Rosiglitazone treatment of patients with extreme insulin resistance and diabetes mellitus due to insulin receptor mutations has no effects on glucoseand lipid metabolism

Background. Rosiglitazone, a thiazolidinedione (TZD), increases insulin sen sitivity by reducing levels of plasma NEFA, triglycerides (TG), glucose and serum insulin. Rosiglitazone treatment decreases insulin resistance in typ e 2 diabetic patients, but no data exist concerning rosiglitazone treatment of patients with syndromes of extreme insulin resistance. Objectives. To evaluate whether hyperglycaemia in two lean patients with pr imary severe insulin resistance due to insulin receptor (IR) mutations and diabetes mellitus could be reduced by supplement of rosiglitazone for 180 d ays and secondary, to evaluate the effects on plasma NEFA, TG, Apo B, PAI-1 and serum insulin. Subjects. Both patients (brothers) have known mutations in the IR gene loca lized to the tyrosine kinase domain and a deletion of exon 17 in part of th eir IR mRNA. Prior to the study the HbA(1C) values were higher than 10% in both patients for more than 12 months during treatment with insulin and met formin. Results. After 180 days of rosiglitazone supplement (8 mg day(-1)), no chan ges were observed in fasting plasma glucose and HbA(1C). Incremental plasma glucose areas under the curves during a 75-g oral glucose tolerance test ( OGTT) were unchanged. Likewise, no improvements were seen in either first o r second phase insulin secretion during a 0.3 g kg(-1) intravenous glucose tolerance test (IVGTT). Fasting plasma VLDL and HDL cholesterol, TG and Apo B levels were unchanged, whereas a small increase was seen in total and LD L cholesterol levels. Fasting plasma NEFA increased by 51% in KC after 90 d ays of treatment, and after 180 days plasma NEFA was still 26% higher, when compared with pretreatment levels. In BC an initial 16% decrease was seen in plasma NEFA after 90 days of treatment. Plasma NEFA was increased 14% af ter 180 days of treatment, when compared with pretreatment levels, but 35% when compared with day 90. Plasma PAM decreased in both patients after 45 a nd 90 days of treatment but the decrease was only maintained in KC (47%). Conclusions. Rosiglitazone treatment, in combination with insulin and metfo rmin, of patients with severe primary insulin resistance due to IR mutation s and diabetes mellitus, had no impact on the measured estimates of glucose and lipid metabolism. These findings may suggest that the effect of rosigl itazone on glucose and lipid metabolism are dependent on the presence of in tact IR protein.