Better understanding of drug’s mechanism of action can lead the way to new treatment options for heart disease in diabetes patients.
Heart disease accounts for more than half of all fatalities in patients with diabetes. The diabetes drug metformin is used by patients with diabetes to help prevent heart disease; however, not all patients can take metformin. New research recently explored for the first time the mechanism by which metformin helps prevent heart disease. By better understanding the mechanism of action, the hope is that it will pave the way for new drugs.
The researchers, from Newcastle University, Queen Elizabeth Hospital, Saudi Arabia, constructed a model that allowed them to simulate a heart attack in the lab, using stem cells from cord blood and cells from umbilical. They found new blood vessel formation, which is essential for heart attack recovery, and established metformin enhances the physiological process through which new blood vessels form.
Their finding is that during a heart attack in patients with diabetes, there is a lack of oxygen in the presence of high glucose levels, which delays blood vessel formation. Metformin seems to reverse that process, while also affecting multiple genes, which help to promote the growth of new blood vessels.
Dr. Jolanta Weaver, Senior Lecturer in Diabetes Medicine at Newcastle University, who led the study, said:
“The outcome of heart disease interventions in patients with diabetes is much worse in comparison with non-diabetic individuals. As a result, there is a demand for improved treatment approaches to enhance the outcomes of those with diabetes in order to increase heart attack survival rates.
“Our research is exciting as it can instantly make a difference to the treatments we are exploring, offering a new approach to heart disease in diabetes and new therapies may now be developed.
“It is believed that our study is the first report describing the effect of the physiological concentration of metformin as seen in patients. Furthermore, our study concentrated on the time period vital during a heart attack when, with new therapy, we can help patients most.”
Recent reports from the International Diabetes Federation highlight that 8.3% of adults have diabetes, affecting 382 million worldwide. It is estimated that this number will rise to 592 million by 2035.
Metformin is a cost-efficient drug usually used as a first-line treatment in type 2 diabetes as it helps to make the body more responsive to insulin.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM). To identify the most effective treatment for CVD, it is paramount to understand the mechanism behind cardioprotective therapies. Although metformin has been shown to reduce CVD in type 2 clinical trials, the underlying mechanism remains unexplored. CD34+ cell-based therapies offer a new treatment approach to CVD. The aim of this study was to investigate the effect of metformin on the angiogenic properties of CD34+ cells under conditions mimicking acute myocardial infarction in diabetes.
CD34+ cells were cultured in 5.5 or 16.5 mmol/L glucose ± 0.01 mmol/L metformin and then additionally ± 4 % hypoxia. The paracrine function of CD34+ cell-derived conditioned medium was assessed by measuring pro-inflammatory cytokines, vascular endothelial growth factor A (VEGFA), and using an in vitro tube formation assay for angiogenesis. Also, mRNA of CD34+ cells was assayed by microarray and genes of interest were validated by qRT-PCR.
The results showed that metformin increased in vitro angiogenesis under hyperglycemia–hypoxia and augmented the expression of VEGFA. It also reduced the angiogenic-inhibitors, chemokine (C–X–C motif) ligand 10 (CXCL10) and tissue inhibitor of metalloproteinase 1 (TIMP1) mRNAs, which were upregulated under hyperglycemia–hypoxia. In addition, metformin increased expression of STEAP family member 4 (STEAP4) under euglycemia, indicating an anti-inflammatory effect.
From the results, it was concluded that metformin has a dual effect by simultaneously increasing VEGFA and reducing CXCL10 and TIMP1 in CD34+ cells in a model of the diabetic state combined with hypoxia. Therefore, these angiogenic inhibitors are promising therapeutic targets for CVD in diabetic patients. Moreover, our data are commensurate with a vascular protective effect of metformin and add to the understanding of underlying mechanisms.
- The research has shown that lack of oxygen in the presence of high glucose levels – as occurs during a heart attack in diabetes – delays blood vessel formation whilst metformin reverses that process.
- Angiogenic inhibitors are promising therapeutic targets for CVD in diabetic patients.
- Metformin affects several new genes important in promoting the growth of new blood vessels.
Researched and prepared by Steve Freed, BPharm, Diabetes Educator, Publisher and reviewed by Dave Joffe, BSPharm, CDE
Cardiovascular Diabetology Published on: 9 February 2016 Sherin Bakhashab; Fahad W. Ahmed Cardiovascular Diabetology. Doi 10.1186/s12933-016-0344-2