Alzheimer’s Disease and Insulin Resistance

For years, researchers have noted a connection between conditions of impaired insulin use and regulation, such as obesity and type 2 diabetes, and Alzheimer’s Disease (AD), but the mechanism of association has not been well-defined. Now, researchers report that proteins that influence the development and progression of AD are suppressed by insulin, encouraging new treatment strategies for AD.

Rates of AD are nearly twice as high among patients with obesity or type 2 diabetes compared to a general population. Decades of research have indicated that this is likely due to a combination of factors: vascular dementia, impaired insulin metabolism and signaling pathways, and dysfunctional glucose transport to the brain. Several studies have supported a causal link between insulin resistance or impaired insulin response, even early in life, with the development of AD.

Insulin and insulin receptors and transporters are densely located in areas of the brain that support memory function. Normal insulin regulation is essential for healthy cognitive functioning, and impaired insulin regulation leads to cognitive and memory deficits seen in AD. Also, insulin regulates proteins involved in the pathophysiology of AD; insulin regulates amyloid precursor protein (APP), which is associated with the formation of the hallmark plaques in the brains of AD patients, and insulin moderates the metabolism of the protein tau, the building block of neurofibrillary tangles, another distinctive finding in AD. The plaques and tangles lead to neurodegeneration and loss of cognitive function in AD.

To uncover the actual mechanism by which insulin influences the pathogenesis of AD, researchers administered a low-dose insulin infusion (two units per hour) for four hours to ten obese patients with type 2 diabetes. On two other days, the same patients received a four-hour infusion of either normal saline or dextrose without insulin. Blood samples were obtained at 0, 2, 4, and 6 hours. The patients were receiving antidiabetic medications, but none were taking insulin as part of their diabetes treatment.

The one-time infusion of insulin suppressed the expression of APP, as well as presenilin-1 (PS1), presenilin-2 (PS2), and glycogen synthase kinase-3-beta (GSK-3-beta). PS1 and PS2 convert APP into beta-amyloid, which forms the plaques in AD brains. GSK-3-beta activates tau, which forms the tangles in AD brains. The results were published a recent issue of Journal of Clinical Endocrinology and Metabolism.

The new study is small, and the long-term effects of a low-dose insulin infusion on AD-related proteins are not known. Also, it is unclear if the findings are applicable to non-obese or non-diabetic patients. The next challenge is to administer insulin directly to the brain, possibly intranasally, to avoid the hypoglycemic effects of insulin.

The exact cause of AD is unknown, though a familial connection is evident, and genetic mutations related to PS1 and PS2 have been noted in early-onset AD. Treatments to slow the progression of AD are limited, and no cure is yet available. The new insulin research offers exciting information, as it paves the way for new therapeutic strategies. Targeting insulin resistance may prevent, or at least slow, the onset of AD.

References

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