Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes
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| Title: | Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes |
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| Authors: | 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 |
| Source: | The FASEB Journal. 33:4458-4472 |
| Publisher Information: | Wiley, 2019. |
| Publication Year: | 2019 |
| Subject Terms: | 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 |
| Description: | 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. |
| Document Type: | Article |
| Language: | English |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.201802043r |
| Access URL: | 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 |
| Accession Number: | edsair.doi.dedup.....f59712d97c285c7c22c37a58fdae89fe |
| Database: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstract: | 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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| ISSN: | 15306860 08926638 |
| DOI: | 10.1096/fj.201802043r |