid (CSF) or intranasal administration of unlabeled IGF-I or vehicle. Both gamma counting of microdissected tissue and high resolution phosphor imaging of tissue sections showed that the tissue concentrations and distribution following intranasal administration were consistent with two routes of rapid entry into the CNS: one associated with the peripheral olfactory system connecting the nasal passages with the olfactory bulbs and rostral brain regions (e.g. anterior olfactory nucleus and frontal cortex) and the other associated with the peripheral trigeminal system connecting the nasal passages with brainstem and spinal cord regions. Intranasal administration of [125I]-IGF-I also targeted the deep cervical lymph nodes, consistent with their possible role in lymphatic drainage of both the nasal passages and the CNS. Cisternal CSF did not contain [125I]-IGF-I following intranasal administration. Intravenous [125I]-IGF-I resulted in blood and peripheral tissue exposure similar to that seen following intranasal administration but CNS concentrations were significantly lower. Finally, delivery of IGF-I into the CNS activated IGF-I signaling pathways, confirming some portion of the IGF-I that reached CNS target sites was functionally intact. The results suggest intranasally delivered IGF-I can bypass the blood-brain barrier via olfactory- and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within the brain and spinal cord.
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            Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype.

            M Reger, G. WATSON, W Frey … (2006)
            Raising insulin acutely in the periphery and in brain improves verbal memory. Intranasal insulin administration, which raises insulin acutely in the CNS without raising plasma insulin levels, provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes. Based on prior research with intravenous insulin, we predicted that the treatment response would differ between subjects with (epsilon4+) and without (epsilon4-) the APOE-epsilon4 allele. On separate mornings, 26 memory-impaired subjects (13 with early Alzheimer's disease and 13 with amnestic mild cognitive impairment) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40 IU). Cognition was tested 15 min post-treatment, and blood was acquired at baseline and 45 min after treatment. Intranasal insulin treatment did not change plasma insulin or glucose levels. Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults. These effects were stronger for memory-impaired epsilon4- subjects than for memory-impaired epsilon4+ subjects and normal adults. Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory. These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E (APOE) related differences in insulin metabolism.
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              Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults.

              Gerard D. Schellenberg, Michelle L Baker, Mark A Reger … (2008)
              Intranasal insulin administration raises central nervous system (CNS) insulin levels in humans and acutely facilitates verbal memory in patients with Alzheimer's disease (AD), an effect that may differ by APOE genotype. The purpose of this study was to examine the cognitive dose response curves for intranasal insulin administration, and determine whether the effects of insulin differ between participants with (epsilon4+) and without (epsilon4-) the APOE- epsilon4 allele. On separate mornings, 33 memory-impaired adults with AD or amnestic mild cognitive impairment and 59 normal adults each underwent five intranasal treatment conditions consisting of insulin (10, 20, 40, or 60 IU) or placebo. Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes post-treatment. Plasma insulin and glucose levels were unaffected by treatment. Insulin administration facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults, with performance generally peaking at 20 IU. In contrast, memory-impaired epsilon4+ subjects demonstrated a relative decline in verbal memory. Insulin also differentially modulated plasma amyloid-beta for memory-impaired subjects and normal controls, effects that again differed by APOE genotype. These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes Care
                Journal ID (iso-abbrev): Diabetes Care
                Journal ID (hwp): diacare
                Journal ID (pmc): dcare
                Journal ID (publisher-id): Diabetes Care
                Title: Diabetes Care
                Publisher: American Diabetes Association
                ISSN (Print): 0149-5992
                ISSN (Electronic): 1935-5548
                Publication date (Print): March 2014
                Publication date (Electronic): 11 February 2014
                Volume: 37
                Issue: 3
                Pages: 751-759
                Affiliations
                [1] 1Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
                [2] 2New England Geriatric, Research, Education and Clinical Center–Boston Division, VA Boston Healthcare, and Department of Psychiatry, Harvard Medical School, Boston, MA
                [3] 3Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
                [4] 4Joslin Diabetes Center, Boston, MA
                [5] 5Department of Neurology, University of Massachusetts Medical School, Worcester, MA
                [6] 6Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR
                [7] 7Division of Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC
                [8] 8Department of Radiology, Ohio State University, Columbus, OH
                Author notes
                Corresponding author: Vera Novak, vnovak@ 123456bidmc.harvard.edu .
                Article
                Publisher ID: 1672
                DOI: 10.2337/dc13-1672
                PMC ID: 3931384
                PubMed ID: 24101698
                SO-VID: f542c7ae-c07e-402c-a98c-97da13dabb33
                Copyright © © 2014 by the American Diabetes Association.
                License:

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                Date received : 16 July 2013
                Date accepted : 1 October 2013
                Page count
                Pages: 9
                Categories
                Subject: Emerging Technologies and Therapeutics

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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