Researchers have discovered a novel mechanism by which biguanides exert their glucose-lowering effect, potentially leading to new therapeutic approaches to the treatment of diabetes and insulin resistance.
"We have shown that it is through an elevation in intracellular AMP [adenosine monophosphate] that metformin substantially abrogates the activation of adenylate cyclase by glucagon. This results in a reduction in the phosphorylation of key substrates for maintaining hepatic glucose output," report Morris Birnbaum (University of Pennsylvania, Philadelphia, USA) and colleagues.
Some experts previously believed that metformin reduces glucose synthesis through activation of AMP-activated protein kinase (AMPK), but this has recently been challenged by studies showing that mice without AMPK still respond to metformin, explain the authors.
In primary mouse hepatocytes, the team found that 24-hour exposure to phenformin at concentrations of 10 µM or greater significantly reduced glucagon-stimulated increases in cyclic AMP (cAMP) levels. Similarly, exposure to metformin at 125 µM also inhibited cAMP accumulation.
Exposure to each of the drugs also resulted in significant increases in intracellular levels of AMP.
The team explains that under usual circumstances, the binding of glucagon to its receptor on hepatocyte membranes activates the enzyme adenylate cyclase, which stimulates the synthesis of cyclic AMP (cAMP) from adenosine triphosphate (ATP) and the activity of protein kinase. Protein kinase activity (PKA) results in the phosphorylation of protein targets, which then work together to increase hepatic glucose output.
However, as metformin and phenformin blocked glucagon-induced cAMP production at concentrations that correlated well with their effects on AMP levels, the authors tested whether AMP could directly inhibit adenylate cyclase.
As reported in Nature, AMP inhibited glucagon-stimulated adenylate cyclase activity when ATP was present at 160 µM (typical assay conditions) as well as at the more physiological ATP concentration of 1.28 mM.
Furthermore, in mice injected with metformin, the glucagon-dependent increases in hepatic cAMP were reduced, as were PKA and the phosphorylation of PKA substrates, demonstrating the in vivo blockade of this pathway by the biguanides, says the team.
"Understanding the mechanism by which the drug metformin reduces hepatic glucose is of considerable importance," write Birnbaum et al.
The findings suggest that adenylate cyclase might represent a novel target for the development of treatments for insulin resistance and Type 2 diabetes, they conclude.
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