Other Systemic Diseases and Acceleration of Microvascular Dysfunction and Atherosclerosis

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A common systemic disease linked to acceleration of vascular pathology and exaggerated periodontal disease is diabetes. Diabetes is a heterogeneous group of disorders affecting millions of people in the United States. Worldwide, the incidence of diabetes is burgeoning. Multiple sequelae of this disorder lead to a wide range of complications in target tissues such as the retina, kidney, peripheral nerves, and micro- and macrovasculature. Multiple epi-demiologic studies have definitively linked the incidence and severity of atherosclerosis to diabetes.

A key defining feature of diabetes is the presence of microvascular dysfunction. Earlier studies showed that enhanced vascular permeability, as measured by tissue-blood isotope ratios in human diabetic subjects, was associated with increased risk of cardiovascular events. Flow-mediated dilation is abnormal in both types 1 and 2 diabetes and often has been found to be reflective of diffuse atherosclerosis. In addition to heightened vascular inflammation, enhanced oxidant stress in diabetes has been ascribed a central role in the development of vascular pathology in diabetes. Increased generation of reactive oxygen species may lead to excessive generation of superoxide; in certain settings such as diabetes, this may lead to a

enhanced generation of peroxynitrite and concomitant tissue injury. In this context, flow-mediated dilation has suggested that treatment of type 1 diabetic subjects with vitamin E resulted in enhanced vascular function by this measure. How such improvement relates to long-term improvement in atherosclerosis and the risk of coronary/cerebral events is not well delineated, especially since clinical trials of antioxidant use have failed to provide objective evidence of improved survival or decreased morbid events.

What is the link to oral pathology? Epidemiologic studies have strongly suggested that diabetes increases the prevalence and severity of periodontitis. Our laboratory developed a murine model with which to test these concepts. Oral/anal inoculation with P gingivalis of mice rendered diabetic with streptozotocin enhanced alveolar bone loss in hyperglycemic animals, in parallel with increased expression of inflammatory and gelatinolytic mediators in the gingival tissue. Multiple pathogenic mechanisms underlie diabetes-accelerated periodontal disease, including the chronic accumulation of advanced glycation end products (AGEs), the products of nonenzymatic glycation/oxidation of proteins/lipids that may form in settings of hyper-glycemia, oxidant stress, and inflammation. AGEs engage a central receptor in the vasculature, receptor for AGE (RAGE). Our previous studies have shown that pharmacological blockade of this receptor, using the extracellular soluble form of RAGE, suppresses accelerated alveolar bone loss in streptozotocin-induced diabetic mice infected with P. gingivalis compared to vehicle-treated infected mice. In parallel, gingival levels of inflammatory mediators such as IL-6 and TNF-a were significantly reduced by RAGE blockade.

These considerations underscore the concept that RAGE is a central mechanism amplifying the inflammatory response. RAGE is expressed in a wide array of cell types, thereby potentially implicating this receptor in a broad range of immune/inflammatory disorders. In this context, we and others have shown that in addition to AGEs, proinflamma-tory S100/calgranulins are signal transduction ligands of RAGE. S100/calgranulins trigger activation of MAP kinases and activation of NF-kB via RAGE. In atherosclerotic lesions, AGEs and S100/calgranulins accumulate to enhanced degrees. When tested in rodent models of vascular dysfunction in diabetes, we demonstrated that pharmacological blockade of RAGE was associated with decreased tissue blood isotope ratio in diabetic rats. In apo E-null mice rendered diabetic with streptozotocin, blockade of RAGE attenuated early acceleration and late progression of atherosclerosis [6, 7].

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Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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