Is it possible to make obesity no longer a trigger for diabetes?

People who are overweight or obese have a significantly increased risk of developing diabetes, but exactly how this happens is unclear
.

A new study from Washington University School of Medicine in St.
Louis may help explain how being overweight causes diabetes and may provide researchers with a goal to help prevent or delay the onset
of diabetes in some high-risk populations.
The findings suggest that many people with elevated insulin levels — an early marker of diabetes risk — also have deficiencies in an enzyme that is important
for the processing of a key fatty acid in the diet.

The study was published Jan.
11 in
the journal Cell Metabolism.

"With 30 million to 40 million people living with type 2 diabetes in the U.
S.
, another 90 million to 100 million people at risk of developing type 2 diabetes in the future, and elevated insulin levels in many people at risk of diabetes, a sign of insulin resistance and a signal
that trouble may be brewing.
" If we can intervene before they actually develop diabetes, we may be able to prevent many people's major health problems, such as heart disease, chronic kidney disease, nerve damage, vision loss and other problems
.
said Clay F.
Semenkovich, senior researcher and director of the Division of Metabolism and Lipid Research
.

When a person has too much fat in their body, it signals β cells in the pancreas to secrete more insulin
.
When insulin levels rise and remain high, the body becomes resistant to insulin, and eventually the β cells that secrete insulin fail, leading to diabetes
.

The researchers found that overproduction of insulin involves a process
called palmitoylation.
This is the process by
which cells attach fatty acid palmitates to proteins.

Thousands of human proteins can attach to palmitate, but the researchers found that diabetes was the end result
when the fatty acid was not removed from the proteins of the β cells.
The researchers examined tissue samples from lean or overweight people, diabetics, and non-diabetics and found that diabetics lacked an enzyme that removes palmitate
from β cells.

"They oversecrete insulin because the process goes awry, they don't properly regulate β cells to release insulin,"
Semenkovich explains.
"The regulation of insulin release is partly controlled
by the palmitoylation process.
"

The team also genetically engineered a mouse that lacked the enzyme APT1, an enzyme
responsible for removing palmitate from proteins.
The genetically modified mice later developed diabetes
.

Because impaired APT1 function increases diabetes risk, the researchers collaborated with the university's Center for Drug Discovery to screen and identify compounds
that could increase APT1 enzyme activity.

Semenkovich said: "We have identified several drug candidates, and we are working on them
.
We believe that by increasing APT1 activity, we may reverse this process and potentially prevent high-risk people from developing diabetes
.
" ”

Although Semenkovich said the new findings identifying APT1 as a target is an important step, he explained that APT1 is just one of
many therapeutic targets.

He said: "Type 2 diabetes can develop in several ways
.
This enzyme isn't the answer all, it's an answer, and we now have some promising tools to prevent some people with prediabetes from developing diabetes
.
”