TY - JOUR
T1 - Insulin deficiency and intranasal insulin alter brain mitochondrial function
T2 - a potential factor for dementia in diabetes
AU - Ruegsegger, Gregory N.
AU - Manjunatha, Shankarappa
AU - Summer, Priska
AU - Gopala, Srinivas
AU - Zabeilski, Piotr
AU - Dasari, Surendra
AU - Vanderboom, Patrick M.
AU - Lanza, Ian R.
AU - Klaus, Katherine A.
AU - Nair, K. Sreekumaran
N1 - Publisher Copyright:
© FASEB
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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. FASEB J. 33, 4458–4472 (2019). www.fasebj.org.
AB - 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. FASEB J. 33, 4458–4472 (2019). www.fasebj.org.
KW - ketones
KW - mitochondrial biogenesis
KW - proteomics
KW - reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85072653492&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072653492&partnerID=8YFLogxK
U2 - 10.1096/fj.201802043R
DO - 10.1096/fj.201802043R
M3 - Article
C2 - 30676773
AN - SCOPUS:85072653492
SN - 0892-6638
VL - 33
SP - 4458
EP - 4472
JO - FASEB Journal
JF - FASEB Journal
IS - 3
ER -