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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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