Selective Targeting of Glucagon-Like Peptide-1 Signalling As a Novel Therapeutic Approach for Cardiovascular Disease in Diabetes

Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the cardiovascular system where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting are limited although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1 based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting, and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes.

Session 4: CVD, diabetes and cancer - Evidence for the use of the Mediterranean diet in patients with CHD

Diet is associated with the development of CHD. The incidence of CHD is lower in southern European countries than in northern European countries and it has been proposed that this difference may be a result of diet. The traditional Mediterranean diet emphasises a high intake of fruits, vegetables, bread, other forms of cereals, potatoes, beans, nuts and seeds. It includes olive oil as a major fat source and dairy products, fish and poultry are consumed in low to moderate amounts. Many observational studies have shown that the Mediterranean diet is associated with reduced risk of CHD, and this result has been confirmed by meta-analysis, while a single randomised controlled trial, the Lyon Diet Heart study, has shown a reduction in CHD risk in subjects following the Mediterranean diet in the secondary prevention setting. However, it is uncertain whether the benefits of the Mediterranean diet are transferable to other non-Mediterranean populations and whether the effects of the Mediterranean diet will still be feasible in light of the changes in pharmacological therapy seen in patients with CHD since the Lyon Diet Heart study was conducted. Further randomised controlled trials are required and if the risk-reducing effect is confirmed then the best methods to effectively deliver this public health message worldwide need to be considered.

A randomised controlled trial of increasing fruit and vegetable intake and how this influences the carotenoid concentration and activities of PON-1 and LCAT in HDL from subjects with type 2 diabetes

Background

High density lipoproteins (HDL) have many cardioprotective roles; however, in subjects with type 2 diabetes (T2D) these cardioprotective properties are diminished. Conversely, increased fruit and vegetable (F&V) intake may reduce cardiovascular disease risk, although direct trial evidence of a mechanism by which this occurs in subjects with T2D is lacking. Therefore, the aim of this study was to examine if increased F&V consumption influenced the carotenoid content and enzymes associated with the antioxidant properties of HDL in subjects with T2D.

Eighty obese subjects with T2D were randomised to a 1- or ≥6-portion/day F&V diet for 8-weeks. Fasting serum was collected pre- and post-intervention. HDL was subfractionated into HDL₂ and HDL₃ by rapid ultracentrifugation. Carotenoids were measured in serum, HDL₂ and HDL₃ by high performance liquid chromatography. The activity of paraoxonase-1 (PON-1) was measured in serum, HDL₂ and HDL₃ by a spectrophotometric assay, while the activity of lecithin cholesterol acyltransferase (LCAT) was measured in serum, HDL₂ and HDL₃ by a fluorometric assay.

In the ≥6- vs. 1-portion post-intervention comparisons, carotenoids increased in serum, HDL₂ and particularly HDL₃, (α-carotene, p = 0.008; β-cryptoxanthin, p = 0.042; lutein, p = 0.012; lycopene, p = 0.016), as did the activities of PON-1 and LCAT in HDL₃ (p = 0.006 and 0.044, respectively).

To our knowledge, this is the first study in subjects with T2D to demonstrate that increased F&V intake augmented the carotenoid content and influenced enzymes associated with the antioxidant properties of HDL. We suggest that these changes would enhance the cardioprotective properties of this lipoprotein.

Multimodal functional and anatomical imaging identifies preclinical microvascular abnormalities in type 1 diabetes mellitus

Structural and functional change in the microcirculation in type 1 diabetes mellitus predicts future end-organ damage and macrovascular events. We explored the utility of novel signal processing techniques to detect and track change in ocular hemodynamics in patients with this disease. 24 patients with uncomplicated type 1 diabetes mellitus, and 18 age-and-sex matched control subjects were studied. Doppler ultrasound was used to interrogate the carotid and ophthalmic arteries and digital photography to image the retinal vasculature. Frequency analysis algorithms were applied to quantify velocity waveform structure and retinal photographic data at baseline and following inhalation of 100% oxygen. Frequency data was compared between groups. No significant differences were found in the resistive index between groups at baseline or following inhaled oxygen. Frequency analysis of the Doppler flow velocity waveforms identified significant differences in bands 3-7 between patients and controls in data captured from the ophthalmic artery (p<0.01 for each band). In response to inhaled oxygen, changes in the frequency band amplitudes were significantly greater in control subjects compared with patients (p<0.05). Only control subjects demonstrated a positive correlation (R=0.61) between change in retinal vessel diameter and frequency band amplitudes derived from ophthalmic artery waveform data. The use of multimodal signal processing techniques applied to Doppler flow velocity waveforms and retinal photographic data identified preclinical change in the ocular microcirculation in patients with uncomplicated diabetes mellitus. An impaired autoregulatory response of the retinal microvasculature may contribute to the future development of retinopathy in such patients.

Creating an eLearning Resource to Improve Knowledge and Understanding of Pregnancy in the Context of HIV Infection

Patient narratives have much to teach healthcare professionals about the experience of living with a chronic condition. While the biomedical narrative of HIV treatment is hugely encouraging, the narrative of living with HIV continues to be overshadowed by a persuasive perception of stigma. This paper presents how we sought to translate the evidence from a qualitative study of the perspectives of HIV affected pregnant women and expectant fathers on the care they received, from the pre conception to post natal period, into educational material for maternity care practice. Narrative scripts were written based on the original research interviews, with care taken to reflect the key themes from the research. We explore the way in which the qualitative findings bring to life patient and partner experiences and what it means for nurses, midwives and doctors to be prepared to care for couples affected by HIV. In so doing, we challenge the inequity between the dominance of biomedical knowledge over understanding the patient experience in the preparation of health professionals to care for HIV affected women and men who are having a baby or seeking to have a baby.

General practice-recorded depression and antidepressant use in young people with newly diagnosed Type 1 diabetes: a cohort study using the Clinical Practice Research Datalink

Aims - To investigate whether young people with Type 1 diabetes have an increased rate of depression andantidepressant use and whether their risk varies by age group, time from diabetes diagnosis, calendar period ofdiagnosis or complications status. Methods - A cohort of incident cases of patients with Type 1 diabetes diagnosed before 35 years of age (n = 5548) wasidentified within the Clinical Practice Research Datalink and individually age and sex matched with up to two controlsubjects without diabetes (n = 10 657). Patients with depression were identified through general practice-recordeddepression codes and antidepressant prescriptions. Cox regression models gave hazard ratios for depression in peoplewith Type 1 diabetes compared with control subjects. Results - People with Type 1 diabetes were twice as likely to have a record of antidepressant use and generalpractice-diagnosed depression as their matched control subjects (hazard ratio 2.08, 95% CI 1.73–2.50, P < 0.001).These associations varied by time from diagnosis, with marked increases observed within the first 5 years of diagnosis(hazard ratio 2.14, 95% CI 1.51–3.03, P < 0.001), and by age at diabetes diagnosis, with excesses noted even in the 10-to 19-year age group (hazard ratio 1.45, 95% CI 1.06–1.98, P = 0.02). Conclusions - This population-based study shows that people with Type 1 diabetes have higher rates of generalpractice-recorded depression and antidepressant use. The excess is present within 5 years of diabetes diagnosis,suggesting psychological input for patients is warranted in the early years of their condition.