Ketosis, Vascular Inflammation and Its Therapy in Type 1 Diabetic Patients

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DESCRIPTION (provided by applicant): This application is highly responsive to three program announcements of the NIH: PAR-06-457 (Translational Research in Diabetes), PA-01-114 (Chromium as Adjuvant Therapy in Diabetes), and PA-01- 071 (Metals in Medicine). Type-1 diabetes is associated with excessive incidence of cardiovascular disease (CVD). Elevated blood levels of the pro-inflammatory cytokines interleukin (IL)-6 and tissue necrosis factor (TNF)-a are markers of vascular inflammation, a known risk factor for CVD. 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 IL-6 and TNF-a in a cell culture model using U937 monocytes; that oxidative stress and levels of IL-6 and TNF-a are higher in the blood of hyperketonemic compared with normoketonemic type 1 diabetic patients; and that chromium (Cr3+) inhibits the secretion of TNF-a and IL-6 caused by AA in a cell culture model. This proposal has two hypotheses. The first is that ketosis increases blood levels of markers of vascular inflammation in type 1 diabetes. The second is that Cr3+ supplementation can prevent/lower blood levels of vascular inflammation markers in type 1 diabetes. These hypotheses will be tested both in vivo in type 1 diabetic patients as well as in vitro in studies using monocytes isolated from subject's blood and purchased human aortic endothelial cells (HAEC). In vivo, the effects of hyperketonemia, and supplementation with either placebo (P) or Cr3+ on the levels of markers of vascular inflammation will be examined. In vitro, monocytes isolated from P or Cr3+ supplemented patients or HAEC will be cultured with ketones to examine their direct effect on markers of vascular inflammation and gene expression related to cytokine production and adhesion molecules in monocytes and HAEC. This is a novel study because no prior study has examined the effect of ketosis or Cr3+ on vascular inflammation in type 1 diabetes. To accomplish these objectives, blood will be collected from type 1 diabetic children. Patients (n=141, ages 12- 18 yrs) will be supplemented with either P or 200 or 500¿g Cr3+-niacinate/day for 3 months. State of the art methodology, such as multiplex PCR, will be used. Data will be analyzed statistically. Diabetes incidence has become epidemic and remains a major public health issue. The long-term goal is to understand the role of ketosis in CVD and to discover a relatively low-cost dietary supplement that could be used as an adjuvant therapy for CVD prevention in type 1 diabetes.