Vascular inflammation and its complications are the leading cause of morbidity and mortality in the diabetic population and their prevention and treatment remain a major public health issue. The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are markers of vascular inflammation. In addition to hyperglycemia, type 1 diabetic patients frequently experience ketosis. Our preliminary studies have demonstrated that the ketone body acetoacetate (AA) can generate superoxide radicals and increase secretion of pro-inflammatory cytokines IL-6 and TNF-alpha in a cell culture model using U937 monocytes, and the oxidative stress, IL-6 and TNF-alpha levels are higher in the blood of hyperketonemic compared with normoketonemic type 1 diabetic patients. Our preliminary studies also show that chromium (Cr3+) and vitamin E (VE) inhibit the secretion of TNF-alpha and IL-6 caused by ketones (AA) and high glucose (HG) in a cell culture model using U937 monocytes and fresh peripheral blood mononuclear cells (PBMC). Based upon these novel findings, this proposal has two hypotheses. First, ketones increase pro-inflammatory cytokine (IL-6, TNF-alpha) secretion and alter gene expression relating to cytokine production and adhesion molecules in isolated human monocytes and aortic endothelial cells (HAEC). Second, combined supplementation with hydrophilic Cr3+ and lipophilic VE can efficiently prevent oxidative stress, TNF-alpha and IL-6 secretion, and the over-expression of genes relating to cytokine and adhesion molecule production in isolated human monocytes and aortic endothelial cells (HAEC) exposed to ketones and HG. To accomplish these objectives, U937, PBMC and HAEC will be cultured with ketones without and with HG. State of the art techniques, such as gene array and multiplex PCR, will be used. Data will be analyzed statistically. The long-term objective is to understand the role of ketosis in vascular inflammation and to discover a relatively low-cost dietary supplement, such as Cr3+ and VE, to be used as an adjuvant therapy for prevention of the vascular inflammation and complications of type 1 diabetes.
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