UC Davis Researchers Discover Novel Pathway To Increased Inflammation In Diabetes Patients

Researchers at UC Davis Health System have
discovered a novel pathway that results in increased inflammation of blood
vessels in patients with type 1 diabetes. Their findings suggest that,
with
good diabetes control, this inflammation may be reduced, possibly
resulting
in a reduction of cardiovascular disease as well.



In a study now available both in the online edition of the Journal of
Clinical Endocrinology & Metabolism as well on the National Institutes of
Health's PubMed, the researchers provide the first-ever demonstration of
increased expression and signaling in type 1 diabetics of two key
receptors
within the body's innate immune system. Called TLR2 and TLR4, they are
part
of a family of pattern recognition receptors known as Toll-like receptors
(TLRs), so-called because of their similarities to the well-defined Toll
gene found in much-studied fruit flies.



Type 1 diabetes is a pro-inflammatory state associated with increased
cardiovascular mortality. Inflammation plays a pivotal role in all stages
of atherosclerosis, the progressive narrowing and hardening of the
arteries
over time. The UC Davis study found that TLR2 and TLR4 expression and
signaling are increased in type 1 diabetes patients and contribute to the
pro-inflammatory state.



"It is not unreasonable to speculate that TLR2 and TLR4 promote
atherogenesis by contributing to the pro-inflammatory state in type 1
diabetes," said lead author Ishwarlal Jialal, director of the Laboratory
for Atherosclerosis and Metabolic Research and professor of internal
medicine at UC Davis. "Inflammation is central to heart disease, playing a
pivotal role in plaque formation and stroke. We may well find that a
serendipitous byproduct of controlling diabetes is the simultaneous
control
of this new pathway, leading to less inflammation and lower risk of heart
problems."



The study represents the first-ever demonstration of increased TLR2 and
TLR4 activity in type 1 diabetes monocytes, which are part of the body's
immune system, protecting against blood-borne pathogens by moving quickly
to sites of infection. The immune system comprises the cells and
mechanisms
that defend the host from infection by other organisms, accomplishing its
defense with the help of such pattern-recognition receptors as TLRs for
early detection of specific classes of pathogens.



"This finding provides us with a totally new insight into the causes of
inflammation in diabetics," adds Jialal, who holds the Robert E. Stowell
Endowed Chair in Experimental Pathology at UC Davis. "It's an exciting
development in the emerging area of TLR research that has potentially
wide-ranging implications."
Further studies will use mice to examine the molecular mechanisms for
increased TLR2 and TLR4 expression and determine their contribution to the
pro-inflammatory state of diabetes.



Co-authors were Sridevi Devaraj, Mohan Dasu and Jason Rockwood in the UC
Davis Laboratory for Atherosclerosis and Metabolic Research; Steven
Griffen, UC Davis assistant professor of endocrinology, clinical nutrition
and vascular medicine; and William Winter, professor of pathology,
immunology and laboratory medicine at the University of Florida.



The study was funded by grants from the Juvenile Diabetes Research
Foundation International and the National Institutes of Health.




UC Davis Health System is the leading tertiary care provider for a
33-county region of Northern California. Research strengths at UC Davis
Health System include clinical and translational science, stem cell
science, infectious diseases, vascular biology, neuroscience, cancer,
functional genomics and mouse biology, comparative medicine, combinatorial
chemistry and nutrition, among many others.

UC Davis Health System