Misinterpretation of Relationship Between TFTs, Diabetes and Effects of Metformin
A worried reader wrote in to express his concern over a recent article that raised concerns over the use of Metformin:
Dear Dr. Dean:
Your friend Dr. Sears has come out against metformin, citing a recent European study. Do you know about this study and do you still recommend Metformin?
On your advice many years ago, I have been taking Metformin, and want to know if I should continue. I am 78.
Many thanks, Ed R.
Dear Mr. R.,
Thanks for your interesting question. Yes, I saw the letter you mentioned from Dr. Sears, and reviewed the studies that he curiously cited that allegedly supported his flawed conclusions.
Frankly, I doubt that Dr. Sears wrote the letter that triggered your question—and will bet that he never even saw it before it was released to the public! Dr. Sears is a lot smarter than that. I assume it was written and sent out by one of his well-meaning but ill-informed, over-eager marketers.
First, the short answer. I still recommend metformin to just about everyone, except those unfortunate rare folks who are allergic to it. Keep taking your metformin.
Whoever wrote Dr. Sears’ piece accurately reported that metformin tends to cause a reduction in TSH (thyroid-stimulating hormone) — but misinterpreted low TSH as an indication of impaired thyroid function. Whoever wrote the letter does not understand endocrinology nor the mechanisms of metformin.
Please re-read “Dr. Sears’” letter (here’s a link, Al Sears Original Letter). The letter cites an Iranian study that correctly reported that Metformin causes a reduction in TSH in those with a high-normal TSH level.1 However, from there the letter goes “downhill.”
First, TSH is not a “thyroid hormone.” TSH is produced by the pituitary, in response to TRH (thyrotropin releasing hormone) from the hypothalamus, and stimulates the thyroid gland to release thyroxine (T4). T4 is “deiodinated” by the body and converted into tri-iodothyronine (T3—the active thyroid hormone). When levels of T4 and T3 are highest, TSH and TRH are reduced, due to negative feedback inhibition on the pituitary and hypothalamus, as shown in Figure 1. When levels of T3 and T4 are low (as in hypothyroidism), TRH and TSH will rise, to try to stimulate the thyroid to produce more hormone.
Fig. 1. Hypothalamus-pituitary=thyroid axis, illustrating
the feedback mechanism that maintains thyroid homeostasis.
The article cited by Dr. Sears which reported the TSH-lowering effect of metformin was confirmed by an even more recent article in a more prestigious journal.2 In this comprehensive review, the scientists reported that “Patients treated with metformin have a smaller thyroid volume and a lower risk of goiter, thyroid nodules and cancer. Metformin inhibits the growth of thyroid cells and thyroid cancer cells by affecting the insulin/IGF1 and mTOR pathways. Metformin treatment is associated with a decrease in the levels of thyroid-stimulating hormone (TSH) in diabetic patients …by enhancing the effects of thyroid hormones in the pituitary and activating adenosine monophosphate-activated protein kinase (AMPK). Metformin appears to be a promising therapeutic tool in patients with thyroid disease.” They concluded that “Metformin lowers TSH, reduces the nodular volume, inhibits the growth of thyroid carcinoma and potentiates the antimitogenic effect of chemotherapeutic agents. These findings suggest a broader use of this drug not only for type 2 diabetics with or without proliferative thyroid disease but also for those with metabolic syndrome and obesity.”
Thus, it is clear that Dr. Sears’ letter has it backwards. He then goes on to say:
“Low TSH levels increase your risk of diabetes.
A new study proves it. Researchers in the Netherlands looked at 8,452 people without diabetes. They found that those with the lowest TSH levels had a 20% higher risk of developing diabetes than those with the highest levels. But for people with prediabetes, the risk of progressing to full diabetes was a whopping 40%.”
But that’s NOT what the study “proved.” In fact, it proved the OPPOSITE! Dr. Sears’ cite by Chaker, et al, from the Netherlands, was from a poster session at a conference. However, the authors later published a more comprehensive report of their findings in the journal, BMC Medicine.4 In this article, the authors reported that “Higher TSH levels were associated with a higher diabetes risk,” and that “Higher FT4 [free T4] levels were associated with a lower diabetes risk amongst all participants”
This is clearly illustrated in the figure that accompanied their report.
Fig. 2. The 7-year absolute risk of progression from prediabetes to
type 2 diabetes is plotted against thyroid-stimulating hormone
(TSH) and free thyroxine (FT4) values within the normal range.
These findings confirm what my mentor, Professor Vladimir Dilman found many years ago, that metformin acts to increase hypothalamic (and peripheral) receptor sensitivity to negative feedback inhibition by most hormones. Although Metformin is generally considered a peripheral insulin receptor sensitizer, acting on insulin receptors in muscle and fat tissues, Dilman demonstrated that it was a “multi-hormone receptor sensitizer,” acting on central (hypohthalamic and pituitary) and peripheral hormone receptors for not only insulin, but also cortisol, estrogen, testosterone, progesterone, etc. Although Dilman implied that metformin also enhanced thyroid hormone receptor sensitivity, he did not perform specific studies in this regard.
However, the studies cited here confirm what Dilman had earlier hypothesized—that Metformin enhances the effect of thyroid hormone as well, resulting in lower levels of TSH!
Thus, a lower TSH as reported in Dr. Sears’ piece and the supporting reference actually confirms that metformin enhances the effect of thyroid hormone by its effect onthe hypothalamus-pituitary axis.
As I said, keep taking your metformin.
Ward Dean, MD
May 11, 2017
References:
1.Karimifar M, Aminorroaya A, Amini M, et al. Effect of metformin on thyroid stimulating hormone and thyroid volume in patients with prediabetes: A randomized placebo-controlled clinical trial. J Res Med Sci: The Official Journal of Isfahan University of Medical Sciences. 2014;19(11):1019-1026.
2. Meng X, Xu S, Chen G, Derwahl M, and Liu C. Metformin and thyroid disease. J Endocrinol April 1, 2017 233 R43-R51.
3. Chaker L, Ligthart, Korevaar TIM, et al. “OR33-2: Thyroid Function and type 2 diabetes risk: a population-based prospective cohort study.” Presented at: ENDO 2016; April 1-4, 2016; Boston, MA.
4. Chaker L, Ligthart S, Korevaar TI, Hofman A, Franco OH, Peeters RP, Dehghan A. Thyroid function and risk of type 2 diabetes: a population-based prospective cohort study. BMC Med. 2016 Sep 30;14(1):150.
