Beta cells to brain cells: the pivotal role of insulin and glucose metabolism in Alzheimer's disease

Brain glucoregulation and insulin pathways have been difficult to study. New approaches have shown that, within the brain, the regulation of glucose operates in a semiautonomous ‘microsystem’ distinct from that of glucoregulation in the periphery. Similar to the periphery, however, pernicious dysglycemia can occur in the brain. Glucolipotoxicity has been broadly linked to cerebral vasculature hemorrhage, microvascular damage, accumulation of β-amyloid peptide, and structural damage. In the localized brain energetic milieu, hyperglycemia, hyperinsulinemia, and insulin resistance constitute independent risk factors for Alzheimer’s disease (AD). Now it has been shown that glucolipotoxicity interferes with endoplasmic reticulum and mitochondrial function, causes impairment and structural damage to proteins, lipids, and nucleic acids, and disrupts redox homeostasis—all of which contribute to neuronal and glial cell damage.

Disturbances in the blood‒brain barrier (BBB) and brain insulin resistance are other crucial, newly understood insults in AD caused by dysglycemia. These research findings come from the laboratories of Elizabeth M Rhea and William A Banks at the University of Washington School of Medicine, coauthors of the review article.

While translating these insights into clinical practice for brain function and dysfunction is relatively nascent, findings from diabetes studies are leading to the incorporation of new gold standards in prescribing into routine care. Major clinical studies have demonstrated that glucose-lowering treatments in patients with type 2 diabetes (T2D) can reduce the risk of developing AD. This has led the American Diabetes Association (ADA) to elevate cognitive issues (or risk) as a comorbidity within T2D patient treatment plans.

“The risk factors and neuropathology of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse”, says Dr. Stanley S. Schwartz, MD, lead author. “Glucose dysmetabolism is a critical predisposing factor to dementia, including AD. Brain dysglycemia waylays insulin signaling, an otherwise potentially protective mechanism against AD plaques”.

The study was published in Neuroprotection on June 9, 2025.

“Improvements in diabetes and cardiovascular treatments—approaches addressing the cardiorenal axis—have improved over the decades. These are allowing individuals to live longer with this disease—long enough to become at risk for age-related complications such as AD and dementia,” adds Dr. Mary E. Herman, PhD, coauthor of the review.

This evidence dramatically influences physicians’ preferred treatment for patients with T2D and comorbid cognitive issues or those at risk of the same.

The updated gold standard for glucose-lowering therapy includes metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors—agents that not only reduce insulin resistance but have also been shown to slow the development and/or progression of AD. In contrast, sulfonylureas are a less favorable option for preserving cognitive function, and the use of injected insulin should be reconsidered as a first-line or long-term treatment strategy.  

The differential impact of individual glucose-lowering agents on neuronal function and integrity may help elucidate the interplay between glucose homeostasis and neural health. Large-scale studies have unexpectedly revealed that specific classes of antidiabetics agents exhibit distinct pleiotropic actions. These agents show selective benefits for organ systems compromised by diabetes, most notably cognitive function. Leveraging these advantageous pleiotropic properties may drive future rational development of therapies against AD and cognitive decline. Promising approaches include formulations designed for enhanced brain penetration, such as intranasal incretin agonists that bypass the BBB. Incretin receptor agonists also mitigate deleterious neuroinflammation through mechanisms still to be identified.

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Reference

DOI: 10.1002/nep3.70008

About Professor Mary E. Herman
Independent Health Researcher and Educator: Building Global Research Competency, Antigua 03001, Guatemala.