Insulin resistance/diabetes/metabolic syndrome/obesity

As with leptin resistance, it has been shown in numerous studies that  insulin resistance, diabetes, or metabolic syndrome have associated  significant reduction in T4 to T3 conversion, an intracellular  deficiency of T3, and an increased conversion of T4 to reverse T3,  further reducing intracellular T3 levels (91,100,92,94,147,184-193,235).  Additionally, the elevated insulin will increase D2 activity and  suppress TSH levels, further decreasing thyroid levels and making it  inappropriate to use the TSH as a reliable marker for tissue thyroid  levels in the presence of elevated insulin levels as occurs with  obesity, insulin resistance, or type II diabetes (91-99,233).

Pittman CS et al. found that normal individuals had a 77% conversion  of T4 to T3, while diabetic individuals had a 45% conversion of T4 to T3  and increased T4 to reverse T3. Improvement in glucose levels only  slightly increased T4 to T3 conversion to 46% (93).

Islam S et al. investigated the T4 to T3 conversion in 50 diabetic  patients compared to 50 non-diabetic controls. There was no difference  in TSH and free T4 levels, but the diabetic individuals had  significantly decrease free T3 levels (p = 0.0001) that averaged 46%  less than controls. The FT3/FT4 ratio was 50% less in diabetic patients  versus controls. The TSH failed to elevate despite the fact that serum  T3 was approximately half of normal (92). Saunders J, et al. also found  that diabetics had approximately a 50% reduction in T3 levels and  significantly increased reverse T3 levels and decreased T3/reverse T3  ratios (94).

In the International Journal of Obesity, Krotkiewski, et al.  published the results of their investigation of the impact of  supplemental T3 on cardiovascular risk in obese patients to partially  reverse the reduced T4 to T3 conversion seen with obesity (53). Seventy  obese patients with “normal” standard thyroid function tests were  treated with 20 mcg of straight T3 for six weeks. While the dose was not  high enough to completely reverse the reduced T4 to T3 conversion seen  with obesity, there was a significant reduction in a number of  cardiovascular risk factors, including cholesterol and markers for  insulin resistance. There were no side-effects in any of the patients.  The authors conclude, “T3 may be considered to ameliorate some of the  risk factors associated with abdominal obesity, particularly in some  subgroups of obese women with a relative resistance to thyroid hormones  possibly dependent on decreased peripheral deiodination of thyroxine  (T4) (53).”

Thus, replacement with timed-released T3 preparations to normalize  the reduced intracellular T3 levels is appropriate in such patients  despite so-called “normal” levels while, on the contrary, T4-only  preparations do not address the physiologic abnormalities of such  patients and should be considered inappropriate replacement for obese  patients or those with insulin resistance, leptin resistance, or  diabetes, as they do not address the physiologic abnormalities in this  group.


The hormone leptin has been found to be a major regulator of body  weight and metabolism. The body secretes leptin as weight is gained to  signal the brain (specifically the hypothalamus) that there are adequate  energy (fat) stores. The hypothalamus should then stimulate metabolic  processes that result in weight loss, including a reduction in hunger,  an increased satiety with eating, an increase in resting metabolism, and  an increase in lipolysis (fat breakdown). New research has found that  this leptin signaling is dysfunctional in the majority of people who  have difficultly losing weight or are unable to lose weight (54-58). The problem is not in the production of leptin; studies show that the  majority of overweight individuals who are having difficulty losing  weight have a leptin resistance, where the leptin is unable to produce  its normal effects to stimulate weight loss (54-58). This leptin  resistance is sensed as starvation, so multiple mechanisms are activated  to increase fat stores, rather than burn excess fat stores (54-83).  Leptin resistance is shown to suppress D1 and stimulate D2, resulting in  reduced cellular T3 but a reduction in serum TSH (47,84-89). A study by  Cettour-Rose et al. published in American Journal of Physiology, Endocrinology and Metabolism demonstrated that physiologic reversal of leptin resistance restored  deiodinase activity except in the presence of elevated reverse T3 (86).  Thus, in the presence of elevated leptin level (above 10) there is a  reduction of cellular T3 and a suppression of TSH, making the TSH an  unreliable indicator of thyroid status, especially when combined with an  elevated reverse T3. Thus, for anyone who has difficulty losing weight,  a leptin level above 10 demonstrates that low intracellular thyroid  levels is contributing to this difficulty, especially if combined with a  high normal or elevated reverse T3 (above 150).


It has been shown that women or men who perform more than moderate  exercise, especially when associated with dieting, have reduced T4 to T3  conversion and increase reverse T3, counteracting many of the positive  effects of exercise in women including weight loss (236,237).  Consequently, T3 and reverse T3 levels should be evaluated in  individuals who exercise and/or diet to better determine cellular  thyroid levels, as TSH and T4 would not necessarily reflect tissue  levels in such patients.