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Glucose-induced toxicity - from mechanisms to therapy

Diabetes and the Heart

In this session, cardiologists had an opportunity to learn about how increased glucose may interact with vascular function in a more intricate way, but also how people are attempting to find novel ways by means of glucose lowering drugs to interact with this toxicity.

In the first presentation, Rosalinda Madonna (Houston, US) discussed molecular mechanisms behind glucose interaction with the vessel wall, elucidating the known pathways: PKC activation, increased polyol pathway, and increased intra-cellular AGE (advanced glycate end-product) formation and hexosamine pathway. She went on to show interesting personal data about the potential hyperglycaemic induced hyperosmotic stress, inducing inflammatory activation of angiogenesis. It should be acknowledged that these data were based on purely experimental studies with very high glucose levels (between 25 and 45 mmol/L). Thus, these data need to be verified in a clinical setting before being accepted.

Tomasz Guzik (Krakow, PL) introduced the audience into the intricate interplay between adipokines and vascular inflammation in obesity, claiming that perivascular adipose tissue may have an important impact on vascular dysfunction and oxidative stress. This is a novel area of research of high interest for further exploration. Thus, the interplay between leptin and adiponectin and hyperglycaemia needs further elucidation.

Following these two theoretical lectures, the next two speakers, Thomas Wascher (Vienna, AT) and Naveed Sattar (Glasgow, GB) informed the audience on novel glucose-lowering drugs, in particular incretin mimetics and ongoing clinical trials with these and other drugs. The GLP-1 group of drugs has several advantages besides the glucose-lowering impact, such as avoiding hypoglycaemia and causing weight reduction. In addition, other, non-hypoglycemic effects are being investigated for these drugs, and several short-term, small studies have shown that there is an improvement in beta-cell function, endothelial function, blood pressure and inflammatory reductions, on top of the glucose-lowering effect. However, all these effects need to be investigated further in randomized clinical trials with cardiovascular endpoints. The short half life means that these drugs have to be administered as daily injections, but new drugs are being developed making it possible to administer these compounds at intervals approaching several days.

From the presentation by Naveed Sattar, it is obvious that many such trials are under way, recruiting thousands of patients with type 2 diabetes, some recently detected and some with longer standing disease. A great number of drugs, such as sitagliptine, saxagliptine, exenatide, liraglutide and taspoglutide, are examples of trials testing incretins. Other studies such as ALECARDIO test PPAR alpha/gamma agonists in patients with acute coronary syndromes, including those with newly detected diabetes, a very interesting concept. The concept that it would be beneficial to lower post-prandial glucose is being tested in ACE a study with acarbose run in China; while ORIGIN, a global study that has recruited 12,612 patients tests the concept that early institution of insulin would be better than conventional management of people with impaired glucose tolerance and type 2 diabetes.

Thus we can look forward with interest to the coming few years as regards the relation between glucose-lowering and cardiovascular events, hopefully, demonstrating improved prognosis of patients with diabetes by managing hyperglycaemia.




Glucose-induced toxicity - from mechanisms to therapy

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.