More Metabolomics

To begin at the beginning, probably the first thyroid question I ever asked was "What does thyroid hormone do?"

Yes - we hear that thyroid hormone controls metabolism. Yes - we see that it reduces cholesterol. And several other effects. But we very rarely hear the details - it tends to be very much an arm-waving exercise which never gets a finger pointing at a specific effect. Rarely does anything explain how thyroid hormones have their impact.

The first abstract below suggests why some substances, medicines or otherwise, might not get metabolised as well if there is a relatively high level T4 present. This is precisely what happens in many people on levothyroxine - their T4 level is relatively high in order to achieve a reasonable T3 level.

The second abstract discusses the effects of T4 and T3 on insulin resistance.

Xenobiotica. 2017 Mar 13:1-18. doi: 10.1080/00498254.2017.1304593. [Epub ahead of print]

The inhibition of UDP-glucuronosyltransferases (UGTs) by tetraiodothyronine (T4) and triiodothyronine (T3).

Chen DW1,2, Du Z2, Zhang CZ3, Zhang WH3, Cao YF4, Sun HZ4, Zhu ZT4, Yang K2, Liu YZ2, Zhao ZW2, Fu ZW2, Gu WQ1, Yu Y1, Fang ZZ2.

Author information

1 a Department of Thyroid and Neck Tumor , Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy , Huanhuxi Road, Ti-Yuan-Bei, Hexi District , Tianjin, 300060 , China.

2 b Department of Toxicology , School of Public Health, Tianjin Medical University , Tianjin, 300070 , China.

3 d Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin 300121 , China.

4 c Key Laborotary of Liaoning Tumor Clinical Metabolomics (KLLTCM) , Jinzhou , Liaoning , China.

Abstract

1. UDP-glucuronosyltransferases (UGTs) are important drug-metabolizing enzymes (DMEs) catalyzing the glucuronidation elimination of various xenobiotics and endogenous substances. Endogenous substances are important regulators for the activity of various UGT isoforms. Triiodothyronine (T3) and thyroxine (T4) are important thyroid hormones essential for normal cellular differentiation and growth. The present study aims to elucidate the inhibition behavior of T3 and T4 on the activity of UGT isoforms.

2. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to screen the inhibition potential of triiodothyronine (T3) and thyroxine (T4) on the activity of various UGT isoforms. Initial screening results showed that T4 exerted stronger inhibition potential than T3 on the activity of various UGT isoforms at 100 μM. Inhibition kinetics was determined for the inhibition of T4 on the representative UGT isoforms, including UGT1A1, -1A3, -1A7, -1A8, -1A10, and -2B7. The results showed that T4 competitively inhibited the activity of UGT1A1, -1A3, -1A7, 1A10, and -2B7, and noncompetitively inhibited the activity of UGT1A8. The inhibition kinetic parameters were calculated to be 1.5, 2.4, 11, 9.6, 4.8, and 3.0 μM for UGT1A1, -1A3, -1A7, -1A8, -1A10, and -2B7, respectively. In silico docking method was employed to demonstrate why T4 exerted stronger inhibition than T3 towards UGT1A1. Stronger hydrogen bonds and hydrophobic interaction between T4 and activity cavity of UGT1A1 than T3 contributed to stronger inhibition of T4 towards UGT1A1.

3. In conclusion, more clinical monitoring should be given for the patients with the elevation of T4 level due to stronger inhibition of UGT isoforms-catalyzed metabolism of drugs or endogenous substances by T4.

KEYWORDS:

UDP-glucuronosyltransferases (UGTs); enzyme inhibition; thyroxine (T4); triiodothyronine (T3)

PMID: 28285550

DOI: 10.1080/00498254.2017.1304593

tandfonline.com/doi/abs/10....

Am J Physiol Endocrinol Metab. 2017 Feb 28:ajpendo.00464.2016. doi: 10.1152/ajpendo.00464.2016. [Epub ahead of print]

Insulin resistance and normal thyroid hormone levels: prospective study and metabolomic analysis.

Ferrannini E1, Iervasi G2, Cobb J3, Ndreu R2, Nannipieri M4.

Author information

1 CNR Institute of Clinical Physiology ferranni@ifc.cnr.it.

2 CNR Institute of Clinical Physiology.

3 Metabolon, Inc.

4 CNR Institute of Clinical Physiology, University of Pisa.

Abstract

While hyper/hypothyroidism causes dysglycemia, the relationship between thyroid hormone levels within the normal range and insulin resistance (IR) is unclear. In 940 participants with strictly normal serum concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH)) followed up for 3 years, we measured insulin sensitivity (by the insulin clamp technique) and a panel of 35 circulating metabolites. At baseline, across quartiles of increasing fT3 levels (or fT3/fT4 ratio) there emerged most features of IR (male sex, higher BMI, waist circumference, heart rate, blood pressure, fatty liver index, free fatty acids, and triglycerides levels, reduced insulin-mediated glucose disposal and ß-cell glucose sensitivity). In multiadjusted analyses, fT3 was reciprocally related to insulin sensitivity and, in a subset of 303 subjects, directly related to endogenous glucose production. In multiple regression models adjusting for sex, age, BMI and baseline value of insulin sensitivity, higher baseline fT3 levels were significant predictors of the decreases in insulin sensitivity. Moreover, baseline fT3 predicted follow-up increases in glycemia independently of sex, age, BMI, insulin sensitivity, ß-cell glucose sensitivity and baseline glycemia. Serum tyrosine levels were higher in IR and were directly associated with fT3; higher α-hydroxybutyrate levels signaled enhanced oxidative stress impairing tyrosine degradation. In 25 morbidly obese patients, surgery-induced weight loss improved IR and consensually lowered fT3 High-normal fT3 levels are associated with IR both cross-sectionally and longitudinally, and predict deterioration of glucose tolerance. This association is supported by a metabolite pattern that points at increased oxidative stress as part of the IR syndrome.

Copyright © 2017, American Journal of Physiology-Endocrinology and Metabolism.

KEYWORDS:

euthyroidism; insulin resistance; metabolomics; oxidative stress; thyroid hormones

PMID: 28246105

DOI: 10.1152/ajpendo.00464.2016

ajpendo.physiology.org/cont...

Two older posts about metabolomics research:

healthunlocked.com/thyroidu...

healthunlocked.com/thyroidu...

5 Replies

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  • What is your interpretation of the first article? It says high T4 levels inhibit certain drug-metabolizing enzymes. Does this mean that drugs become more or less potent if someone has high T4? If more potent, does that mean someone with high T4 levels could take less of a drug and still have the same effect?

    I thought most hypos were ultra-sensitive to drugs. But this is saying the opposite, isn't it? That high, not low T4, inhibits the drug's effect.

  • Strikes me it could go in two directions - if the substance needs to be processed to work, it would be held back, if the active substance gets processed in order to get rid of it, it would hang around longer and possibly get to a higher level.

    My brain kept asking if this (and other differences) is, possibly, why some people seem to have different reactions to some medicines.

  • Forgive my mush brain but is it saying that high normal t3 levels are causing diabetes?

  • Well, that higher FT3 is associated with reduced insulin sensitivity. Causation is not proved.

  • OK thanks, i get it, the two may be there but not necessarily have directly caused each other as there may be more factors involved. Thanks Helvella

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