Amyloid-beta produced in peripheral tissues provides a link between diabetes and Alzheimer’s disease risk.

Type 2 diabetes, a metabolic disorder characterized by glucose intolerance and insulin resistance, poses a significant public health concern, affecting roughly 470 million people worldwide. Having type 2 diabetes greatly increases a person’s risk of developing Alzheimer’s disease, but scientists don’t fully understand the mechanisms that drive the increased risk. Findings from a recent study suggest that amyloid-beta produced in tissues outside the brain provides the link between type 2 diabetes and Alzheimer’s disease.

Amyloid-beta, a toxic peptide produced in the brain, clumps together and forms plaques with age. Its accumulation is a pathological hallmark of Alzheimer’s disease. However, amyloid-beta is produced in peripheral tissues, as well, including those that are sensitive to glucose or insulin, such as the pancreas, adipose tissues, skeletal muscles, and liver. Scientists don’t fully understand the roles peripheral amyloid-beta plays in human health.

The investigators conducted a three-part experiment in mice, live mouse tissues, and cell cultures. First, they injected mice with glucose after they had fasted for 16 hours to examine the effects of glucose and insulin on blood amyloid-beta levels. They found that the mice experienced a transient increase in blood levels of glucose, insulin, and amyloid-beta. Then they injected amyloid-beta and glucose into mice that can’t produce the protein and found that amyloid-beta suppressed the animals’ insulin response.

Next, they applied glucose and insulin to live tissues from the pancreas, adipose tissue, skeletal muscle, liver, and kidneys of mice. They found that glucose stimulated the release of amyloid-beta from the pancreas, whereas insulin stimulated its release from adipose tissue, skeletal muscle, and liver tissue. However, when the scientists added glucose along with amyloid-beta to the pancreatic tissue, insulin release was suppressed.

Finally, they used antibodies that target the amyloid-beta protein to determine where the protein was produced. They found that amyloid-beta was produced and stored in the beta cells of the pancreas and released into circulation when stimulated with glucose.

These findings suggest that amyloid-beta protein produced in peripheral tissues modulates insulin secretion. They may further provide a mechanism linking type 2 diabetes to Alzheimer’s disease. The investigators posited that high blood glucose and insulin levels that occur in the setting of diabetes increase peripheral amyloid-beta production, altering the balance between brain and peripheral amyloid-beta levels and suppressing the protein’s efflux from the brain. Furthermore, high insulin levels in the brain may impair normal degradation of brain amyloid-beta, increasing the protein’s levels in the brain and driving its accumulation. Learn more about the role of amyloid-beta in Alzheimer’s disease in this clip featuring Dr. Dale Bredesen.

• View study abstract.