Scientists at Washington University School of Medicine in St. Louis have made a
surprising discovery about the origin of
diabetes. Their research suggests that problems
controlling blood sugar - the hallmark of diabetes - may begin in the
intestines.
The new study, in mice, may upend long-held theories about
the causes of the disease. Because insulin is produced in the pancreas and sugar
is stored in the liver, many scientists have looked to those organs for the
underlying causes of diabetes.
The findings are reported in the journal
Cell Host & Microbe.
In the new research, scientists studied
mice that are unable to make fatty acid synthase (FAS) in the intestine. FAS, an
enzyme crucial for the production of lipids, is regulated by insulin, and people
with diabetes have defects in FAS. Mice without the enzyme in the intestines
develop chronic inflammation in the gut, a powerful predictor of diabetes.
"Diabetes may indeed start in your gut," says principal investigator
Clay F. Semenkovich, MD. "When people become resistant to insulin, as happens
when they gain weight, FAS doesn't work properly, which causes inflammation
that, in turn, can lead to diabetes."
First author Xiaochao Wei, PhD,
and Semenkovich, the Herbert S. Gasser Professor of Medicine, professor of cell
biology and physiology and director of the Division of Endocrinology, Metabolism
and Lipid Research, collaborated with specialists in gastroenterology and genome
sciences to determine what happens in mice that can't make FAS in their
intestines.
"The first striking thing we saw was that the mice began
losing weight," says Wei, a research instructor in medicine. "They had
diarrhea and other gastrointestinal symptoms,
and when we looked closely at the tissue in the gut, we found a lot of
inflammation."
Initially, the researchers thought that the mice became
sick because of changes to the mix of microbes that naturally live in the gut,
where they help digest food and synthesize vitamins.
In collaboration
with Jeffrey I. Gordon, MD, director of the Center for Genome Sciences and
Systems Biology at the School of Medicine, they looked more closely at gut
microbes in the mice.
"The mice had substantial changes in their gut
microbiome," Semenkovich says. "But it wasn't the composition of microbes in the
gut that caused the problems."
Instead, Wei says, the mice got sick
because of a defect in fatty acid synthase. The mice without fatty acid synthase
had lost the protective lining of mucus in the intestines that separates the
microbes from direct exposure to cells. This allowed bacteria to penetrate
otherwise healthy cells in the gut, making the mice sick.
In a further
collaboration with Nicholas O. Davidson, MD, director of the Division of
Gastroenterology, the researchers found gastrointestinal effects resembling some
features of inflammatory bowel disease. Other investigators studying humans with
ulcerative colitis had previously made the unexplained observation that colon
biopsies from these patients have low amounts of fatty acid synthase.
"Fatty acid synthase is required to keep that mucosal layer intact," Wei
says. "Without it, bad bacteria invade cells in the colon and the small
intestine, creating inflammation, and that, in turn, contributes to insulin
resistance and diabetes."
Inflammation and insulin resistance reinforce
each other. Inflammatory substances can cause insulin resistance and inhibit the
production of insulin, both of which interfere with the regulation of blood
sugar. In turn, insulin resistance is known to promote inflammation.
Further study showed that the ability to build the thin, but important,
layer of mucosal cells was hindered by faulty FAS.
That the gut is so
important to the development of diabetes makes sense because many people with
the condition not only have faulty FAS, but they also frequently develop
gastrointestinal difficulties, Semenkovich says.
"Abdominal pain and
diarrhea are some of the most common problems we see in people with diabetes,"
he says. "We could only connect these 'dots' because other experts at the
university could help us link what we observed in these mice to what occurs in
patients with diabetes and inflammatory bowel disease," Semenkovich says.
Semenkovich and Wei say much more study is needed, but they say that FAS
and a key component of the intestinal mucosa called Muc2 may be potential
targets for diabetes therapy. They now plan to study people with diabetes to see
whether FAS is altered in a similar way, producing damage to the mucosal layer
in the intestines.
http://www.medicalnewstoday.com/releases/241750.php
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