Link found between type 2 diabetes and Alzheimer's

Osaka Metropolitan University researchers have suggested a possible mechanism linking diabetes to Alzheimer’s disease, in a new discovery that amyloid beta (Aβ) in the blood comes from periphery organs like the pancreas and liver — not only the brain — and aids in blood glucose clearance by inhibiting insulin secretion. Their study, which urges us to be careful when using blood Aβ levels as a diagnostic marker for Alzheimer’s disease (AD), was published in the journal PNAS.

As AD is caused by the accumulation of Aβ in the brain, it is thought that Aβ levels in the blood reflect the pathology in the brain and so these are currently used as a diagnostic marker. However, Aβ is generated from the amyloid precursor protein (APP) through the function of two enzymes — β- and γ-secretases — and this mechanism is expressed in many of the body’s peripheral tissues, not only in the brain, causing the origin of blood Aβ to remain unknown. Furthermore, while epidemiological studies have shown type 2 diabetes to be a strong risk factor for the development of AD, the mechanism linking these two diseases has so far eluded researchers.

“In our previous studies on mice injected with glucose, we showed a transient increase in glucose and insulin to peak at 15 minutes, but blood Aβ levels to peak some 30–120 minutes later,” said Osaka Professor Takami Tomiyama. In addition, previous studies have shown the oral administration of glucose to increase blood Aβ levels in patients with AD. These findings led Prof Tomiyama and his research team to explore the hypothesis that blood Aβ is secreted from peripheral tissues (pancreas, adipose tissue, skeletal muscle, liver, etc) and that it may contribute to the metabolism of glucose and insulin.

First, they examined the effects of glucose and insulin on blood Aβ levels of mice fasted for 16 hours. Collected blood samples from the tail vein at 0, 15, 30, 45, 60, 120 and 180 min intervals after the injection showed a transient increase in glucose, insulin and Aβ, confirming previous studies.

Next, they explored the effect of Aβ on blood insulin levels by administering Aβ and glucose to fasted mice that cannot produce Aβ, called APP knockout mice. Measuring insulin in blood samples over time found that Aβ suppressed the glucose-stimulated rise in insulin.

Given that blood Aβ levels changed immediately upon introduction of glucose and insulin, the team focused on the mice pancreas, adipose tissue, skeletal muscle, liver and kidneys to determine the origin of blood Aβ. They added glucose and insulin to isolated live peripheral tissues and measured the secreted Aβ. Results showed that Aβ was secreted from the pancreas upon glucose stimulation and from adipose tissue, skeletal muscle and liver upon insulin stimulation; the kidneys, which are not involved in glucose or insulin metabolism, did not secrete Aβ upon either stimulus. They also found that when glucose and Aβ were added to pancreas tissue, levels of secreted insulin were suppressed.

Now that the origin of blood Aβ had been clarified, the team wanted to localise Aβ in the periphery tissues studied. “This would elucidate the cells involved with Aβ,” Prof Tomiyama explained. “In addition to providing further validation to our findings, this would give us a more detailed picture from which we could draw conclusions to possible mechanisms connecting type 2 diabetes and AD.”

Using immunohistochemistry to exploit the fact that antibodies bind to certain proteins, the team started with the pancreas tissue, detecting Aβ only in insulin (β cells). The team also found the β cells of mice with glucose injections to have fewer immunoreactions to Aβ and insulin, suggesting during periods of fast, Aβ and insulin are stored in β cells and then released into circulation when stimulated with glucose. Similarly, tissue sections of each insulin-targeted organ were prepared and immunostained for Aβ and the bioactive substances specific to each tissue, called organokines. Aβ was found with the organokines of all the organ tissues tested, with fewer immunoreactions when stimulated with insulin.

“Our findings suggest that Aβ and organokines are stored during periods of fast and released into circulation when stimulated with insulin,” Prof Tomiyama said. “A comprehensive understanding of the organokine action of peripheral Aβ is something we hope to develop in future work.”

In addition to an explanation for the origin of Aβ in the blood, the research findings suggest a mechanism by which type 2 diabetes is a strong risk factor for the development of AD. In diabetes, Aβ levels in the blood are constantly elevated due to high levels of glucose and insulin. This inhibits Aβ to leave the brain to the periphery (transport through the blood–brain barrier and by body fluid flow through the brain parenchyma called the glymphatic system), causing Aβ to accumulate in the brain and develop into AD.

“Our data suggest that as blood Aβ levels fluctuate significantly with diet, special care should be taken when diagnosing AD with blood Aβ,” Prof Tomiyama said.

Image credit: ©stock.adobe.com/au/didesign

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