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

Ferrannini E, Iervasi G, Cobb J et al.

CNR Institute of Clinical Physiology

American journal of physiology. Endocrinology and metabolism. Feb 2017.

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.


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