In 2004, Clifford Bailey of the Diabetes Group from Aston University in Birmingham, United Kingdom described metformin, the most widely prescribed drug for treating diabetes, as ironic: In our high-tech era of drug discovery and development this first-line treatment for type 2 diabetes is little removed from an herbal remedy of the Middle Ages. Despite its chemical simplicity and detailed investigation, metformin continues to evade a complete exposé of its cellular activity (Pract Diab Int April 2004 Vol.21 No. 3)
Now, almost a decade later, a team led by Morris Birnbaum, M.D., Ph.D. from the Institute for Diabetes, Obesity and Metabolism, is getting closer to a clear picture of how this drug works, which, in addition to its widespread use for diabetes, is being tested for treating dementia and cancer.
The Birnbaum lab and colleagues found that metformin works in a different way than previously understood. They found that in mice it suppresses the liver hormone glucagon’s ability to generate an important signaling molecule, which points to new drug targets.
For fifty years, one of the few classes of therapeutics effective in reducing the overactive glucose production associated with diabetes has been the biguanides, which includes metformin. The inability of insulin to keep liver glucose output in check is a major factor in the high blood sugar of type 2 diabetes and other diseases of insulin resistance.
“Overall, metformin lowers blood glucose by decreasing liver production of glucose,” says Birnbaum. “But we didn’t really know how the drug accomplished that.”
Birnbaum’s Nature study describes a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. The team showed that metformin leads to the accumulation of the protein AMP in mice, which inhibits an enzyme called adenylate cyclase, thereby reducing levels of key enzymes and eventually blocking glucagon-dependent glucose output from liver cells. Insulin Resistance in the Brain
In the spring of 2012, another Penn team led by geriatric psychiatrists Steve Arnold, M.D. and Konrad Talbot, Ph.D., described the first direct demonstration that insulin resistance occurs in the brains of people with Alzheimer's disease.
Insulin resistance in the brain precedes and contributes to cognitive decline above and beyond other known causes of Alzheimer's disease. Insulin is also important to the health of brain cells. The team identified extensive abnormalities in the activity of two major signaling pathways for insulin and insulin-like growth factor in non-diabetic people with Alzheimer's disease.
In preliminary trials, metformin has been shown to stimulate the development of new nerve cells in the areas of the brain responsible for learning and memory. A new Phase 2 clinical trial being conducted at Penn will investigate the safety, tolerability, and cognitive effects of the drug on non-diabetic individuals with mild cognitive impairment and early Alzheimer’s disease. The trial will also examine the drug’s impact on biomarkers of Alzheimer’s.
Metformin and Cancer
Five years ago, Penn researchers found that metformin kills tumor cells that lack the p53 gene, and more than half of all human cancers have lost the p53 gene, so the cells have no ability to put the brakes on their cancerous growth. Metformin activates AMP-related pathways, which exert changes on cellular metabolism by affecting p53 function. Observational studies at the time had already shown that diabetic patients who take metformin have a lower rate of cancer diagnosis and mortality than other diabetics.
The researchers found that metformin instructs cells to switch metabolic pathways. Instead of using the most energy efficient pathway – called oxidative phosphorylation – the cells are forced to use stress-related ones, which are typically used when the cell is short on oxygen, glucose or other nutrient sources. But in the absence of p53, the cells can’t make the switch.
Birnbaum mentions that he has been conferring with cancer researchers about exploring the relationship between metformin and how it affects cancer cells. He says that his lab’s work re-emphasizes that metformin has the ability to work independent of AMPK, something not generally considered by investigators looking for direct effects of metformin on tumors.
Metformin seems to have come full circle from a home remedy in the European medieval apothecary called goat’s rue to now being investigated for a host of modern chronic conditions. Miller, R., Chu, Q., Xie, J., Foretz, M., Viollet, B., & Birnbaum, M. (2013). Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP Nature DOI: 10.1038/nature11808