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

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. FASEB J. 33, 4458–4472 (2019). http://www.fasebj.org

Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain

“…Here, insulin resistance increased cerebral ROS emission. We previously reported similar elevations in ROS were absent in insulin-deficient mice (2). Insulin deficiency is accompanied by increased cerebral lactate and ketone levels, which contribute to increased antioxidant defense to mitigate ROS emission (2).…”

“…Immunoblotting. Samples were homogenized in RIPA buffer (EMD Millipore) with protease and phosphatase inhibitor cocktail (Thermo Fisher Scientific), resolved on SDS-PAGE gels, and blotted on nitrocellulose membranes, as previously described (2). Membranes were blocked in TBST with 5% nonfat milk, and primary antibodies, as presented in Supplemental Table 5, were diluted in TBST with 5% BSA and applied to membranes overnight at 4°C.…”

“…DNA was extracted using a DNA mini kit (Qiagen) and analyzed for mtDNA copy number using ND1 and ND4 genes. The abundance of each target gene was normalized to 28S ribosomal DNA and assayed in duplicate by quantitative PCR (qPCR) using a ViiA7 thermocycler (Applied Biosystems), as previously described (2). Gene-specific primers are shown in Supplemental Table 6.…”

“…Insulin is not critical for glucose metabolism in the brain, but insulin receptors are extensively distributed in the brain regions that influence cognitive function and regulate peripheral metabolism (1). Insulin-deprivation reduces brain mitochondrial ATP production rate, and increasing insulin concentration in the brain by nasal administration enhances ATP production, supporting a direct role of insulin on brain mitochondrial function (2). Little is known about the effect of insulin resistance on brain mitochondrial function.…”

Diabetes Mellitus

“…28 Preclinical studies indicate that IR adversely affects energetics and increases oxidative stress of brain areas involved in memory and cognition 29 that could contribute pathologies that adversely affect cognition. Studies performed during an insulindeficient state suggest the potential role of ketones and lactate in ameliorating oxidative stress, 30 but this protective effect does not occur when insulin levels are high. The respective contributions of vascular lesions, hypoglycemia, and altered energetics and oxidative stress to the pathogenesis of dementia in diabetes remain to be fully understood.…”