New Metformin Works in Different Way Than Previously Thought

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New Metformin Works in Different Way Than Previously Thought


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Old 01-07-2013, 14:00   #1
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Default New Metformin Works in Different Way Than Previously Thought

Diabetes Drug Works in Different Way Than Previously Thought

http://www.nature.com/nature/journal...ture11808.html

Imperfectly Understood

Despite metformin's success, its mechanism of action remained imperfectly understood. About a decade ago, researchers suggested that metformin reduces glucose synthesis by activating the enzyme AMPK. But this understanding was challenged by genetic experiments in 2010 by collaborators on the present Nature study. Coauthors Marc Foretz and Benoit Viollet from Inserm, CNRS, and Université Paris Descartes, Paris, found that the livers of mice without AMPK still responded to metformin, indicating that blood glucose levels were being controlled outside of the AMPK pathway.

(snip)

The 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 AMP in mice, which inhibits an enzyme called adenylate cyclase, thereby reducing levels of cyclic AMP and protein kinase activity, eventually blocking glucagon-dependent glucose output from liver cells.

From this new understanding of metformin's action, Birnbaum and colleagues surmise that adenylate cyclase could be a new drug target by mimicking the way in which it is inhibited by metformin. This strategy would bypass metformin's affect on a cell's mitochondria to make energy, and possibility avoid the adverse side effects experienced by many people who take metformin, perhaps even working for those patients resistant to metformin.

Most-used diabetes drug works in different way than previously thought

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Old 01-07-2013, 16:04   #2
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Fascinating! It sure works for me ... and I have seriously doubted some of the hypotheses of WHY.

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Old 01-07-2013, 16:28   #3
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That's this week's theory anyway. Interesting.

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Old 01-07-2013, 16:41   #4
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Quote:
Originally Posted by silvertiger View Post
That's this week's theory anyway. Interesting.
Better than witchcraft, so to speak, anyhow!

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Old 01-07-2013, 19:31   #5
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This is what I thought. I kept reading many descriptions of what exactly Met does to the liver. Lots of ambiguous language is used. The liver has "input" and "output" when it comes to glycogen. It makes/stores glycogen and it secretes glycogen or rather converts it back to glucose and sends it into circulation.

OK, so Met causes there to be less glucose coming out of the liver. But WHICH process does it affect? Does it inhibit the production of glycogen, its re-conversion and secretion as glucose or both?

I think this answers the question. It "caps" the glycogen and keeps it in the liver. It acts on the "output" end of the equation.

This confirms that it is of zero interest to me personally and conflicts with my treatment goals. I want my glycogen DEPLETED. I want it OUT and not to be replenished. I WANT glucagon so it will make this happen. And, the last thing I need is a substance to keep it bottled up. Of course for people using other approaches it could be just what the doctor ordered (what is it with these puns popping up?)

If it worked on the "input" side I might have been interested.

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Old 01-07-2013, 19:54   #6
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It does work on the input side. This story just adds to the existing understanding but doesn't alter the previous mechanism. Glucagon signals the liver to degrade and release glycogen but it also stimulates the liver to make new glucose via gluconeogenesis. For me, this seems to be the main problem. Usually the glucagon is balanced by insulin, but in it's absence the liver is making glucose full time.

Regarding the AMP increase by metformin, that has been known for awhile, and the mechanism (mitochondrial ETC block) is still valid. AMP via AMPK has numerous effects, the novel regulation of AC in this paper is interesting but is just another piece of the puzzle.

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Old 01-07-2013, 20:18   #7
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I want some glycogen around for those hypos, however ...

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