Jan. 6, 2013 ? A team, led by comparison author Morris J. Birnbaum, MD, PhD, a Willard and Rhoda Ware Professor of Medicine, with a Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, found that a diabetes drug metformin works in a opposite approach than formerly understood. Their investigate in mice found that metformin suppresses a liver hormone glucagon’s ability to beget an critical signaling molecule, indicating to new drug targets. The commentary were published online this week in Nature.
For fifty years, one of a few classes of therapeutics effective in shortening a overactive glucose prolongation compared with diabetes has been a biguanides, that includes metformin, a many frequently prescribed drug for form 2 diabetes. The inability of insulin to keep liver glucose outlay in check is a vital cause in a high blood sugarine of form 2 diabetes and other diseases of insulin resistance.
“Overall, metformin lowers blood glucose by dwindling liver prolongation of glucose,” says Birnbaum. “But we didn’t unequivocally know how a drug achieved that.”
Imperfectly Understood
Despite metformin’s success, a resource of movement remained imperfectly understood. About a decade ago, researchers suggested that metformin reduces glucose singularity by activating a enzyme AMPK. But this bargain was challenged by genetic experiments in 2010 by collaborators on a benefaction Nature study. Coauthors Marc Foretz and Benoit Viollet from Inserm, CNRS, and Université Paris Descartes, Paris, found that a livers of mice but AMPK still responded to metformin, indicating that blood glucose levels were being tranquil outward of a AMPK pathway.
Taking another demeanour during how glucose is regulated normally, a group knew that when there is no food intake and glucose decreases, glucagon is secreted from a pancreas to vigilance a liver to furnish glucose. They afterwards asked if metformin works by interlude a glucagon cascade.
The Nature investigate describes a novel resource by that metformin antagonizes a movement of glucagon, so shortening fasting glucose levels. The group showed that metformin leads to a accumulation of AMP in mice, that inhibits an enzyme called adenylate cyclase, thereby shortening levels of intermittent AMP and protein kinase activity, eventually restraint glucagon-dependent glucose outlay from liver cells.
From this new bargain of metformin’s action, Birnbaum and colleagues presupposition that adenylate cyclase could be a new drug aim by mimicking a approach in that it is indifferent by metformin. This plan would bypass metformin’s impact on a cell’s mitochondria to make energy, and probability equivocate a inauspicious side effects gifted by many people who take metformin, maybe even operative for those patients resistant to metformin.
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The above story is reprinted from materials supposing by University of Pennsylvania School of Medicine, around EurekAlert!, a use of AAAS.
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Journal Reference:
- Russell A. Miller, Qingwei Chu, Jianxin Xie, Marc Foretz, Benoit Viollet, Morris J. Birnbaum. Biguanides conceal hepatic glucagon signalling by dwindling prolongation of intermittent AMP. Nature, 2013; DOI: 10.1038/nature11808
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