Metformin Weight Loss: Theoretical Implications

Metformin is a popular diabetes drug that is often sold under the brand name Glucophage. Due to its apparent clinical success at reducing overweight and eliminating some symptoms of type 2 diabetes, the drug boasts many fans among physicians and patients. But what can the Metformin weight loss phenomenon tell us in general about the nature of obesity and weight loss?

The Caloric Balance Hypothesis tells us that, for Metformin to effect weight loss, it must do so by somehow manipulating "Calories In" and "Calories Out."

The Lipophilia Hypothesis tells us the drug probably works by doing something like reducing concentrations of insulin in the fat tissue or otherwise impeding the lipogenic effect of insulin (i.e. the ability of insulin to make new fat).

A cursory search on the internet for scientific articles about Glucophage, insulin, and weight loss reveals some provocative tidbits.

1. For instance, here's a link[1] to an article from The Journal of Metabolism that talks about "Sustainability of 8% weight loss, reduction of insulin resistance, and amelioration of atherogenic-metabolic risk factors for over 4 years by metformin-diet in women with polycystic ovary syndrome."

2. Here's another article: "Metformin (Glucophage) inhibits tyrosine phosphatase activity to stimulate the insulin receptor tyrosine kinase."[2]

The authors state:

"Metformin is a commonly used antidiabetic... whether its mechanism involves action on the insulin receptor or on downstream events is still controversial... [The authors later conclude that] "there was evidence that [the drug] acted directly upon the insulin receptor and indirectly through inhibition of tyrosine phosphatases."

So here we have a scientific article that claims that the Glucophage acts directly on insulin receptors. Once again, if you're believer in the Caloric Balance Hypothesis, you have to start scratching your head. How does this all relate back to calories? How does this relate to appetite or exercise?

On the other hand, if you're an advocate for the Lipophilia Hypothesis, even without really understanding the biochemical mechanisms at play here, the story sounds familiar. Somehow this drug appears to change fat tissue metabolism, which in turn drives a negative caloric balance; that's why people lose weight on the therapy.

3. Here's another article: "The effects of Glucophage on insulin secretion and insulin activity."[3]

Unfortunately, the article is in French, and a translation is currently unavailable. But the title alone is sufficient to indirectly support the Lipophilia Hypothesis.

After all, if you're talking about how this drug changes the ability to secrete insulin and changes the activity of insulin, then you're going down the Lipophilia path. You're not talking about calories. You're not talking about appetite. You're not talking about going to the gym. You're not talking about exercising more. You're talking about insulin.

The "eat less and exercise more" theory cannot account for weight loss on drugs like Glucophage.

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1. C. Glueck, D. Aregawi, M. Agloria, M. Winiarska, L. Sieve, P. Wang. "Sustainability of 8% weight loss, reduction of insulin resistance, and amelioration of atherogenic metabolic risk factor for over 4 years by metformin diet and women with polycystic ovary syndrome." Metabolism, Volume 55, Issue 12, Pages 1582-1589.

2. William Holland, Thomas Morrison, Ying Chang, Nicholas Wiernsperger and Bradley J. Stith. "Metformin (Glucophage) inhibits tyrosine phosphatase activity to stimulate the insulin receptor tyrosine kinase."Biochemical Pharmacology Volume 67, Issue 11, 1 June 2004, Pages 2081-2091.

3. Lavieuville M."The effects of Glucophage on insulin secretion and insulin activity." Journ Annu Diabetol Hotel Dieu. 1969;10:407-10.

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