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Hyperinsulinemia May Increase Alzheimer’s Disease Risk

Moderately high insulin levels are associated with increased levels of inflammatory markers and beta-amyloid in cerebrospinal fluid, suggesting a causal link between hyperinsulinemia and Alzheimer’s disease.

Dr. Suzanne Craft and her team report that Hyperinsulinemia and insulin resistance are recognized risk factors for Alzheimer’s disease. They theorized that insulin’s effects on the inflammatory network mediate its role in Alzheimer’s disease.

Dr. Craft, of the University of Washington, Seattle, explained that, "It is well known that high levels of insulin increase inflammation in the body, so we attempted to determine whether or not high insulin levels also increase inflammation in the brain and the central nervous system."

To test their theory, they recruited 16 healthy subjects ages 55 to 81 years. Subjects were infused with insulin, along with dextrose to maintain euglycemia, to achieve plasma insulin levels observed in insulin resistance. Plasma and CSF were collected after infusions of approximately 105 minutes.

"We observed striking increases in levels of inflammatory markers in spinal fluid, as well as increases in a protein that is a critical factor in Alzheimer’s disease, beta amyloid protein," Dr. Craft said. "The degree to which inflammation was increased was strongly related to the degree to which amyloid was increased."

Specifically, increased insulin levels were associated with increases in CSF concentrations of interleukin (IL)-1-alpha, IL-1-beta, IL-6, tumor necrosis factor (TNF)-alpha, and F-2-isoprostane, whereas plasma levels were unaffected.

In both plasma and CSF, levels of amyloid beta-42 were increased with insulin.

Subjects with greater BMIs had the highest plasma amyloid beta-42 elevations in response to elevated insulin concentrations. "Thus, the interactive effects of hyperinsulinemia and BMI on plasma amyloid beta-42 levels may contribute to" the increased risk of AD, the authors suggest.

Elevated insulin levels also increased CSF apoE in older subjects, higher levels of which were associated with higher CSF IL-1-alpha levels.

"Conditions that are associated with high levels of insulin, which are common age-related conditions, such as diabetes, hypertension and obesity, may also be associated with increases in inflammation in the brain," Dr. Craft added, "and over time this inflammation may have a very serious impact on brain aging."

"The underlying insulin resistance needs to be addressed in hypertension and type 2 diabetes," she continued. "There are a number of strategies that could improve insulin resistance, ranging from traditional diet and exercise to insulin sensitizers."
Arch Neurol 2005;62:1-6.

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