
THE
Diabetes
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Inflammation and
Atherosclerosis worsen Glycemic Control (not vice-versa)
in Type 2 Diabetes....
- Targeting
(FABP4) aP2 may prevent and treat type 2 diabetes
and atherosclerosis (doi:10.1038/nature05844) Adipocyte
fatty-acid-binding protein, aP2 (FABP4) is
expressed in adipocytes and macrophages, and
integrates inflammatory and metabolic responses.
Studies in aP2-deficient mice have shown that
this lipid chaperone has a significant role in
several aspects of metabolic syndrome, including
type 2 diabetes and atherosclerosis. Here we
demonstrate that an orally active small-molecule
inhibitor of aP2 is an effective therapeutic
agent against severe atherosclerosis and type 2
diabetes in mouse models. In macrophage and
adipocyte cell lines with or without aP2, we also
show the target specificity of this chemical
intervention and its mechanisms of action on
metabolic and inflammatory pathways. Our findings
demonstrate that targeting aP2 with
small-molecule inhibitors is possible and can
lead to a new class of powerful therapeutic
agents to prevent and treat metabolic diseases
such as type 2 diabetes and atherosclerosis.
"CHD Worsens
Glycemic Control"
"Smokers are
almost twice as likely to develop type 2 diabetes as nonsmokers"
"Ramipril intervention into
atherosclerosis not only improves survival but also
improves glycemic control and decreases incidence of type
2 diabetes"
"Pravachol
intervention into atherosclerosis not only
improves survival but also improves glycemic control
and decreases incidence of type 2 diabetes"
"Local [adipocyte]
expression of TNF and plasma IL-6 are higher
in subjects with obesity-related insulin resistance.(Am J Physiol -Endo/Metab [2001] 280:
E745-E751)"
"Tumor
Necrosis Factor (TNF) impairs insulin signaling through Insulin Receptor Substrate-1 (IRS-1) by activation
of a PhosphatidylInositol-3 kinase (PI-3k)/ Serine and threonine
kinase c-Akt (cloned from
directly transforming murine retrovirus AKT8, isolated
from an AKR mouse Thymoma cell line) also
known as Rac-alpha -Related to the A and C kinases - or protein kinase B-alpha (Akt)/mammalian Target Of
Rapamycin (mTOR) pathway, which is antagonized
by [3' phospholipid-] Phosphatase and Tensin Homologue Deleted from Chromosome ten
(PTEN/MUTATED IN MULTIPLE
ADVANCED CANCERS 1-MMAC1)".....(Proc. Natl. Acad. Sci. USA, [2001]
10.1073/pnas.051042298)"
Higher BMI
is associated with higher CRP concentrations, even among
young adults aged 17 to 39 years. These findings suggest
a state of low-grade systemic inflammation in overweight
and obese persons......";
"Could Type 2
Diabetes be an inflammatory disease? (Adipocyte IL-6
correlates with BMI, insulin resistance,endothelial
dysfunction, TNF-alpha, AND CRP)..........";
"Leptin induces IL-1 which causes
fever and anorexia in rats.....";
"C-Reactive
Protein is Strongly-Associated With Measures of Obesity,
Insulin Resistance, and Subclinical Atherosclerosis in
Healthy, Middle-Aged Women...........";
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