Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2?

Background: During the last two decades, it has become obvious that 3,5-diiodothyronine (3,5-T2), a well-known endogenous metabolite of the thyroid hormones thyroxine (T4) or triiodothyronine (T3), not only represents a simple degradation intermediate of the former but also exhibits specific metabolic activities. Administration of 3,5-T2 to hypothyroid rodents rapidly stimulated their basal metabolic rate, prevented high-fat diet-induced obesity as well as steatosis, and increased oxidation of long-chain fatty acids. Objective: The aim of the present study was to analyze associations between circulating 3,5-T2 in human serum and different epidemiological parameters, including age, sex, or smoking, as well as measures of anthropometry, glucose, and lipid metabolism. Methods: 3,5-T2 concentrations were measured by a recently developed immunoassay in sera of 761 euthyroid participants of the population-based Study of Health in Pomerania. Subsequently, analysis of variance and multivariate linear regression analysis were performed. Results: Serum 3,5-T2 concentrations exhibited a right-skewed distribution, resulting in a median serum concentration of 0.24 nM (1st quartile: 0.20 nM; 3rd quartile: 0.37 nM). Significant associations between 3,5-T2 and serum fasting glucose, thyrotropin (TSH), as well as leptin concentrations were detected (p<0.05). Interestingly, the association to leptin concentrations seemed to be mediated by TSH. Age, sex, smoking, and blood lipid profile parameters did not show significant associations with circulating 3,5-T2. Conclusion: Our findings from a healthy euthyroid population may point toward a physiological link between circulating 3,5-T2 and glucose metabolism.