Changes in eye protrusion in patients treated with pioglitazone. Open-label prospective. Thirty-six patients with type 2 diabetes and HbA1c >or= 6.5% were included in a study where pioglitazone was added to current therapy with metformin and sulphonylurea. The degree of eye protrusion before and 26 weeks after treatment with pioglitazone was measured using Krahn's exophthalmometer. Thirteen patients (group A) exhibited an increase of >or= 2 mm and 23 patients (group B) exhibited an increase of < 2 mm (P (between groups) = 0.036). Patients of group A vs. group B had the same BMI, HbA1c and mean doses of pioglitazone, but had lower levels (mean +/- SD) of adiponectin in microg/ml at the start (4.9 +/- 2.1) vs. (7.1 +/- 2.5), P = 0.017 and at the end of study (10.2 +/- 4) vs. (14.9 +/- 5), P = 0.007. Patients with thyroid disturbance were more frequent in group A (five vs. one), P = 0.02. In a logistic regression analysis, thyroid disturbance, low adiponectin levels and pioglitazone dose predicted a significant change in eye protrusion. A subgroup of patients with type 2 diabetes treated with pioglitazone responded with increased eye protrusion. This subgroup showed decreased plasma concentration of adiponectin and more frequent thyroid disturbance, and was treated with higher doses of pioglitazone. The relationship between insulin resistance, thyroid disturbance and thiazolidinedione-induced eye protrusion should be further studied.