A single dose of metformin improves whole body insulin sensitivity and alters cellular redox state in skeletal muscle of Zucker fa/fa rats
Lark, Daniel Stephen
Energy balance is considered a fundamental requirement of life forms from single cell organisms to higher mammals such as humans. Unfortunately, our species has also discovered the detrimental metabolic responses to excess dietary intake: obesity and the accompanying pathologies collectively known as the metabolic syndrome. Central to the metabolic syndrome is insulin resistance, defined as a relative failure of insulin to stimulate glucose transport in peripheral tissues such as skeletal muscle. It is generally accepted that prolonged insulin resistance often results in the onset of type 2 diabetes, which is one of the most common diseases in the world. Current treatment for type 2 diabetes generally begins with dimethylbiguanide, an insulin sensitizing drug also known as metformin. In the last 10 years, scientific discovery has identified mitochondrial function as a key player in a variety of metabolic diseases, including insulin resistance and type 2 diabetes. As such, a variety of investigations have been performed in an attempt to indentify [sic] mechanisms by which altered mitochondrial function or physiology may contribute to the pathogenesis of these diseases. Recent evidence from our laboratory indicates that mitochondria derived oxidant (mROS) generation is a key player in the mitochondrial regulation of insulin sensitivity in vivo. Additionally, recent evidence has demonstrated that acute metformin treatment in vitro decreases liver mROS, and that chronic metformin treatment in vivo decreases skeletal muscle mROS concurrent with improvements in whole body glucose tolerance. Together, this evidence indicates that metformin may alter peripheral insulin sensitivity by decreasing the elevated mROS associated with insulin resistance in the obese population. Therefore, the purpose of the current study was to investigate the effects of a single oral dose of metformin on whole body glucose tolerance and mROS in red and white gastrocnemius of Zucker fa/fa rats, a genetically obese animal model. A single oral dose of metformin resulted in improved whole body glucose tolerance compared to controls independent of alterations in serum insulin. Cellular redox state was significantly more oxidized in animals treated with glucose or metformin alone compared to controls or animals which received both treatments. Succinate and palmitoylcarnitine/malate induced mROS was not altered by glucose and/or metformin in red or white gastrocnemius. Mitochondrial respiration with pyruvate/malate or palmitoylcarnitine/malate was unchanged in response to glucose and/or metformin treatment in red or white gastrocnemius. Akt phosphorylation was significantly elevated in both red and white gastrocnemius in response to glucose or metformin alone, but no additive effect was observed when administered simultaneously, indicating that metformin may act as an insulin mimetic in vivo. AMPK phosphorylation was not elevated in response to metformin treatment in either tissue, which suggests that metformin may act through AMPK-independent mechanisms in skeletal muscle in vivo. The results of this study demonstrate that a single oral dose of metformin can improve whole body glucose tolerance independent of changes in mitochondrial respiration, mROS, or altered AMPK signaling in red and white gastrocnemius of Zucker fa/fa rats, but may be associated with altered cellular redox state.
Lark, Daniel Stephen. (January 2010). A single dose of metformin improves whole body insulin sensitivity and alters cellular redox state in skeletal muscle of Zucker fa/fa rats (Master's Thesis, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/2938.)
Lark, Daniel Stephen. A single dose of metformin improves whole body insulin sensitivity and alters cellular redox state in skeletal muscle of Zucker fa/fa rats. Master's Thesis. East Carolina University, January 2010. The Scholarship. http://hdl.handle.net/10342/2938. April 07, 2020.
Lark, Daniel Stephen, “A single dose of metformin improves whole body insulin sensitivity and alters cellular redox state in skeletal muscle of Zucker fa/fa rats” (Master's Thesis., East Carolina University, January 2010).
Lark, Daniel Stephen. A single dose of metformin improves whole body insulin sensitivity and alters cellular redox state in skeletal muscle of Zucker fa/fa rats [Master's Thesis]. Greenville, NC: East Carolina University; January 2010.
East Carolina University