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

While hyperthyroidism and hypothyroidism cause 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 yr, we measured insulin sensitivity (by the insulin clamp technique) and 35 circulating metabolites. At baseline, across quartiles of increasing fT3 levels (or fT3/fT4 ratio) most features of IR emerged [i.e., male sex, greater body mass index (BMI), waist circumference, heart rate, blood pressure, fatty liver index, free fatty acids, and triglycerides; reduced insulin-mediated glucose disposal; and β-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 decreases in insulin sensitivity. Moreover, baseline fT3 predicted follow-up increases in glycemia independently of sex, age, BMI, insulin sensitivity, β-cell glucose sensitivity, and baseline glycemia. Serum tyrosine levels were higher with IR and were directly associated with fT3; higher α-hydroxybutyrate levels signaled enhanced oxidative stress, thereby impairing tyrosine degradation. In 25 patients with morbid obesity, surgery-induced weight loss improved IR and consensually lowered fT3 levels. 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.