Date of Award

2010

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Professor Seamus K Sreenan

Keywords

Diabetes Mellitus, Diabetic Angiopathies

Abstract

The aims of this thesis are to attempt to identify subjects at increased risk of diabetes-associated cardiovascular disease (CVD) at various stages of the condition, focusing predominantly on the most common form of the condition, type 2 diabetes mellitus (T2DM). This includes attempting to identify a subset of the population that already has diabetes who may be at particularly increased risk of CVD, to determine if measuring some of the novel markers of CVD risk in subjects with diabetes may be useful in assessing cardiovascular risk, assessing risk of CVD in newly diagnosed diabetes and attempting to identify prevalence of cardiovascular complications in newly diagnosed patients. Finally I will determine whether genetic heterogeneity in the Calpain 10 (CAPN10) gene might be a useful indicator of diabetes risk in Irishsubjects and as such be a way of identifying subjects at future risk of CVD prior to the onset of DM when interventions may be more effective in reducing CVD risk.

The specific aims are:

  1. To determine the prevalence of the metabolic syndrome (MS) in patients with diabetes. To estimate and compare the prevalence of the MS in both TlDM and T2DM patients.
  2. To evaluate the medium and long term cardiovascular risk utilizing the United Kingdom Prospective Diabetes Study (UKPDS) risk engine in patients who are newly diagnosed with T2DM.
  3. To evaluate patients with newly diagnosed diabetes for the presence of significant subclinical macrovascular disease.
  4. To study the association of novel risk of cardiovascular factors, fibrinogen and C-reactive protein (CRP) and albuminuria as markers of CVD risk in newly diagnosed patients with T2DM.
  5. To estimate the prevalence and the relationship of three polymorphisms (43, 63 and 2037) and insertion-deletion 19 of the CAPN10 gene in a cohort of Irish patients with T2DM.

Despite major improvements in the management of T2DM, subjects with the condition remain at considerable risk of cardiovascular disease. In this work a number of strategies have been discussed whereby subjects with increased CVD risk could be identified earlier and targeted for particularly aggressive interventions. We suggest that an integral component of the annual assessment of patients with diabetes should be the calculation of an MS score and patients with particularly high cardiovascular risk can be targeted for especially aggressive risk factor management, with particular attention to hypertension and obesity, which are the most prevalent components of the MS. The Steno-2 study highlighted the importance of treatment of hyperglycaemia, dyslipidaemia and hypertension in patients with T2DM as measures to reduce the risk of life-threatening complications, particularly CVD which is the most common cause of death in population. Using an MS score could help identify those who require particularly aggressive, steno-2 style interventions.

The risk of vascular complications in patients with T2DM can also be calculated using the UKPDS risk engine. In newly diagnosed T2DM this risk is considerable in both genders at the time of the diagnosis. The determination of the risk of vascular events using this risk engine should be estimated at diagnosis and recalculated during subsequent years in order to ensure that optimized treatment of vascular risk factors is achieved.

Patients with newly diagnosed T2DM may have subclinical vascular complications that mainly involve the coronary and peripheral circulation. Screening for these asymptomatic or subclinical vascular complications at the time of the diagnosis in high risk patients may identify those who may most benefit from these interventions. Significant abnormalities may be identified in some subjects as was found in this study. Monitoring of inflammatory markers and/or WCM, BMI may also be helpful to identify high CVD risk patients.

Finally, modification of risk factors for developing T2DM and thus CVD, prior to the development of any dysglycaemia may be the most effective way of reducing the cardiovascular burden of the disease. Genetic screening of high risk subjects may be worthwhile to identify highly susceptible subjects. CAPN10 gene study suggests associations between genetic variability in this gene and T2DM in the Irish population and further exploration of this and other genes may lead to earlier identification of subjects for interventions to reduce the risk of development of the disease.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

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Comments

A thesis submitted to the Faculty of Medicine, Royal College of Surgeons in Ireland for the degree of Doctor of Medicine from the National University of Ireland in 2009.

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