Zinc and Diabetes in Patients With Thalassemia: a Pilot Study

Patients with Thalassemia major (Thal) require frequent blood transfusions and are at risk
for iron overload. High tissue iron increases the risk of various endocrinopathies,
including diabetes, as well as cardiovascular disease, and infections due to the formation
of free radicals. This systemic condition of oxidative stress elicits an antioxidant
response to reduce tissue damage. Zinc is an important component of that response because it
can compete with iron for multiple cellular binding sites and, therefore, reduce the
redox-cycling of iron and minimize iron-mediated oxidation of lipids, proteins, and DNA.

In Thal patients with chronic hepatic iron overload, tissue zinc redistribution is likely to
be persistent. This could create an unbalanced tissue zinc distribution with excessive
amounts in the liver and deficient levels in other tissues altering zinc-dependent
functions, such as growth, skeletal development, immunity, and glucose regulation. There is
a rich body of literature focused on the 'diabetogenic effects' of altered zinc status which
will be reviewed herein. Our group has recently shown that supplementation with 25 mg/d of
zinc can improve bone density in patients with Thal. This provides evidence for a functional
zinc deficiency, which may also affect other whole body zinc functions, such as insulin
secretion and glucose homeostasis.

Our hypothesis is that hepatic iron overload induces a sub-clinical inflammatory response
that alters the expression of MT and zinc-transport proteins leading to hepatic zinc
sequestration, and an associated zinc-depletion in other tissues. Marginal zinc depletion in
turn leads to increased oxidative stress, cellular apoptosis and altered glucose homeostasis
and insulin secretion. This proposal will focus on cross-sectional differences in markers of
glucose homeostasis and zinc status in diabetic and non-diabetic Thal patients, combined
with a short- term zinc supplementation to explore the effect on glucose and insulin
homeostasis.

Inclusion Criteria:

- patients diagnosed with transfusion dependent thalassemia

- > 12 years of age

Exclusion Criteria (for both cross-sectional and interventional studies)

- patients who are pregnant

- patients who are on growth hormone therapy

Exclusion criteria (for intervention study only)

- patients who currently have diabetes (therefore cannot have an oral glucose tolerance
test)