Author: Samira Tajbakhsh
Tajbakhsh, Samira, 2017 CEREBRAL VASCULAR HEALTH AND ACCELERATED LEUKOCYTE TELOMERE SHORTENING IN TYPE II DIABETES, Flinders University, School of Health Sciences
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Background: Hyperglycaemia and insulin resistance are the main causes of type 2 diabetes
(T2D). The prevalence of T2D is rapidly growing with 257 million people worldwide having
the disease in 2010. T2D increases the risk of emergent cardiovascular disease in patients.
Within the vasculature, the endothelium becomes dysfunctional and the cells develop a
senescence-like phenotype. Senescent cells can no longer replicate and, more importantly,
release destructive factors that promote other diseases such as cardiovascular disease.
Preventing cellular senescence could therefore curtail the onset of T2D-related diseases. Cells
can become senescent through disruption of their telomeres; protective DNA-protein caps at
the end of the chromosome. Damaged telomeres predisposes the cell to chromosomal
instability, DNA damage and disease risk. Despite the profound effects of inflammation and
oxidative stress (key events in T2D) on telomeres, there is virtually nothing known regarding
telomere integrity in the T2D vasculature. Therefore the objective of this project is to assess
DNA telomeric length in an established animal model of T2D. We will test the hypothesis
that T2D causes both vascular cell and leukocyte telomere shortening.
Methods: Male Hooded Wistar rats were split into two groups, control and T2D and were fed
either a normal diet or high-fat diet, followed by an injection of a low dose of vehicle or
streptozotocin. Blood parameters were measured and SIRT1, eNOS, and immunoblotting in
cerebral artery lysates was used to assess the markers of oxidative stress including manganese
superoxide dismutase (MnSOD), p66Shc, 3-nitrotyrosine (3-NT) and Nox2. DNA was
extracted from whole blood DNA and femoral artery and telomere length (T/S ratio)
measured using qPCR.
Results: Fasting blood glucose, free fatty acids and C-reactive protein were significantly
higher in T2D rats in comparison with control rats. Plasma insulin and leptin were
significantly lower in T2D rats. Cerebral artery protein expression of SIRT1, eNOS, MnSOD
and p66Shc were significantly reduced in T2D rats compared with control rats. However, 3
NT and Nox2 protein expression were comparable between groups. Arterial telomere length
was comparable while leukocyte telomere length was significantly shorter in T2D rats
compared with their control counterparts.
Conclusions: Our results suggest that telomere length was shortened in leukocytes but not in
arteries, in T2D compared with control rats. T2D was associated with reduced vascular
SIRT1, eNOS and MnSOD protein expression. We have demonstrated that hyperglycaemia
and down regulation of vascular SIRT1 are not sufficient to prematurely shorten vascular
telomeres.
Keywords: Type II Diabetes, Teleomere Shortening, Cerebral Vasculature, Leukocyte Telomere, Rats, artery telomere length, leukocyte telomere length, SIRT1, eNOS, MnSOD, T2D.
Subject: Health Sciences thesis
Thesis type: Masters
Completed: 2017
School: School of Health Sciences
Supervisor: Dr. Elke Sokoya