PhD defence: Role of metformin in regulation of AMPK activation, glucose uptake
and mitochondrial function in skeletal muscle and adipose tissue
Jonas Møller Kristensen
PhD-thesis
Metformin is the most used drug for treatment of type II diabetic patients, and has been applied in diabetes treatment for more than 50 years. Metformin ameliorates insulin resistance in these patients. Metformin decreases blood glucose concentration by reducing glucose release from the liver and stimulation of peripheral glucose uptake. The molecular mechanism(s) behind the effects of metformin is not fully elucidated, but activation of the enzyme 5´AMP-actviated protein kinase (AMPK) has been reported in adipose tissue and skeletal muscle. Focus in this PhD project has been investigation of AMPK activity regulation in relation to metformin treatment and the role of AMPK in regard to the effects of metformin treatment on glucose uptake and mitochondrial function.
The aims of the present project have been to elucidate the acute effect of in vivo metformin treatment on AMPK activation and signaling in human skeletal muscle and adipose tissue at rest and during exercise. Furthermore, to explore causal relations between AMPK and the effect of in vivo metformin treatment on glucose uptake and mitochondrial function in mouse skeletal muscle. These topics have been addressed in 3 studies described in manuscript I-III enclosed in the PhD thesis.
We found that neither acute nor short-term metformin treatment activated AMPK or enhanced exercise-induced AMPK activation in human skeletal muscle and adipose tissue from healthy subjects. Moreover, we have shown that chronic metformin treatment induces AMPK dependent enhancement of insulin stimulated glucose uptake in mouse skeletal muscle. Lastly we found that chronic metformin treatment did not affect mitochondrial function in muscles from normal mice but in muscles from mice with a compromised AMPK function.
2012, 210 pages, 100,- d.kr.,
ISBN 978 87 917 71 42 2.
Time
Friday March 16, 2012 at 12.30 o'clock
Place
Auditorium 1, August Krogh building, Universitetsparken 13, Copenhagen.
Opponents
Professor Ylva Hellsten (chair), Department of Exercise and Sport Sciences, University of Copenhagen, Denmark.
Professor Benoit Viollet, Department Endocrinology, Metabolism and Cancer, Institut Cochin, Université Paris Descartes, France.
Professor Sten Lund, Department of Clinical Medicine - The Department of Endocrinology and Diabetes, Aarhus University, Denmark.
Supervisor
Professor Jørgen Wojtaszewski, Department of Exercise and Sport Sciences, Faculty of Science, University of Copenhagen, Denmark.