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Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes

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Název: Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes
Autoři: Srinivas Gopala, Patrick M. Vanderboom, Katherine A. Klaus, Priska Summer, Shankarappa Manjunatha, K. Sreekumaran Nair, Gregory N. Ruegsegger, Piotr Zabeilski, Ian R. Lanza, Surendra Dasari
Zdroj: The FASEB Journal. 33:4458-4472
Informace o vydavateli: Wiley, 2019.
Rok vydání: 2019
Témata: Male, 0301 basic medicine, Dementia - etiology, Protein processing, Coumaric acids - pharmacology, Mice, Diabetes mellitus, Adenosine Triphosphate, Mitochondria - physiology, Insulin - therapeutic use, Homeostasis, Insulin, post-translational - drug effects, Phosphorylation, Monocarboxylic acid transporters - metabolism, Drug Implants, Dementia - metabolism, Dementia - prevention & control, 0303 health sciences, Brain - drug effects, experimental - metabolism, Monocarboxylic acid transporters - antagonists & inhibitors, Reactive oxygen species - metabolism, intranasal, Brain, Drug implants, Ketones, Insulin - pharmacology, Mitochondria, 3. Good health, Lactic acid - metabolism, Administration, Mitochondria - enzymology, experimental - drug therapy, Monocarboxylic Acid Transporters, Coumaric Acids, Nerve Tissue Proteins, Mitochondria - drug effects, Diabetes Mellitus, Experimental, 03 medical and health sciences, Energy metabolism - drug effects, inbred C57BL, Animals, experimental - psychology, Ketones - metabolism, Lactic Acid, Nerve tissue proteins - metabolism, Insulin - deficiency, Brain - metabolism, Administration, Intranasal, Insulin - administration & dosage, Mice, Inbred C57BL, Oxidative Stress, Oxidative stress, Adenosine triphosphate - biosynthesis, Dementia, Energy Metabolism
Popis: Despite the strong association between diabetes and dementia, it remains to be fully elucidated how insulin deficiency adversely affects brain functions. We show that insulin deficiency in streptozotocin-induced diabetic mice decreased mitochondrial ATP production and/or citrate synthase and cytochrome oxidase activities in the cerebrum, hypothalamus, and hippocampus. Concomitant decrease in mitochondrial fusion proteins and increased fission proteins in these brain regions likely contributed to altered mitochondrial function. Although insulin deficiency did not cause any detectable increase in reactive oxygen species (ROS) emission, inhibition of monocarboxylate transporters increased ROS emission and further reduced ATP production, indicating the causative roles of elevated ketones and lactate in counteracting oxidative stress and as a fuel source for ATP production during insulin deficiency. Moreover, in healthy mice, intranasal insulin administration increased mitochondrial ATP production, demonstrating a direct regulatory role of insulin on brain mitochondrial function. Proteomics analysis of the cerebrum showed that although insulin deficiency led to oxidative post-translational modification of several proteins that cause tau phosphorylation and neurofibrillary degeneration, insulin administration enhanced neuronal development and neurotransmission pathways. Together these results render support for the critical role of insulin to maintain brain mitochondrial homeostasis and provide mechanistic insight into the potential therapeutic benefits of intranasal insulin.-Ruegsegger, G. N., Manjunatha, S., Summer, P., Gopala, S., Zabeilski, P., Dasari, S., Vanderboom, P. M., Lanza, I. R., Klaus, K. A., Nair, K. S. Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes.
Druh dokumentu: Article
Jazyk: English
ISSN: 1530-6860
0892-6638
DOI: 10.1096/fj.201802043r
Přístupová URL adresa: https://faseb.onlinelibrary.wiley.com/doi/pdfdirect/10.1096/fj.201802043R
https://pubmed.ncbi.nlm.nih.gov/30676773
https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.201802043R
https://europepmc.org/article/PMC/PMC6404590
https://www.fasebj.org/doi/10.1096/fj.201802043R
https://onlinelibrary.wiley.com/doi/abs/10.1096/fj.201802043R
https://pubmed.ncbi.nlm.nih.gov/30676773/
https://mayoclinic.pure.elsevier.com/en/publications/insulin-deficiency-and-intranasal-insulin-alter-brain-mitochondri
https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.201802043R
https://doi.org/10.1096/fj.201802043R
Rights: Wiley Online Library User Agreement
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  Data: Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes
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  Data: <i>The FASEB Journal</i>. 33:4458-4472
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  Data: Wiley, 2019.
