A missense mutation in the human type 2 5’-deiodinase (5’DII) gene is associated with obesity, diabetes and insulin resistance

The Metabolic Syndrome characterized by obesity, hypertension, insulin resistance and glucose intolerance/diabetes is a multifactorial disease caused by several susceptibility genes and modified by environmental factors. Polymorphisms in several candidate genes such as ß-3 adrenergic receptor, insulin receptor substrate-1, peroxisome proliferator-activated receptor γ, fatty acid binding protein-2 have shown to be associated with this syndrome. An important determinant of energy and glucose metabolism is the action of thyroid hormones stimulating resting metabolic rate and modulating the number of adrenergic receptors. 5’DII, expressed in skeletal muscle and brown adipose tissue, is regulated by metabolic stressors and its transcription is stimulated by the ß-3adrenergic pathway. A Thr92Ala missense mutation in 5’DII demonstrated a strong association with insulin resistance. We analyzed polymorphisms in the 5’DII gene by PCR and restriction fragment length polymorphism analysis as a candidate gene for obesity and insulin resistance in a population of morbidly obese patients. The patients are a heterogeneous group with BMI ranging between 29 and 75kg/m2, recruited for a study on the efficiency of gastric banding for weight reduction, and 60% thereof eventually underwent the operation. Most of them are hypertensive and hyperinsulinemic, their blood cholesterol level is morbidly increased, about 13% have type 2 diabetes mellitus. Of the 151 patients examined, 67 had a Thr92Ala mutation in the 5’DII gene, 9 of them were homozygous. A subgroup of 20 patients showed symptoms of type 2 diabetes; in this group, 14 had the 5’DII mutation. We found a polymorphism frequency of 0,25 in the whole group, which was strongly increased in the group with type 2 diabetes mellitus. These data confirm an association of the Thr92Ala mutation in the 5’DII gene with type 2 diabetes in a group of morbidly obese patients, suggesting a role of local T3-production by 5’DII in the regulation of energy metabolism.

Supported by EU, DFG and foundation