www.sciencedaily.com/releases/2007/11/071106133106.htm

Type 2 Diabetes: Inflammation, Not Obesity, Cause Of Insulin
Resistance

ScienceDaily (Nov. 7, 2007) - Researchers at the University of
California, San Diego (UCSD) School of Medicine have discovered that
inflammation provoked by immune cells called macrophages leads to
insulin resistance and Type 2 diabetes. Their discovery may pave the
way to novel drug development to fight the epidemic of Type 2 diabetes
associated with obesity, the most prevalent metabolic disease
worldwide.

In recent years, it has been theorized that chronic, low-grade tissue
inflammation related to obesity contributes to insulin resistance, the
major cause of Type 2 diabetes. In research done in mouse models, the
UCSD scientists proved that, by disabling the macrophage inflammatory
pathway, insulin resistance and the resultant Type 2 diabetes can be
prevented.

The findings of the research team, led by principle investigators
Michael Karin, Ph.D., Professor of Pharmacology in UCSD's Laboratory
of Gene Regulation and Signal Transduction, and Jerrold Olefsky,
Distinguished Professor of Medicine and Associate Dean for Scientific
Affairs, will be published as the feature article of the November 7
issue of Cell Metabolism.

"Our research shows that insulin resistance can be disassociated from
the increase in body fat associated with obesity," said Olefsky.

Macrophages, found in white blood cells in the bone marrow, are key
players in the immune response. When these immune cells get into
tissues, such as adipose (fat) or liver tissue, they release
cytokines, which are chemical messenger molecules used by immune and
nerve cells to communicate. These cytokines cause the neighboring
liver, muscle or fat cells to become insulin resistant, which in turn
can lead to Type 2 diabetes.

The UCSD research team showed that the macrophage is the cause of this
cascade of events by knocking out a key component of the inflammatory
pathway in the macrophage, JNK1, in a mouse model. This was done
through a procedure called adoptive bone marrow transfer, which
resulted in the knockout of JNK1 in cells derived from the bone
marrow, including macrophages.

With this procedure, bone marrow was transplanted from a global JNK1
knockout mouse (lacking JNK1 in all cell types) into a normal mouse
that had been irradiated to kill off its endogenous bone marrow. This
resulted in a chimeric mouse in which all tissues were normal except
the bone marrow, which is where macrophages originate. As a control,
the scientists used normal, wild-type mice as well as mice lacking
JNK1 in all cell types. These control mice were also subjected to
irradiation and bone marrow transfer.

The mice were all fed a high-fat diet. In regular, wild-type mice,
this diet would normally result in obesity, leading to inflammation,
insulin resistance and mild Type 2 diabetes. The chimeric mice,
lacking JNK1 in bone marrow-derived cells, did become obese; however,
they showed a striking absence of insulin resistance -- a pre-
condition that can lead to development of Type 2 diabetes.

"If we can block or disarm this macrophage inflammatory pathway in
humans, we could interrupt the cascade that leads to insulin
resistance and diabetes," said Olefsky. "A small molecule compound to
block JNK1 could prove a potent insulin-sensitizing, anti-diabetic
agent."

The research also proved that obesity without inflammation does not
result in insulin resistance. Olefsky explained that when an animal or
a human being becomes obese, they develop steatosis, or increased fat
in the liver. The steatosis leads to liver inflammation and hepatic
insulin resistance.

The chimeric mice did develop fatty livers, but not inflammation.
"Their livers remained normal in terms of insulin sensitivity," said
Olefsky, adding that this shows that insulin resistance can also be
disassociated from fatty liver.

"We aren't suggesting that obesity is healthy, but indications are
promising that, by blocking the macrophage pathway, scientists may
find a way to prevent the Type 2 diabetes now linked to obesity and
fatty livers," Olefsky said.