Metabolic Improvement and Abdominal Fat Redistribution in Werner Syndrome by Pioglitazone

To the Editor: Werner syndrome is a rare autosomal recessive disorder known for its premature aging phenotype including loss of hair, cataracts, atrophy of peripheral soft tissue, diabetes mellitus, and atherosclerosis. Mutations in the deoxyribonucleic acid (DNA) helicase gene have been identified as the cause of this disease.1 One common feature of Werner syndrome is insulin resistance, but the mechanism by which insulin resistance occurs in this syndrome is unknown. We have previously described that visceral fat accumulation is strongly associated with insulin resistance in Werner syndrome.2 We report a case of Werner syndrome in which administration of pioglitazone, a thiazolidinedione derivative, improved insulin sensitivity, glucose tolerance, lipid metabolism, and abdominal fat distribution. A 46-year old woman with Werner syndrome came to our hospital for glycemic control. After obtaining written informed consent, we analyzed genomic DNA from peripheral leukocytes, which revealed that the patient was homozygote for type 4 mutation in the Werner helicase gene.3 She was thin (body mass index=16.5 kg/m2) but had accumulated visceral fat in excess, as determined using a computed tomography scan at the umbilical level (visceral fat area=111.6 cm2, normal range for Japanese women <90).4 She also had type IIb hyperlipidemia according to World Health Organization classification. She had significant insulin resistance, as determined using an insulin sensitivity index calculated from the value of steady state plasma glucose (19.4, normal range 55–162).5 After 1 week of treatment with diet, pioglitazone 15 mg daily was initiated. After 16 weeks of pioglitazone treatment, the patient's fasting plasma glucose had decreased from 198 mg/dL to 115 mg/dL, glycated hemoglobin A1c from 8.4% to 5.9% (normal=5.9% or less), serum total cholesterol from 270 mg/dL to 209 mg/dL (normal=130–220 mg/dL), serum triglyceride from 301 mg/dL to 90 mg/dL (normal=80–150 mg/dL), and serum high-density lipoprotein-cholesterol increased from 52 mg/dL to 64 mg/dL (normal≥40 mg/dL). Fasting serum insulin decreased from 45.5 μU/mL to 13.0 μU/mL (normal=6–26 μU/mL), and insulin sensitivity index had improved to 24.9 (Figure 1, July to November). Although the patient gained weight, from 35.9 kg to 39.0 kg, during the period, her visceral fat area (V) decreased to 104.3 cm2. In contrast, abdominal subcutaneous fat area (S) increased from 162.5 cm2 to 218.5 cm2. As a result, her V/S ratio decreased from 0.69 to 0.48 (normal range for Japanese <0.4).4 Liver function monitored using serum transaminase level did not show abnormality throughout the period. Metabolic parameters and abdominal fat areas before and during pioglitazone treatment. HDL=high-density lipoprotein; Hb=hemoglobin. These results suggest that pioglitazone was effective in ameliorating impaired insulin sensitivity, glycemic control, and hyperlipidemia in the patient. Human and animal studies have shown that a possible mechanism for thiazolidinedione to improve insulin sensitivity is through the specific promotion of subcutaneous adipocyte differentiation through the activation of peroxisome proliferator-activated receptor-γ.6 It has also been reported that troglitazone-treatment of type 2 diabetic patients resulted in subcutaneous fat increase in accordance with improvement of glucose tolerance.7 It was also proven experimentally that, in lipoatrophic diabetes mellitus, lack of fat is directly associated with insulin resistance and hyperglycemia.8 Marked atrophy of soft tissues in the extremities, a characteristic feature of Werner syndrome, may at least in part account for the insulin resistance. Leptin administration was recently reported to ameliorate severe insulin resistance in leptin-deficient lipodystrophic patients,9 but in our patient, serum leptin levels were in the normal range before and during the pioglitazone treatment (data not shown). Therefore, in this case, induction of subcutaneous fat using pioglitazone would have accompanied production of another mediator than leptin to improve insulin sensitivity. Recently, accumulating evidence suggests that thiazolidinedione has direct antiatherosclerotic effects on vascular cells.10 Because atherosclerotic vascular disease is a leading cause of middle-age mortality in Werner syndrome, pioglitazone may provide an ideal choice for the treatment of metabolic disorders to improve prognosis of this syndrome.