Aspirin and Metformin share common mechanism

I have personally benefited from the use of Metformin as a pre-diabetic with a strong family history of type II diabetes mellitus. Recent American Diabetes Association (ADA) consensus panel recommends the use of Metformin to prevent or delay the development of diabetes. In a study published by Rhee MK et al  in Diabetes Care, 2010 Jan; 33(1):49-54. Epub 2009 Oct 6, more than 96% of individuals with both impaired fasting glucose and impaired glucose tolerance test are likely to meet ADA consensus criteria for consideration of metformin

A report by scientists from McMaster University, the University of Dundee and the University of Melbourne, published online on April 19, 2012 in the journal Science, suggests a common mechanism for salicylate—aspirin’s active compound—and the drug metformin in decreasing the risk of several diseases.

“Salicylate, a plant product, has been in medicinal use since ancient times,” Simon A. Hawley and colleagues write in their introduction to the article. “More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both rapidly broken down to salicylate in vivo.”

The authors explain that salsalate or aspirin administered in high doses result in the activation by salicylate of adenosine monophosphate-activated protein kinase (AMPK), a regulator of cell growth and metabolism. AMPK is known to be activated by exercise as well as the antidiabetic drug metformin. “We’re finding this old dog of aspirin already knows new tricks,” commented co-principle investigator Dr Greg Steinberg, who is an associate professor of medicine in the Michael G. DeGroote School of Medicine at McMaster University and the Canada Research Chair in Metabolism and Obesity. “In the current paper we show that, in contrast to exercise or metformin which increase AMPK activity by altering the cells’ energy balance, the effects of salicylate are totally reliant on a single Ser108 amino acid of the beta 1 subunit.

“We show that salicylate increases fat burning and reduces liver fat in obese mice and that this does not occur in genetically modified mice lacking the beta1 subunit of AMPK,” he noted.

The fact that both metformin and aspirin activate AMPK suggests that their recently publicized benefits in reducing the risk of cancer could be d5e to a shared mechanism. However, only further studies can confirm the validity of this interesting hypothesis.

Further elucidation of the action of metformin:

Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin’s beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Metformin activates AMPK in hepatocytes; as a result,

  1. Acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed – Phosphorylation and inactivation of ACC, as a result of AMPK activation,kserves to inhibit the proximal and rate-limiting step of lipogenesis. Reduced synthesis of the ACC product, malonyl-CoA, is also predicted to relieve inhibition of CPT-1, resulting in increased fatty acid oxidation. These effects are likely to contribute to metformin’s in vivo ability to lower triglycerides and VLDL.
  2. Suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; Known target genes for SREBP-1, which include FAS and S14, are also downregulated in liver, further contributing to metformin’s effects to modulate circulating lipids and to reduce hepatic lipid synthesis and fatty liver. It should be noted that increased SREBP-1 is postulated as a central mediator of insulin resistance in DM2 and related metabolic disorders and that increased liver lipid content is implicated in hepatic insulin resistance
  3. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. this effect is also additive with insulin (12). Thus, the observed association of increased glucose uptake and AMPK activation in isolated skeletal muscles suggests that metformin’s effect to augment muscle insulin action in vivo may be attributed to AMPK as well.
  4. Metformin-mediated effects on hepatic glucose production contribute to its glucose-lowering efficacy. AMPK activation is required for inhibition of hepatocyte glucose production by metformin. Additional studies will be required to further elucidate precise mechanism(s) by which metformin-stimulated AMPK activation could result in inhibition of hepatic glucose production.

 

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