Mechanism linking typediabetes to Alzheimer's disease

Date:
March 15, 2022
Source:
Osaka City University
Summary:
A research group has revealed that amyloid-beta detected in blood is
secreted from peripheral tissues (pancreas, adipose tissue, skeletal
muscle, liver, etc.) that are sensitive to glucose and insulin.



FULL STORY ========================================================================== Osaka City University suggests a possible mechanism linking diabetes to Alzheimer's disease in new discovery that amyloid-b 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.


==========================================================================
A research group has revealed that amyloid-b (Ab) detected in blood is
secreted from peripheral tissues (pancreas, adipose tissue, skeletal
muscle, liver, etc.) that are sensitive to glucose and insulin. Also,
that Ab secreted from peripheral tissues acts as a regulator on pancreatic b-cells to suppress insulin secretion. The results of this study indicate
that blood Ab levels fluctuate significantly with diet, and special
care should be taken when using blood samples as a diagnostic marker
for Alzheimer's disease, such as taking blood samples during fasting.

Researchers have identified amyloid beta (Ab) detected in blood
to originate from peripheral tissues, and that the peptide acts on pancreaticb-cells to suppress insulin secretion, thereby regulating
blood glucose levels. The study, which urges us to be careful when using
blood Ab levels as a diagnostic marker for Alzheimer's disease (AD),
was published in The Proceedings of the National Academy of Sciences
(PNAS), the official journal of the National Academy of Sciences.

"This work was finally published after about 11 years," says Professor
Takami Tomiyama of the Department of Translational Neuroscience,
Osaka City University Graduate School of Medicine. "It is not only an
academic discovery, but also has implications in how we diagnose AD."
Based on what is known, this study sought to explore some unknowns. First,
as AD is caused by the accumulation of Ab in the brain, it is thought
that Ab levels in the blood reflect the pathology in the brain and are currently used as a diagnostic marker. However, Ab is generated from the amyloid precursor protein (APP) through the function of two enzymes, b-
and g-secretases, and this mechanism is expressed in many of the body's peripheral tissues, not only in the brain, causing the origin of blood
Ab to remain unknown. Second, epidemiological studies have shown type 2 diabetes to be a strong risk factor for the development of AD, yet the mechanism linking these two diseases has eluded researchers as well.

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



========================================================================== First, they examined the effects of glucose and insulin on blood Ab
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 Ab,
confirming previous studies.

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

Given that blood Ab 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 Ab. They added glucose and insulin to isolated live peripheral
tissues and measured the secreted Ab. Results showed that Ab was secreted
from the pancreas upon glucose stimulation and from adipose tissue,
skeletal muscle, and liver upon insulin stimulation. The kidneys, which
is not involved in glucose or insulin metabolism, did not secrete Ab upon either stimulus. They also found that when glucose and Ab were added to pancreas tissue, levels of secreted insulin were suppressed.

Now that the origin of blood Ab had been clarified, the team wanted to
localize Ab in the periphery tissues studied. "This would elucidate
the cells involved with Ab," adds Professor Tomiyama. "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 Abonly in insulin (b
cells). The team also found the b cells of mice with glucose injections
to have less immunoreactions to Aband insulin, suggesting during periods
of fast, Ab and insulin are stored in b cells and then released into circulation when stimulated with glucose. Similarly, tissue sections of
each insulin-targeted organ were prepared and immunostained for Ab and
the bioactive substances specific to each tissue, called organokines. Ab
was found with the organokines of all the organ tissues tested, with
less immunoreactions when stimulated with insulin.

"Our findings suggest that Ab and organokines are stored during periods
of fast and released into circulation when stimulated with insulin,"
adds Prof.

Tomiyama. "A comprehensive understanding of the organokine action
of peripheral Ab is something we hope to develop in future work."
In addition to an explanation for the origin of Ab 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, Ab levels
in the blood are constantly elevated due to high levels of glucose and
insulin. This inhibits Ab 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 Ab to accumulate in
the brain and develop into AD.

"Other more practical suggestions can be gleaned from this study,"
concludes Prof. Tomiyama, "our data suggest that as blood Ab levels
fluctuate significantly with diet, special care should be taken when
diagnosing AD with blood Ab."

========================================================================== Story Source: Materials provided by Osaka_City_University. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Keiko Shigemori, Sachiko Nomura, Tomohiro Umeda, Shuko Takeda,
Takami
Tomiyama. Peripheral Ab acts as a negative modulator of insulin
secretion. Proceedings of the National Academy of Sciences, 2022;
119 (12) DOI: 10.1073/pnas.2117723119 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220315095012.htm

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