Cellular changes in fat tissue, not the immune system, lead
to the “hyper-inflammation” characteristic of obesity-related
glucose intolerance and type 2 diabetes, according to new
research from the University of Cincinnati (UC).
Cancer and cell biology experts say this new discovery about the
cellular mechanisms behind glucose intolerance may provide a
different target for drugs to treat type 2 diabetes as well as insights
into how aggressive cancers form.
The study is reported in the July 7, 2010, issue of the scientific
journal Cell Metabolism.
For this study, the research team looked at the role of a specific
gene known as protein kinase C (PKC)-zeta, which has been
implicated as a key cellular contributor to malignant tumor growth.
Using a preclinical animal model, they found that PKC-zeta had
a dual role in the molecular signaling that leads to inflammation,
switching from acting as a regulator of inflammation to a
pro-inflammation agent in different circumstances.
“This finding is quite novel because current drug development
efforts target immune cells (macrophages, T-cells) to eliminate
this hyper-inflammation. Our research suggests obesity-related
glucose intolerance has nothing to do with the immune system.
It may be more effective to target adipocytes (fat cells),”
explained the investigators from the University of Cincinnati’s
cancer and cell biology department.
In normal cells, they explain, PKC-zeta regulates the balance
between cellular inflammatory responses to maintain glucose
control. During obesity-induced inflammation, however, the
function of PKC-zeta changes and the molecule begins to promote
inflammation by causing adipocytes to secrete a substance (IL-6)
that travels in large quantities to the liver to cause insulin resistance.
”We believe a similar mechanism of action is at play in malignant
Now we are trying to understand how PKC-zeta regulates IL6 to
better determine how we can manipulate the protein to help prevent
diabetes and cancer,” they add.
This University of Cincinnati team is working with investigators at
UC’s Drug Discovery Center to screen compounds that will inhibit
PKC-zeta to be used in further research.
Funding for this research was provided by grants from the National
Institutes of Health, American Diabetes Association, UMass Diabetes
Endocrinology Research Center and Marie Curie Foundation.
Scientists from the University of Massachusetts also participated
in the study.
University of Cincinnati Academic Health Center (2010, July 12).
Fat cells play key role in development of type 2 diabetes.