Insulin signaling could link Alzheimer’s and diabetes

Mouse models of Alzheimer’s disease were found to have impaired insulin signaling and insulin resistance, a precursor of diabetes

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NEW YORK—While it’s well known that obesity, high blood sugar levels and genetics are risk factors for diabetes, a new factor is now being brought into the spotlight: Alzheimer’s disease (AD). Recent research from the Icahn School of Medicine at Mount Sinai has found that Alzheimer’s disease impairs insulin signaling in the brain, which increases the risk of developing diabetes.
These results were published in the paper “Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer’s disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels,” which appeared in Alzheimer’s and Dementia. Dr. Christoph Buettner, associate professor of medicine, endocrinology, diabetes, bone disease and neuroscience at Icahn School of Medicine at Mount Sinai, was lead author of the study. Dr. Henry Ruiz, a postdoctoral fellow in the Buettner lab, also collaborated in the study. This work is part of ongoing research funded by the National Institutes of Health.
The most obvious effects of Alzheimer’s are its degradation of memory and autonomy, but as noted in the 2015 article “Metabolic and Non-Cognitive Manifestations of Alzheimer’s Disease: The Hypothalamus as Both Culprit and Target of Pathology” in Cell Metabolism: “metabolic and non-cognitive abnormalities, such as alterations in body weight and neuroendocrine functions, are also present, often preceding the cognitive decline. Furthermore, hypothalamic dysfunction can also be a driver of AD pathology.”
As noted in the recent Alzheimer’s and Dementia paper’s abstract, “Insulin signaling within the brain, in particular within the hypothalamus, regulates carbohydrate, lipid and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue.” The team’s hypothesis was that “cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis, resulting in increased susceptibility to diabetes.”
The study was conducted in mice, and was the first to show that mice with AD present with insulin resistance, a precursor to type 2 diabetes, in the hypothalamus. In the mouse models, the researchers found that “APP/PS1 mice were more susceptible to high-fat feeding and aging-induced metabolic dysregulation including disrupted BCAA homeostasis and exhibited impaired hypothalamic insulin signaling.” Elevated levels of branched chain amino acids (BCAA) in the blood were also found in these mouse models, and a previous study from the Mount Sinai researchers show that brain insulin signaling regulates BCAA levels in the blood. This could denote BCAAs as a biomarker for monitoring insulin signaling in AD patients, though its potential applicability has yet to be confirmed in humans.
“Our findings represent a turning point in the understanding of the relationship between Alzheimer’s disease, type 2 diabetes and insulin resistance,” said Dr. Sam Gandy, professor of neurology and psychiatry, associate director of the Mount Sinai Alzheimer’s Disease Research Center and co-author of the study. “Compelling and unexpected results such as Dr. Buettner’s are driving a complete re-evaluation of how these diseases interact. Now that we have disease genes for dementia and diabetes, those genes are our ground zero, and the challenge is to work out all the steps and missteps between the gene and the patient and then to find interventions that cure those missteps.”
In other recent work from Mount Sinai, scientists from the Icahn School of Medicine and Sage Bionetworks reported on their collaboration to conduct the largest genome study to date, consisting of more than 589,000 genomes. The team reported their first systematic search across hundreds of Mendelian disorders in individuals apparently not inflicted with any of the disorders to find people carrying disease-protective factors. The retrospective study was a first step of the Resilience Project, and was conducted with scientists from 23andMe, BGI, the Ontario Institute for Cancer Research and other institutions.
The team studied DNA from 12 previously collected data sets using a newly developed targeted sequencing panel to screen 874 genes for 584 distinct genetic diseases. Those diseases consisted primarily of metabolic conditions, neurological diseases or developmental disorders, and all of them are known to present in childhood with severe symptoms. All of the studied genomes came from adults that had never been diagnosed with any of the diseases, and the analysis identified 13 healthy individuals with genetic variants associated with eight diseases.
However, there were roadblocks with identifying promising individuals. Of the original list of almost 16,000 candidates, more than 75 percent were eliminated due to inaccurate or low-confidence variant calls in the existing data, implying that better protocols and standards for interpreting genetic data are needed. Additionally, none of the 13 final candidates could be contacted to confirm whether they were truly resistant to disease in light of limitations in the original studies’ informed consent policies.
The work was published in Nature Biotechnology, under the title “Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases.”

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