"This had been found nearly 150 years but had been forgotten or
ignored."
"A chelate theory for aspirin-like drugs."

Anti Inflammatory Medication May Treat Type 2 Diabetes
Article Date: 22 May 2008 - 3:00 PDT

Researchers at the Joslin Diabetes Center who reported earlier this
year that an inexpensive, non-steroidal anti-inflammatory drug called
salsalate might prevent type 2 diabetes are now reporting that the
drug may also be beneficial in the treatment of the disease.

The paper, which appears in the May 2008 issue of the journal Clinical
and Translational Science (CTS), reports on three proof-of-concept
studies that demonstrate that salsalate, which has been used for
decades to treat arthritis, may benefit patients with type 2 diabetes
by lowering blood sugar and reducing inflammation.

"These are the first studies showing that potentially safe and
tolerable doses of salsalate lower blood sugars and have other
favorable effects in patients with type 2 diabetes," notes Allison B.
Goldfine, M.D., Director of Clinical Research at Joslin and Associate
Professor at Harvard Medical School, and senior author of the report.

Goldfine was also the lead researcher for an earlier study, published
in the February issue of Diabetes Care, which demonstrated that
salsalate may prevent type 2 diabetes by lowering blood glucose and
reducing inflammation.

Together, these four proof-of-concept studies have led to three large,
ongoing multi-center clinical trials that seek to confirm the benefit
of targeting inflammation using salsalate to lower glucose in patients
with type 2 diabetes or who are at risk for diabetes, or to reduce
atherosclerosis in patients with coronary artery disease.

The clinical studies are a direct extension of the findings of study
co-author and collaborator Steven Shoelson, M.D., Ph.D., Helen and
Morton Adler Chair, Head of the Section of Cellular and Molecular
Physiology at Joslin, and Professor at Harvard Medical School. Dr.
Shoelson studies the molecular pathogenesis of type 2 diabetes and the
role of obesity in promoting diabetes and other metabolic conditions,
including atherosclerosis.

It had originally been noted nearly 150 years ago that salicylates
could lower blood glucose levels, but this had either been forgotten
or ignored. Dr. Shoelson's laboratory used this as clue to probe
potential reasons why obesity promotes disease. They found that the
inflammatory pathway regulated by NF-kB is activated in animals with
obesity and diabetes. They went on to demonstrate that this pathway
could be inhibited using salicylates, thus showing that the effects of
obesity are mediated through inflammation. This was not an accepted
concept at the time, and is still debated in field.

Studies in animals showed that high doses of salicylates, including
aspirin, could be effective, but since these could not be used safely
in patients due to the risk of stomach upset and bleeding the
researchers considered alternative drugs. Together, Drs. Goldfine and
Shoelson opted to study salsalate, which is a salicylate similar to
aspirin but that does not cause stomach upset or bleeding.

Shoelson notes that the studies now being reported in CTS provide a
'smoking gun' new evidence that incriminates inflammation as a major
pathogenic mediator in type 2 diabetes as well as a potentially safe
new way to treat the disease.

"It is rare to see basic discoveries move from bench to bedside so
quickly. This was fueled by at least two things, first the ready
availability of a safe drug, and second the environment at the Joslin
Diabetes Center which is ideally suited to rapid advancements in
clinical discovery," he said.

Goldfine further opines, "much of the pharmacokinetic and long-term
safety data for salsalate is already established, so clinical studies
could move forward rapidly."

"Our findings are potentially very exciting because we show that a
medication that treats inflammation may also treat diabetes and
related medical conditions," said Goldfine. "If we can show in the
larger clinical trials now underway that it is safe and effective, it
means salsalate may be a new way to treat diabetes."

In the paper out today, two of the studies involved small numbers of
patients with type 2 diabetes. One tested salsalate on seven subjects
at a dose of 4.5 grams per day, while the other used 3 grams per day
on nine subjects. Patients in both groups showed benefits such as
reductions in blood sugar between 10 and 20 percent, but improvements
were greatest in the group taking the higher dose. Glucose utilization
also improved in both groups, although those taking the higher dose
showed a 50 percent improvement, compared to 15 percent for those on
the lower dose. The studies ran for two weeks each.

Impressive reductions were also seen in circulating levels of
triglycerides and free fatty acids, particularly at the higher dose.
This is important because patients with diabetes often have elevated
lipid levels that potentially contribute to complications of type 2
diabetes.

