EFFECT OF ZINC SUPPLEMENTATION ON GLUCOSE METABOLISM, OXIDATIVE STRESS AND IRON TRAFFICKING PROTEINS IN TRANSFUSION DEPENDENT PATIENTS WITH THALASSEMIA
Author(s): ,
Patrick Walter
Affiliations:
Hematology,UCSF Benioff Children's Hospital,Oakland,United States;Biology,University of Victoria,Victoria,Canada
,
Caitlin Curtis
Affiliations:
Biology,University of Victoria,Victoria,Canada
,
Maeve Hodge
Affiliations:
Biology,University of Victoria,Victoria,Canada
,
Morty Razavi
Affiliations:
Biochemistry,University of Victoria,Victoria,Canada
,
Michael Minkley
Affiliations:
Biology,University of Victoria,Victoria,Canada
,
Ashutosh Lal
Affiliations:
Hematology,UCSF Benioff Children's Hospital,Oakland,United States
,
Annie Higa
Affiliations:
Hematology,UCSF Benioff Children's Hospital,Oakland,United States
,
David Killilea
Affiliations:
Hematology,UCSF Benioff Children's Hospital,Oakland,United States
,
Terry Pearson
Affiliations:
Biochemistry,University of Victoria,Victoria,Canada
Ellen Fung
Affiliations:
Hematology,UCSF Benioff Children's Hospital,Oakland,United States
(Abstract release date: May 19, 2016) EHA Learning Center. Walter P. Jun 9, 2016; 133039
Label: Abstracts 2016
Assoc. Prof. Patrick Walter
Assoc. Prof. Patrick Walter

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Abstract
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Abstract: E1490

Type: Eposter Presentation

Background
Thalassemia (Thal) is a genetic anemia of incomplete erythropoiesis causing iron overload and roughly 25% of patients to be marginally zinc (Zn) deficient. Nearly 30% of adult subjects with Thal will develop diabetes, thought to be related to transfusional iron overload, but the diabetogenic effects of altered Zn status are not well known. It is hypothesized that a functional Zn deficiency in Thal may affect insulin secretion, glucose homeostasis and/or oxidative stress. Oxidative stress can be manifested by labile plasma iron (LPI), a component of non-transferrin bound iron that is often found in Thal suffering from iron overload. LPI is both redox-active and chelatable, and is the likely culprit of distributing iron to peripheral tissues inducing tissue iron overload. LPI can catalyze lipid peroxidation and release malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) from cells, which are lipid peroxide damage-associated molecular patterns that indicate tissue damage and induce inflammation. To monitor the proteins that may traffic this free iron we used an advanced proteomics technique, measuring soluble transferrin receptor (sTfR), transferrin, haptoglobin, hemopexin and inflammatory proteins C-reactive protein (CRP) and Immunoglobulin G (TgG).

Aims
The purpose of this pilot project is to determine Zn supplementation effects on 1) circulating levels of oxidative stress and iron trafficking proteins and 2) glucose homeostasis and insulin secretion in Thal.

Methods
39 subjects with informed consent were enrolled (9 Thal with diabetes (DM), 20 Thal without DM, 10 controls). Thal on intervention (60% Female, 28.4 ± 11.0y) had a 2 hr OGTT at 3 time points (0, 3 and 6 mos) and took 25 mg Zn/d between 3 and 6 mos. 30% of Thal and 44% of DM had low serum Zn at baseline. LPI was measured using fluorogenic dihydrorhodamine 123 (measures reactive radicals) with desferrioxamine as a chelator.  Both MDA and MDA+4-HNE was measured using N-methyl-2-phenylindole. Iron trafficking proteins were measured by MRM mass spectrometry.

Results
C-peptide levels were significantly reduced in DM compared to controls (p=0.002) as were lipase levels compared to controls (33 vs. 21 IU/L, p=0.04). Serum Zn was related to beta cell function by the Homeostatic Model Assessment (HOMA) (r=0.45, p=0.049) and in subjects with low serum Zn supplementation improved insulin response to the glucose challenge (p=0.04). LPI, MDA, and 4-HNE were significantly elevated in Thal vs Control (4.95μM ± 3.12 vs -1.81 ± 2.45 p=0.0004; 4.8 vs 3.0 µM, p=0.005; 9.37 ± 2.94 vs 13.9 ± 5.84 µM, p=0.024). MDA patients with low iron levels at baseline were found to have an increase in MDA over time vs those with high iron (p=0.005). LPI, MDA, and 4-HNE comparisons between all three time points of Zn therapy in Thal patients–with results of both Control and DM patients–did not show significant differences. However, significant differences were noted in Thal patients vs Controls for the following iron trafficking related proteins: sTfR, transferrin, haptoglobin, hemopexin and TgG (p<0.05).

Conclusion
These preliminary data suggest that in patients with Thal, Zn status is related to insulin resistance and beta cell function, possibly related to circulating LPI, oxidative stress and some iron trafficking proteins such as sTfR or hemopexin. More results are needed to explore how non-invasive therapy may improve glucose tolerance in Thal patients.

Session topic: E-poster

Keyword(s): Chelation, Iron overload, Thalassemia, Zinc
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