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Moderate
use may avert failure of Type 2 Diabetes
Drugs
Newswise — Drugs widely used to treat type 2
diabetes may be more likely to keep working
if they are used in moderation, researchers
at Washington University School of Medicine
in St. Louis have found in a study using an
animal model.
The drugs, sulfonylureas, help type 2
diabetics make more insulin, improving
control of blood sugar levels.
But in most patients the effects of
sulfonylureas are lost after several years
of use, causing insulin secretion to shut
down.
This typically forces patients to switch to
regular insulin injections.
"Why this happens isn't clear yet, but we've
found what may be cause for hope," says
senior author Colin G. Nichols, Ph.D., Carl
F. Cori Professor and professor of cell
biology and physiology.
"We've shown in a mouse model that whatever
causes this shutdown doesn't kill the
insulin-making beta cells of the pancreas or
stop them from making insulin. Instead, it
somehow stops them from secreting insulin."
When they stopped receiving the drug, beta
cells began secreting insulin again hours
later. Nichols and co-author Maria Sara
Remedi, Ph.D., instructor of cell biology
and physiology, report the findings in
Public Library of Science Medicine.
"I find these experimental observations very
exciting," says Alan Permutt, M.D.,
professor of medicine and of cell biology
and physiology.
"But
I'm very cautious that patients understand
that the relevance of this model to human
diabetes and its treatment still needs to be
tested."
If human beta cells also survive and can
continue to produce insulin after long-term
sulfonylurea exposure, it may be possible to
rethink treatment strategies, Nichols
suggests.
"Doctors now prescribe new long-acting
sulfonylureas to establish a chronic
presence of the drug in the bloodstream," he
notes.
"But
it may be beneficial to use the older drugs
that go away more quickly, allowing the beta
cells time to recover."
Another potential option would be
alternating periods of drug treatment with
periods when the patient's symptoms are
managed by insulin injections, Nichols
suggests.
Type 2 diabetes accounts for 90 to 95
percent of the estimated 16 million
Americans with diabetes. Patients with the
disorder develop resistance to insulin, a
hormone that helps the body control blood
sugar levels.
In many cases, their beta cells also make
less insulin. Physicians typically treat the
condition with a sulfonylurea and metformin,
a drug that increases insulin sensitivity.
Sulfonylureas bind to potassium channels on
the surfaces of beta cells.
These channels normally control electrical
activity and hence the levels of calcium in
the cell; when the drug blocks the channels,
calcium levels rise in the beta cell,
causing release of insulin.
Nichols and Remedi saw an important
opportunity to learn about the long-term
failure of sulfonlyureas with the
availability of an implantable time-release
capsule form of one of the drugs,
glibenclamide.
They implanted the capsules in the necks of
mice.
As
expected, the drugs initially caused mouse
beta cells to release more insulin and blood
sugar levels dropped rapidly.
Within a few days, though, the response to
the drug reversed: Insulin secretion levels
dropped, and blood sugar levels rose
dramatically.
Examination of the pancreas showed that the
animals’ beta cells were still alive and
contained normal levels of insulin.
"The problem seems to lie somewhere between
the trigger for secreting insulin, which was
hyperactivated while they were on the
medication, and the actual mechanisms that
release insulin," Nichols says.
"The insulin is there, it's just not ready
to release."
Nichols and Remedi are currently seeking
further insight into the causes of this
breakdown.
###
Remedi SM, Nichols CG. Chronic antidiabetic
sulfonylureas in vivo: reversible effects on
mouse pancreatic beta-cells. Public Library
of Science-Medicine, online Oct. 27
The National Institutes of Health and the
Washington University Diabetes Research and
Training Center supported this research.
Washington University School of Medicine's
2,100 employed and volunteer faculty
physicians also are the medical staff of
Barnes-Jewish and St. Louis Children's
hospitals.
The School of Medicine is one of the leading
medical research, teaching and patient care
institutions in the nation, currently ranked
third in the nation by U.S. News & World
Report.
Through its affiliations with Barnes-Jewish
and St. Louis Children's hospitals, the
School of Medicine is linked to BJC
HealthCare.
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