The third study, a double blind, placebo-controlled trial that ran for
four weeks, involved eight patients on the drug and nine on placebo.
Study participants on the drug showed improvements similar to those
reported in the patients in the other two studies analyzed.

In an accompanying commentary, Barry J. Goldstein, M.D., of the
Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson
Medical College, wrote: "The testing of a commonly used class of
drugs, with a well-known safety profile, offers an exciting
translational approach that promises to help in the management of
glycemia in type 2 diabetes."

He noted: "A world-wide epidemic of type 2 diabetes is underway that
shows no signs of remitting in the next several years. In order to
address the basic therapeutic needs of these millions of patients,
additional treatment options will need to be made available,
especially to have some hope of getting the majority of patients to
accepted glucose treatment goals."

The studies were funded by grants from the National Institutes of
Health; fellowships from the William Randolph Hearst Foundation and
American Diabetes Association; and the Helen and Morton Adler Chair at
Joslin Diabetes Center.

Other researchers participating included Robert Silver, Elizabeth
Tatro and Jongsoon Lee at Joslin; Waleed Aldahi of Mubarik Alkabeer
University Hospital, Kuwait; and Dongsheng Cai of the University of
Wisconsin.

Salsalate Clinical Trials

Dr. Goldfine is the principal investigator of a study that targets
inflammation using salsalate in patients with coronary artery disease
and metabolic syndrome. The study, called Targeting INflammation using
SALsalate or Lifestyle intervention in the Metabolic Syndrome and
Cardiovascular Disease (TINSAL-CVD), is funded by The National Heart,
Lung and Blood Institute and is currently enrolling patients. It will
look at the effects of lifestyle intervention (diet, exercise and
omega-3 fatty acid supplement) or salsalate compared to placebo to
reduce progression or promote regression of hard and soft coronary
artery calcification as assessed by multi-detector CT angiography
(MDCTA), a relatively new method to image the coronary arteries.
Patients are randomized to lifestyle, salsalate or placebo with images
of the coronary arteries at baseline and after 30 months of
intervention. Dr. Shoelson is co-PI on the salsalate arm of the trial,
while study collaborators Dr. Ernest Schaefer of The Jean Mayer USDA
Human Nutrition Center on Aging at Tufts University and Dr. Francine
Welty of Beth Israel Deaconess Medical Center (BIDMC) are running the
lifestyle intervention arm; Dr. Melvin Clouse of BIDMC is leading the
imaging core.

A second study called Targeting Inflammation using SALsalate in Type 2
Diabetes (TINSAL-T2D) headed by Drs. Goldfine and Shoelson is using
salsalate in patients with type 2 diabetes to target inflammation and
thus lower blood glucose. This study is ongoing and is funded by the
National Institute of Diabetes and Digestive and Kidney Diseases.

Another study led by Dr. Goldfine and Dr. Peter Reaven of the Carl T.
Hayden VA Medical Center in Phoenix targets inflammation using
salsalate in patients with impaired glucose tolerance in order to
improve insulin sensitivity. This study, called TINSAL-IGT, is ongoing
and is funded by the VA.

About Joslin Diabetes Center

Joslin Diabetes Center is the world's largest diabetes clinic,
diabetes research center and provider of diabetes education. Joslin is
dedicated to ensuring people with diabetes live long, healthy lives
and offers real hope and progress toward diabetes prevention and a
cure for the disease. Founded in 1898 by Elliott P. Joslin, M.D.,
Joslin is an independent nonprofit institution affiliated with Harvard
Medical School.

Joslin Diabetes Center
One Joslin Pl.
Boston, MA 02215
United States
http://www.joslin.org

-------------------------
Med Hypotheses 1998 Mar;50(3):239-51

A chelate theory for the mechanism of action of aspirin-like drugs.
Wang X
Department of Pathology, Cornell University Medical College, New York,
NY 10021, USA. xw...@mail.med.cornell.edu

Two hundred years after the discovery of the pharmaceutical usefulness
of aspirin, it and aspirin-like drugs, a family with an
ever-increasing number of members, are an indispensable part of modern
life. However, the question as to how these drugs work in the body
has  remained unsettled. It is postulated here that this group of
drugs may exert their therapeutic (and adverse) effects by chelating
various  physiologically important metallic cations in the body.
The chelate theory is supported by the vast majority, if not all, of
the observations on these drugs made in the past.

PMID: 9578329, UI: 98237440

Who loves ya.
Tom

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