GLP-1 and Microvascular Function in Type 2 Diabetes (GLP-1ADDS)

Some gut hormones, called incretins, stimulate insulin production in order to control sugar levels but also activate brain centres and signal to stop eating. Current administration of incretin-based therapies mimicking these gut hormones is by subcutaneous (just under the skin) injection and has been routinely available for diabetic patients for more than 4 years. It is an effective treatment for the lowering of blood glucose with an average weight loss of about 3-4kg.Recent evidence, from animal studies and limited human studies, suggests that incretins based treatments may also have beneficial effects on blood vessel function. However, it is not known whether this effect is by direct action on the blood vessel independent of an improvement of latent inflammation which is typically associated with weight loss or an anti-inflammatory effect of the incretin treatment itself. The aim of this study is to determine whether the incretin-based diabetes treatment with the GLP-1 (Glucagon-like peptide 1) analogue Liraglutide (also known as Victoza), which mimics the actions of incretins, improves blood vessel function in individuals with type 2 diabetes. It will determine whether the improvement in blood vessel function is independent of the effect of weight loss and changes in inflammation. This by the study of vascular function before and after 4 months of Victoza treatment in subjects with Type 2 diabetes in comparison with 1) participants randomized to hypo-caloric diet to achieve a similar weight loss than with Victoza and 2) participants randomized to treatment with once daily aspirin. Comprehensive assessment of blood vessel function, body fat distribution and metabolic profile at baseline and at the end of the treatment phase will be combined with assessments of inflammation markers in blood and in fat tissue biopsies.

adipose tissue biopsies will be analysed for gene expression and protein content of inflammatory cytokines

Inclusion Criteria: Type 2 diabetes and an HbA1C between 7-8.5% on a stable dose of sulphonylurea and/or metformin Exclusion Criteria: use of insulin corticosteroids contraceptives, tamoxifen methotrexate DPP-IV inhibitors pregnancy lactation endocrine disorders acute MI or cerebrovascular disease Raynaud's disease or connective tissue disease current or previous history of malignancy subjects treated with ergotamine derivatives unstable blood pressure for the last 3 months current treatment with warfarin subjects on any anti-inflammatory or anti-platelet agents history of any bleeding disorders and GI bleeds.

Pastel E, McCulloch LJ, Ward R, Joshi S, Gooding KM, Shore AC, Kos K. GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction. Clin Sci (Lond). 2017 Mar 1;131(5):343-353. doi: 10.1042/CS20160803. Epub 2017 Jan 3.