Werner’s syndrome (WS) is a disease of adult progeria characterized by various phenotypical abnormalities, including prematurely graying hair, a bird-like face, slender extremities, cataracts, and endocrine dysfunction. Mutations in the DNA helicase gene WRN have been shown to be responsible for this disorder. The condition is associated with glucose intolerance in ∼70% of patients, a complication predominantly resulting from insulin resistance. Since thiazolidinediones have been shown to enhance insulin sensitivity in patients with insulin resistance, we have treated a WS patient with pioglitazone.
A 58-year-old woman with WS was admitted for improvement of glycemic control. The diagnosis of WS was based on her clinical features and the reduced life-span of her fibroblasts in vitro. The genotype of this patient was heterozygote with mutation one in the WS gene, suggesting a compound heterozygote (1). Her glycemia was poorly controlled (HbA1c 9.4%) without any hypoglycemic agents or insulin. Liver dysfunction was also observed (aspartate aminotransferase 123, alanine aminotransferase 108). After 1 week of treatment with dietary restriction alone, administration of 15 mg pioglitazone daily was initiated. After 16 weeks of pioglitazone treatment, fasting plasma glucose improved from 152 (before pioglitazone) to 113 mg/dl, and the ameliorating effects of pioglitazone on insulin resistance were also indicated by the decrease in immunoreactive insulin from 39 (before pioglitazone) to 17 μU/ml. HbA1c fell to within the normal range from 9.4%, and liver dysfunction also normalized.
Adiponectin, a protein secreted by adipose tissue, is present at lower levels in the plasma in subjects with obesity or type 2 diabetes and is closely correlated with the degree of insulin resistance as assessed by glucose clamp technique (2). Adiponectin also has a number of vascular protective effects. Although plasma adiponectin levels were very low (1.83 μg/ml) in this patient, they increased to 9.7 μg/ml at 12 weeks and 17.4 μg/ml at 24 weeks of pioglitazone treatment. In contrast, leptin levels were initially high (20.3 ng/ml) but decreased to the high end of normal (11.2 ng/ml) following pioglitazone treatment. Interestingly, serum levels of high-sensitivity C-reactive protein were initially >0.5 mg/dl but normalized to 0.03 mg/dl at 12 weeks of pioglitazone treatment.
These results suggest that pioglitazone was effective in ameliorating impaired insulin sensitivity, thereby improving glycemic control. It may also counteract atherosclerosis by diminishing inflammatory processes. Pioglitazone activates peroxisome proliferator-activated receptor γ, which increases the triglyceride content of white adipose tissue and lessens the triglyceride content in liver and muscle, leading to amelioration of insulin resistance (3). In fact, liver dysfunction that had been seen in this patient for years returned to normal after 12 weeks of pioglitazone treatment. Pioglitazone may induce adipocyte differentiation from preadipocytes, allowing further uptake of energy overflow as fatty acids and also leading to additional production of adiponectin, which decreases insulin resistance. Additionally, the apoptosis of large adipocytes may lead to decreases in tumor necrosis factor-α, free fatty acids, and resistin (4), resulting in lowered insulin resistance and inflammation.
The insulin resistance and low adiponectinemia of WS may result from alterations in “adipocyte.” Abnormalities of fat distribution have been reported in WS patients (5), and, indeed, though the present patient was thin and had lipoatrophy in the extremities, she had augmented abdominal adipose tissue. The area ratio of visceral to subcutaneous fat was 0.51 by abdominal computed tomography, though this ratio was reduced to 0.36 at 24 weeks of pioglitazone treatment, suggesting that the effects of pioglitazone on adipose tissues could have had a role in improving insulin sensitivity. Furthermore, this effect of pioglitazone might retard, at least partly, the progress of WS, though this remains to be observed in the future.