Rosiglitazone treatment of patients with extreme insulin resistance and diabetes mellitus due to insulin receptor mutations has no effects on glucose and lipid metabolism.
BACKGROUND
Rosiglitazone, a thiazolidinedione (TZD), increases insulin sensitivity by reducing levels of plasma NEFA, triglycerides (TG), glucose and serum insulin. Rosiglitazone treatment decreases insulin resistance in type 2 diabetic patients, but no data exist concerning rosiglitazone treatment of patients with syndromes of extreme insulin resistance.


OBJECTIVE
To evaluate whether hyperglycaemia in two lean patients with primary severe insulin resistance due to insulin receptor (IR) mutations and diabetes mellitus could be reduced by supplement of rosiglitazone for 180 days and secondary, to evaluate the effects on plasma NEFA, TG, Apo B, PAI-1 and serum insulin.


METHODS
Both patients (brothers) have known mutations in the IR gene localized to the tyrosine kinase domain and a deletion of exon 17 in part of their IR mRNA. Prior to the study the HbA1c values were higher than 10% in both patients for more than 12 months during treatment with insulin and metformin.


RESULTS
After 180 days of rosiglitazone supplement (8 mg day(-1)), no changes were observed in fasting plasma glucose and HbA1c. 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 or 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 LDL cholesterol levels. Fasting plasma NEFA increased by 51% in KC after 90 days 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% after 180 days of treatment, when compared with pretreatment levels, but 35% when compared with day 90. Plasma PAI-1 decreased in both patients after 45 and 90 days of treatment but the decrease was only maintained in KC (47%).


CONCLUSIONS
Rosiglitazone treatment, in combination with insulin and metformin, of patients with severe primary insulin resistance due to IR mutations and diabetes mellitus, had no impact on the measured estimates of glucose and lipid metabolism. These findings may suggest that the effect of rosiglitazone on glucose and lipid metabolism are dependent on the presence of intact IR protein.
Vestergaard
H
H
Department of Endocrinology, Herlev Hospital, University of Copenhagen, Denmark. heve@herlevhosp.kbhamt.dk
Lund
S
S
Pedersen
O
O
D000293:Adolescent; D000328:Adult; D001055:Apolipoproteins B / Q000097:blood / Q000187:drug effects; D015992:Body Mass Index; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000235:genetics*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011972:Receptor, Insulin / Q000235:genetics*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D014280:Triglycerides / Q000097:blood
D001055:Apolipoproteins B; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D011972:Receptor, Insulin