Free triiodothyronine/free thyroxine (FT3/FT4) ratio is strongly associated with insulin resistance in euthyroid and hypothyroid adults: a cross-sectional study
, 1, 3, 1, 4, 5, 6
Abstract
Introduction: Insulin resistance (IR) is a key and early pathogenetic mechanism of cardiometabolic diseases with huge potential if detected early and mitigated, for lowering the burden of the disease. Available data are conflicting to what extent adult thyroid dysfunction is associated with IR. Therefore, we aimed to investigate the association and to identify which thyroid parameters are predictors of IR.
Material and methods: After undergoing basic anthropometric and biochemical studies including thyroid hormones, oral glucose tolerance test (OGTT), and insulin, 1425 middle-aged individuals were divided into three groups according to thyroid parameters: overt hypothyroidism (OH), subclinical hypothyroidism (SH), and euthyroidism (EU).
Results: The homeostasis model assessment of IR (HOMA-IR), fasting insulin, and two-hour glucose levels of OGTT showed a steady, yet insignificant, increase from EU through SH to OH. The strongest noted correlations were those of insulin levels with free triiodothyronine/free thyroxine (FT3/FT4) ratio (r = 0.206, p < 0.001) and FT3 (r = 0.205, p < 0.001). Also in the case of HOMA-IR, the only statistically significant correlations were observed for FT3 (r = 0.181, p < 0.001) and the FT3/FT4 ratio (r = 0.165, p < 0.001). Among other thyroid hormones, linear logistic regression proved the FT3/FT4 ratio as the only significant predictor of HOMA-IR (linear coefficient = 5.26, p = 0.027) and insulin levels (linear coefficient = 18.01, p = 0.023), respectively. Thyroid-stimulating hormone was not associated with IR in either correlation or regression analysis.
Conclusions: The FT3/FT4 ratio should be more emphasised in the diagnosis and treatment of thyroid disorders. Patients could benefit from a pharmacological reduction of the FT3/FT4 ratio, potentially leading to a decrease in insulin resistance, and thus a corresponding decrease in the risk of the cardiometabolic diseases.
Keywords: thyroid disorderinsulin resistanceFT3/FT4 ratiohypothyroidismeuthyroidism
References
- Chaker L, Bianco A, Jonklaas J, et al. Hypothyroidism. Lancet. 2017; 390(10101): 1550–1562.
- Biondi B, Cappola AR, Cooper DS. Subclinical Hypothyroidism: A Review. JAMA. 2019; 322(2): 153–160.
- Leo SDe, Lee S, Braverman L. Hyperthyroidism. Lancet. 2016; 388(10047): 906–918.
- Jabbar A, Pingitore A, Pearce SHS, et al. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol. 2017; 14(1): 39–55.
- Gierach M, Gierach J, Junik R. Insulin resistance and thyroid disorders. Endokrynol Pol. 2014; 65: 70–76.
- Garduño-Garcia Jd, Camarillo Romero E, Loe Ochoa A, et al. Thyroid function is associated with insulin resistance markers in healthy adolescents with risk factors to develop diabetes. Diabetol Metab Syndr. 2015; 7: 16.
- Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest. 2016; 126(1): 12–22.
- Emokpae MA, Obazelu PA. The Association of Triiodothyronine-to-Thyroxine Ratio with Body Mass Index in Obese Nigerian Children and Adolescents. Med Sci (Basel). 2017; 5(4).
- Pasqualetti G, Schirripa M, Dochy E, et al. Thyroid hormones ratio is a major prognostic marker in advanced metastatic colorectal cancer: Results from the phase III randomised CORRECT trial. Eur J Cancer. 2020; 133: 66–73.
- Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004; 27(6): 1487–1495.
- Ebrahimpour A, Vaghari-Tabari M, Qujeq D, et al. Direct correlation between serum homocysteine level and insulin resistance index in patients with subclinical hypothyroidism: Does subclinical hypothyroidism increase the risk of diabetes and cardio vascular disease together? Diabetes Metab Syndr. 2018; 12(6): 863–867.
- Wang G, Liu J, Yang N, et al. Levothyroxine treatment restored the decreased circulating fibroblast growth factor 21 levels in patients with hypothyroidism. Eur J Intern Med. 2016; 31: 94–98.
- Maleki N, Kazerouni F, Hedayati M, et al. Assessment of cardiovascular risk factors in patients with subclinical hypothyroidism. Acta Cardiol. 2016; 71(6): 691–697.
- Aksoy N, Yeler MT, Ayan NN, et al. Association between thyroid hormone levels and insulin resistance and body mass index. Pak J Med Sci. 2015; 31(6): 1417–1420.
- Maratou E, Hadjidakis DJ, Kollias A, et al. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol. 2009; 160(5): 785–790.
- Mazaheri T, Sharifi F, Kamali K. Insulin resistance in hypothyroid patients under Levothyroxine therapy: a comparison between those with and without thyroid autoimmunity. J Diabetes Metab Disord. 2014; 13(1): 103.
- Sanyal D, Raychaudhuri M. Hypothyroidism and obesity: An intriguing link. Indian J Endocrinol Metab. 2016; 20(4): 554–557.
- Wang B, Song R, He W, et al. Sex Differences in the Associations of Obesity With Hypothyroidism and Thyroid Autoimmunity Among Chinese Adults. Front Physiol. 2018; 9: 1397.
- Xu R, Huang F, Zhang S, et al. Thyroid function, body mass index, and metabolic risk markers in euthyroid adults: a cohort study. BMC Endocr Disord. 2019; 19(1): 58.
- Urrunaga-Pastor D, Guarnizo-Poma M, Moncada-Mapelli E, et al. Insulin Resistance and Metabolic Syndrome Research Group. High free triiodothyronine and free-triiodothyronine-to-free-thyroxine ratio levels are associated with metabolic syndrome in a euthyroid population. Diabetes Metab Syndr. 2018; 12(2): 155–161.
- Park SoY, Park SeE, Jung SW, et al. Free triiodothyronine/free thyroxine ratio rather than thyrotropin is more associated with metabolic parameters in healthy euthyroid adult subjects. Clin Endocrinol (Oxf). 2017; 87(1): 87–96.
- Ettleson MD, Bianco AC. Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone? J Clin Endocrinol Metab. 2020; 105(9).
- Strich D, Chay C, Karavani G, et al. Levothyroxine Therapy Achieves Physiological FT3/FT4 Ratios at Higher than Normal TSH Levels: A Novel Justification for T3 Supplementation? Horm Metab Res. 2018; 50(11): 827–831.
