Metformin, thyroid-pituitary axis, diabetes mellitus, and metabolism
Larry H, Bernstein, MD, FCAP, Author and Curator
and Aviva Lev-Ari, PhD, RN
The following article is a review of the central relationship between the action of
metformin as a diabetic medication and its relationship to AMPK, the important and
essential regulator of glucose and lipid metabolism under normal activity, stress, with
its effects on skeletal muscle, the liver, the action of T3 and more.
We start with a case study and a publication in the J Can Med Assoc. Then we shall look
into key literature on these metabolic relationships.
Part I. Metformin , Diabetes Mellitus, and Thyroid Function
Hypothyroidism, Insulin resistance and Metformin
May 30, 2012 By Janie Bowthorpe
The following was written by a UK hypothyroid patient’s mother –
My daughter’s epilepsy is triggered by unstable blood sugars. And since taking
Metformin to control her blood sugar, she has significantly reduced the number of
seizures. I have been doing research and read numerous academic medical journals,
which got me thinking about natural thyroid hormone and Hypothyroidism. My hunch
was that when patients develop hypothyroid symptoms, they are actually becoming
insulin resistant (IR). There are many symptoms in common between women with
polycystic ovaries and hypothyroidism–the hair loss, the weight gain, etc.
A hypothyroid person’s body behaves as if it’s going into starvation mode and so, to
preserve resources and prolong life, the metabolism changes. If hypothyroid is prolonged
or pronounced, then perhaps, chemical preservation mode becomes permanent even
with the reintroduction of thyroid hormones. To get back to normal, they need
a “jump-start” reinitiate a higher rate of metabolism. The kick start is initiated through
AMPK, which is known as the “master metabolic regulating enzyme.”
(http://en.wikipedia.org/wiki/AMP-activated protein kinase).
Guess what? This is exactly what happens to Diabetes patients when Metformin is
Suggested articles: http://www.springerlink.com/content/r81606gl3r603167/ and
Note the following comments/partial statements:
“Hypothyroidism is characterized by decreased insulin responsiveness”;
“the pivotal regulatory role of T3 in major metabolic pathways”.
The community knows that T3/NTH (natural thyroid hormone [Armour]) makes
hypothyroid patients feel better – but the medical establishment is averse to T3/NTH
(treating subclinical hypoT (T3/T4 euthyroid) with natural dessicated thyroid (NDT).
The medical establishment might find an alternative view about impaired metabolism
more if shown real proof that the old NDT **was/is** having the right result –i.e., the
T3 is jump-starting the metabolism by re-activating AMPK.
If NDT also can be used for hypothyroidism without the surmised “dangers” of NTH,
then they should consider it. [The reality in the choice is actually recombinant TH
(Synthroid)]. Metformin is cheap, stable and has very few serious side effects. I use the
car engine metaphor, and refer to glucose as our petrol, AMPK as the spark plug and
both T3 and Metformin as the ignition switches. Sometimes if you have flat batteries in
the car, it doesn’t matter how much you turn the ignition switch or pump the petrol
pedal, all it does is flatten the battery and flood the engine.
Dr. Skinner in the UK has been treating “pre-hypothyroidism” the way that some
doctors treat “pre-diabetes”. Those hypothyroid patients who get treated early
might not have had their AMPK pathways altered and the T4-T3 conversion still works.
There seems to be no reason why thyroid hormone replacement therapy shouldn’t
logically be given to ward off a greater problem down the line.
It’s my belief that there is clear and abundant academic evidence that the AMPK/
Metformin research should branch out to also look at thyroid disease.
Point – direct T3 is kicking the closed -down metabolic process back into life,
just like Metformin does for insulin resistance.
There is serotonin resistance! http://www.ncbi.nlm.nih.gov/pubmed/17250776
Metformin Linked to Risk of Low Levels of Thyroid Hormone
CMAJ (Canadian Medical Association Journal) 09/22/2014
Metformin, the drug commonly for treating type 2 diabetes,
- is linked to an increased risk of low thyroid-stimulating hormone
- in patients with underactive thyroids (hypothyroidism),
according to a study in CMAJ (Canadian Medical Association Journal).
Metformin is used to lower blood glucose levels
- by reducing glucose production in the liver.
previous studies have raised concerns that
- metformin may lower thyroid-stimulating hormone levels.
- Retrospective long-term
- 74 300 patient who received metformin and sulfonylurea
- 25-year study period.
- 5689 had treated hypothyroidism
- 59 937 had normal thyroid function.
Metformin and low levels of thyroid-stimulating hormone in
patients with type 2 diabetes mellitus
Jean-Pascal Fournier, Hui Yin, Oriana Hoi Yun Yu, Laurent Azoulay +
Centre for Clinical Epidemiology (Fournier, Yin, Yu, Azoulay), Lady Davis Institute,
Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational
Health (Fournier), McGill University; Division of Endocrinology (Yu), Jewish General
Hospital; Department of Oncology (Azoulay), McGill University, Montréal, Que., Cananda
CMAJ Sep 22, 2014, http://dx.doi.org:/10.1503/cmaj.140688
- metformin may lower thyroid-stimulating hormone (TSH) levels.
- determine whether the use of metformin monotherapy, when compared with
- is associated with an increased risk of low TSH levels(< 0.4 mIU/L)
- in patients with type 2 diabetes mellitus.
- Used the Clinical Practice Research Datalink,
- identified patients who began receiving metformin or sulfonylurea monotherapy
between Jan. 1, 1988, and Dec. 31, 2012.
- 2 subcohorts of patients with treated hypothyroidism or euthyroidism,
followed them until Mar. 31, 2013.
- Used Cox proportional hazards models to evaluate the association of low TSH
levels with metformin monotherapy, compared with sulfonylurea monotherapy,
in each subcohort.
- 5689 patients with treated hypothyroidism and 59 937 euthyroid patients were
included in the subcohorts.
For patients with treated hypothyroidism:
- 495 events of low TSH levels were observed (incidence rate 0.1197/person-years).
- 322 events of low TSH levels were observed (incidence rate 0.0045/person-years)
in the euthyroid group.
- metformin monotherapy was associated with a 55% increased risk of low TSH
levels in patients with treated hypothyroidism (incidence rate 0.0795/person-years
vs.0.1252/ person-years, adjusted hazard ratio [HR] 1.55, 95% confidence
interval [CI] 1.09– 1.20), compared with sulfonylurea monotherapy,
- the highest risk in the 90–180 days after initiation (adjusted HR 2.30, 95% CI
- No association was observed in euthyroid patients (adjusted HR 0.97, 95% CI 0.69–1.36).
Interpretation: The clinical consequences of this needs further investigation.
|Crude and adjusted hazard ratios for suppressed thyroid-stimulating hormone|
levels (< 0.1 mIU/L) associated with the use metformin monotherapy, compared
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