Siewiera 2017 Abstract MITOEAGLE Barcelona
The effect of metformin on blood platelet bioenergetics and platelet function.
Event: MitoEAGLE Barcelona 2017
Metformin is the most commonly used antidiabetic drug that forms the first line of defense in a treatment of type 2 diabetes. This drug demonstrates numerous side benefits associated with the reduction of diabetes-related deaths, heart attacks and strokes . The mechanism responsible for this beneficial effect is still unknown. Metformin has been revealed to decrease the activity of complex I in mitochondria and thus it can lead to elevated lactate production. Mitochondrial dysfunction occurring in response to this agent, including decreased mitochondrial complex I activity, reduced mitochondrial membrane potential and oxygen consumption, was also observed for blood platelets. However, most of these changes were noted merely at extremely high in vitro concentrations of metformin . Since blood platelet activation highly depends on energy supply, the increased mitochondrial activity occasionally observed in diabetic subjects , could be causatively linked to blood platelet activation. The above-mentioned facts lead us to raise the hypothesis that a mild limitation of respiratory chain by metformin can reduce exaggerated platelet activation in diabetes and the response of these cells to stimulating agents. In consequence this may lead to lowered risk of micro- and macrovascular complications in patients treated with metformin. Therefore, our aim was to evaluate the in vitro impact of metformin on blood platelet mitochondrial respiration and blood platelet activation. For this purpose we used a wide range of metformin concentrations, including those observed in plasma of metformin-treated diabetic patients (20 µM and 100 µM), those observed in patients with drug-induced acidosis (500 µM), as well as much higher, not observed in clinical practice in plasma of diabetic patients (1 mM and 10 mM). The mitochondrial respiration parameters in intact blood platelets were monitored with the use of high resolution respirometry (HRR) (Oxygraph-2k, Oroboros Instruments, Innsbruck, Austria). Expressions of platelet surface activation markers (CD62P and the active form of GPIIb/IIIa complex) were evaluated with the use of flow cytometry. Our results indicate that short-term (30 minut) incubation of platelets with metformin is sufficient to affect platelet mitochondria respiration but merely at extremely high concentrations of metformin (reduced ROUTINE respiration at 1 mM and 10 mM, reduced ET capacity at 10 mM and lowered R/E ratio at 10 mM). However, at lower (more physiological) concentrations metformin failed to inhibit the respiratory chain following such a short period of incubation. Since, the mechanism of metformin action is underlied by its accumulation in cells, we conclude that probably a much longer incubation is needed to better mimic the situation that occurs in an organism.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Diabetes
Organism: Human Tissue;cell: Blood cells, Platelet Preparation: Intact cells
Coupling state: ROUTINE, ET Pathway: N HRR: Oxygraph-2k Event: A4 PMBCs, Metformin
- Siewiera K(1), Hertel J(2), Labieniec-Watala M(2), Kassassir H(1), Watala C(1)
- Dept Haemostasis Haemostatic Disorders, Chair of Biomedical Sciences, Med Univ;
- Fac Biol Environmental Protection, Dept Medical Biophysics; Univ Lodz, Poland. [email protected]
References and support
- Anonymous (1998) Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group Lancet 352´:854-65.
- Orban JC, Fontaine E, Ichai C (2012) Metformin overdose: time to move on. Crit Care 16:164.
- Protti A, Lecchi A, Fortunato F, Artoni A, Greppi N, Vecchio S, Fagiolari G, Moggio M, Comi GP, Mistraletti G, Lanticina B, Faraldi L, Gattinoni L (2012). Metformin overdose causes platelet mitochondrial dysfunction in humans. Crit Care 16:R180.
- Siewiera K, Kassassir H, Talar M, Wieteska L, Watala C (2016) Higher mitochondrial potential and elevated mitochondrial respiration are associated with excessive activation of blood platelets in diabetic rats. Life Sci 148:293–304.
- Acknowledgements The study supported by the National Centre of Science (NCN 2015/17/N/NZ5/02603 and NCN 2016/20/T/NZ3/00505).