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. ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-D (02))
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Jones, Teresa L Z
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Louisiana State University Hsc Shreveport
Schools of Medicine
United States
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Kanikarla-Marie, Preeti; Jain, Sushil K (2016) Hyperketonemia and ketosis increase the risk of complications in type 1 diabetes. Free Radic Biol Med 95:268-77
Kanikarla-Marie, Preeti; Jain, Sushil K (2016) 1,25(OH)2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis). J Steroid Biochem Mol Biol 159:94-101
Rains, Justin L; Jain, Sushil K (2015) Effect of hyperketonemia (Acetoacetate) on nuclear factor-?B and p38 mitogen-activated protein kinase activation mediated intercellular adhesion molecule 1 upregulation in endothelial cells. Metab Syndr Relat Disord 13:71-7
Manna, Prasenjit; Gungor, Neslihan; McVie, Robert et al. (2014) Decreased cystathionine-?-lyase (CSE) activity in livers of type 1 diabetic rats and peripheral blood mononuclear cells (PBMC) of type 1 diabetic patients. J Biol Chem 289:11767-78
Kanikarla-Marie, Preeti; Jain, Sushil K (2014) L-Cysteine supplementation reduces high-glucose and ketone-induced adhesion of monocytes to endothelial cells by inhibiting ROS. Mol Cell Biochem 391:251-6
Jain, S K; Micinski, D; Huning, L et al. (2014) Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients. Eur J Clin Nutr 68:1148-53
Jain, Sushil K; Huning, Laura; Micinski, David (2014) Hydrogen sulfide upregulates glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, and glutathione and inhibits interleukin-1? secretion in monocytes exposed to high glucose levels. Metab Syndr Relat Disord 12:299-302
Manna, Prasenjit; Jain, Sushil K (2014) Effect of PIP3 on adhesion molecules and adhesion of THP-1 monocytes to HUVEC treated with high glucose. Cell Physiol Biochem 33:1197-204
Manna, Prasenjit; Jain, Sushil K (2013) PIP3 but not PIP2 increases GLUT4 surface expression and glucose metabolism mediated by AKT/PKC?/? phosphorylation in 3T3L1 adipocytes. Mol Cell Biochem 381:291-9
Manna, Prasenjit; Jain, Sushil K (2013) L-cysteine and hydrogen sulfide increase PIP3 and AMPK/PPAR? expression and decrease ROS and vascular inflammation markers in high glucose treated human U937 monocytes. J Cell Biochem 114:2334-45

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