Mitochondrial toxicity of metformin and phenformin in human peripheral blood cells assessed by high-resolution respirometry
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Summary, in English
Popular science summary
Do metformin and phenformin cause toxicity to mitochondria of human blood cells?
Metformin and phenformin are anti-diabetic drugs associated with lactic acidosis as a rare side effect. This side effect is thought to be due to drug-induced mitochondrial dysfunction. In this project, the mitochondrial toxicity of metformin and phenformin was assessed in human blood cells. It was shown that both drugs impair the function of mitochondria in human blood cells and, that this effect aggravated with time and dose.
Mitochondria produce up to 90 % of the cell’s energy, a process which is called respiration. Metformin and phenformin are anti-diabetic drugs which have been reported to interfere with respiration. Metformin is the first choice treatment for Type 2 diabetes, a disease characterized by high glucose levels in the blood due to impaired response to insulin, which is a blood glucose-lowering hormone. Both drugs achieve their anti-diabetic effect by lowering the production of glucose, increasing its uptake into tissues and by increasing the sensitivity to insulin. However, they are associated with lactic acidosis as side effect. Lactic acidosis is a condition where the blood pH is lowered due to accumulation of lactate in the blood. Because of this phenformin has been withdrawn from the market in most countries. Although it is thought that the side effect lactic acidosis is due to drug-induced damage to mitochondria, the exact mechanism remains unresolved. The number of Type 2 diabetes cases and use of metformin is expected to rise in the future. Therefore, the aim of this project was to explore how metformin and phenformin cause toxicity to mitochondria in human blood cells.
Energy production by mitochondria is linked to oxygen consumption. Therefore, the healthiness of mitochondria of human platelets and white blood cells was assessed by measuring their oxygen consumption in response to exposure to metformin and phenformin.
Results
Metformin and phenformin damaged mitochondria of human platelets at complex I, one of the primary centres of the energy production of the cell. The toxic effect was more pronounced with phenformin than with metformin. But for both drugs it aggravated with increasing dose. Further, we were the first to show that metformin causes the same toxic effect to human white blood cells as it does to human platelets. The damage also was found to be caused at complex I and increased with higher doses. Additionally we showed that with prolonged time of exposure to metformin, as it occurs during treatment conditions, the damaging effect on mitochondria in human platelets increased.
In summary, the study demonstrates that metformin and phenformin impair mitochondrial function at complex I in two types of human blood cells, an effect that aggravates with time and dose.
Supervisors: Eskil Elmér, Magnus Hansson
Master´s Degree Project in Pharmacology, 30 ECTS, 2013
Department of Biology, Lund University
Do metformin and phenformin cause toxicity to mitochondria of human blood cells?
Metformin and phenformin are anti-diabetic drugs associated with lactic acidosis as a rare side effect. This side effect is thought to be due to drug-induced mitochondrial dysfunction. In this project, the mitochondrial toxicity of metformin and phenformin was assessed in human blood cells. It was shown that both drugs impair the function of mitochondria in human blood cells and, that this effect aggravated with time and dose.
Mitochondria produce up to 90 % of the cell’s energy, a process which is called respiration. Metformin and phenformin are anti-diabetic drugs which have been reported to interfere with respiration. Metformin is the first choice treatment for Type 2 diabetes, a disease characterized by high glucose levels in the blood due to impaired response to insulin, which is a blood glucose-lowering hormone. Both drugs achieve their anti-diabetic effect by lowering the production of glucose, increasing its uptake into tissues and by increasing the sensitivity to insulin. However, they are associated with lactic acidosis as side effect. Lactic acidosis is a condition where the blood pH is lowered due to accumulation of lactate in the blood. Because of this phenformin has been withdrawn from the market in most countries. Although it is thought that the side effect lactic acidosis is due to drug-induced damage to mitochondria, the exact mechanism remains unresolved. The number of Type 2 diabetes cases and use of metformin is expected to rise in the future. Therefore, the aim of this project was to explore how metformin and phenformin cause toxicity to mitochondria in human blood cells.
Energy production by mitochondria is linked to oxygen consumption. Therefore, the healthiness of mitochondria of human platelets and white blood cells was assessed by measuring their oxygen consumption in response to exposure to metformin and phenformin.
Results
Metformin and phenformin damaged mitochondria of human platelets at complex I, one of the primary centres of the energy production of the cell. The toxic effect was more pronounced with phenformin than with metformin. But for both drugs it aggravated with increasing dose. Further, we were the first to show that metformin causes the same toxic effect to human white blood cells as it does to human platelets. The damage also was found to be caused at complex I and increased with higher doses. Additionally we showed that with prolonged time of exposure to metformin, as it occurs during treatment conditions, the damaging effect on mitochondria in human platelets increased.
In summary, the study demonstrates that metformin and phenformin impair mitochondrial function at complex I in two types of human blood cells, an effect that aggravates with time and dose.
Supervisors: Eskil Elmér, Magnus Hansson
Master´s Degree Project in Pharmacology, 30 ECTS, 2013
Department of Biology, Lund University
Department/s
- Degree Projects in Molecular Biology
Publishing year
2013
Language
English
Document type
Student publication for Master's degree (two years)
Topic
- Biology and Life Sciences
Supervisor
- Magnus Hansson