We are Metformin enthusiasts
The molecule dubbed LKB1 (now STK11) has an important “traffic cop” function in determining the cell's needs for sensing nutritional needs, communication, cell shape and growth. Initially discovered as a cancer gene, it is clear that its role in cancer is related to its more basic physiologic function.
If LKB1 is genetically deleted from cells, the ability of metformin to mediate its effect on insulin action and glucose transport is completely eliminated.
So, although metformin has been in clinical use for over 50 years, we are finally starting to understand the many and varied ways metformin works in diabetes, insulin resistance and PCOS.
It also appears that LKB1 gene comes in different isoforms or flavours and these isoforms are inherited in families. A study by Legro et al. (1) has shown that one LKB1 flavour is associated with much more responsive to metformin than persons carrying a different flavour. Not only that, but there is a gene dose effect, in that those with two copies of the responsive (GG) gene isoform respond better than those with a single copy (GC). Those with only the “slow”(CC) gene isoform have half the chance of ovulating compared with the GG group.
This study quite clearly pins down a genetic background as to why there is lack of uniformity in response to metformin.
Furthermore, given its place in the cellular communication network, we have no doubt that LKB1 would be modulated by diet.
The efficacy of metformin in managing PCOS particularly in ovulation induction and securing life pregnancy has been muddied by the fact that important life-style, adiposity and genetic background have not been factored in.
The success rate in ovulation of metformin compared to clomid using was diametrically the opposite in Americans (poor) (2, also see our comments) to that in different European centres (Italian) (3,4).
We have previously pointed out that the studies did not take into account diet, exercise as well as other life style measures. Italians generally eat low GI and healthy fats and have lower BMI than Americans. There is also evidence that in the spectrum of insulin resistance in women with PCOS, Southern European women tend to be less so than other groups studied. It would be extremely instructive to explore the distribution of LKB1 isoforms in these populations.(2, our comments)
Our experience in large open studies in which we adopted a program of strict low GI eating (in preparation for conception), appropriate weight loss, regular aerobic exercise 3-times/week, stress reduction strategies and micro-nutrient supplementation have yielded excellent results. Pregnancies happen promptly with few early foetal losses and uniform easy pregnancies. We rarely had to add clomid after 3 months of metformin alone, but we are aware that our clientele are a different group from those seeking help in fertility clinics.
Metformin has morphed into something that needs intense attention.
References
- Legro RS et al, Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism of the SKT11 gene, J. Clin Endocrinol Metab 2007 Nov 13
- Legro RS et al, New England Journal of Medicine 356:551-566,2007
- Palomba S et al, Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infertile patients with polycystic ovarian syndrome, J.Clin.Endocrinol Metabol 92:3498-3503, 2007
- Nestler JE, Metformin for the treatment of polycystic ovary syndrome, New England Journal of Medicine, 358:47-54, 2008.