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– Name: Abstract
  Label: Description
  Group: Ab
  Data: Despite the strong association between diabetes and dementia, it remains to be fully elucidated how insulin deficiency adversely affects brain functions. We show that insulin deficiency in streptozotocin-induced diabetic mice decreased mitochondrial ATP production and/or citrate synthase and cytochrome oxidase activities in the cerebrum, hypothalamus, and hippocampus. Concomitant decrease in mitochondrial fusion proteins and increased fission proteins in these brain regions likely contributed to altered mitochondrial function. Although insulin deficiency did not cause any detectable increase in reactive oxygen species (ROS) emission, inhibition of monocarboxylate transporters increased ROS emission and further reduced ATP production, indicating the causative roles of elevated ketones and lactate in counteracting oxidative stress and as a fuel source for ATP production during insulin deficiency. Moreover, in healthy mice, intranasal insulin administration increased mitochondrial ATP production, demonstrating a direct regulatory role of insulin on brain mitochondrial function. Proteomics analysis of the cerebrum showed that although insulin deficiency led to oxidative post-translational modification of several proteins that cause tau phosphorylation and neurofibrillary degeneration, insulin administration enhanced neuronal development and neurotransmission pathways. Together these results render support for the critical role of insulin to maintain brain mitochondrial homeostasis and provide mechanistic insight into the potential therapeutic benefits of intranasal insulin.-Ruegsegger, G. N., Manjunatha, S., Summer, P., Gopala, S., Zabeilski, P., Dasari, S., Vanderboom, P. M., Lanza, I. R., Klaus, K. A., Nair, K. S. Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes.
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        Value: 10.1096/fj.201802043r
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      – Text: English
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        PageCount: 15
        StartPage: 4458
    Subjects:
      – SubjectFull: Male
        Type: general
      – SubjectFull: 0301 basic medicine
        Type: general
      – SubjectFull: Dementia - etiology
        Type: general
      – SubjectFull: Protein processing
        Type: general
      – SubjectFull: Coumaric acids - pharmacology
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      – SubjectFull: Insulin - therapeutic use
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      – SubjectFull: Homeostasis
        Type: general
      – SubjectFull: Insulin
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      – SubjectFull: post-translational - drug effects
        Type: general
      – SubjectFull: Phosphorylation
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      – SubjectFull: Monocarboxylic acid transporters - metabolism
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      – SubjectFull: Monocarboxylic acid transporters - antagonists & inhibitors
        Type: general
      – SubjectFull: Reactive oxygen species - metabolism
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      – SubjectFull: intranasal
        Type: general
      – SubjectFull: Brain
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        Type: general
      – SubjectFull: Mitochondria
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      – SubjectFull: 3. Good health
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      – SubjectFull: Mitochondria - enzymology
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      – SubjectFull: experimental - drug therapy
        Type: general
      – SubjectFull: Monocarboxylic Acid Transporters
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      – SubjectFull: Coumaric Acids
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      – SubjectFull: Energy metabolism - drug effects
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      – SubjectFull: inbred C57BL
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      – SubjectFull: Animals
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      – SubjectFull: experimental - psychology
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      – SubjectFull: Ketones - metabolism
        Type: general
      – SubjectFull: Lactic Acid
        Type: general
      – SubjectFull: Nerve tissue proteins - metabolism
        Type: general
      – SubjectFull: Insulin - deficiency
        Type: general
      – SubjectFull: Brain - metabolism
        Type: general
      – SubjectFull: Administration, Intranasal
        Type: general
      – SubjectFull: Insulin - administration & dosage
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      – SubjectFull: Mice, Inbred C57BL
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      – SubjectFull: Adenosine triphosphate - biosynthesis
        Type: general
      – SubjectFull: Dementia
        Type: general
      – SubjectFull: Energy Metabolism
        Type: general
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      – TitleFull: Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes
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            – Type: issn-locals
              Value: edsairFT
          Numbering:
            – Type: volume
              Value: 33
          Titles:
            – TitleFull: The FASEB Journal
              Type: main
ResultId 1