Werner syndrome (WS) (Mendelian Inheritance in Man no. 277700) is an autosomal recessive disorder known for progeroid phenotypes including graying and loss of hair, juvenile cataracts, insulin-resistant diabetes, skin atrophy, premature atherosclerosis, and cancer (1). Mutations in WRN, a RECQ family DNA/RNA helicase gene, have been identified to cause this disease. The mechanism for insulin resistance in WS remains to be elucidated.

Adipocytes secrete a number of hormones (or adipocytokines), such as tumor necrosis factor-α (TNF-α), leptin, adiponectin, and resistin, thereby regulating insulin sensitivity (2). WS patients typically show the lipoatrophic skinny extremities with an obese trunk (1). The accumulated intra-abdominal visceral fat (3) suggests an altered production of adipocytokines.

To investigate the role of adipocytokines in the pathophysiology of WS, we examined the serum levels of TNF-α and adiponectin in WS. Sera sampled from 24 WS patients (14 men and 10 women; 16 with and 8 without diabetes) proven to be homozygous for WRN mutations, and 40 age- and sex-matched normoglycemic healthy volunteers were assayed after informed consent was obtained. Age (43 ± 8.1 vs. 41.6 ± 7.5 years) and BMI (19.4 ± 1.9 vs. 18.8 ± 2.0 kg/m2) were similar for diabetic and nondiabetic WS patients.

The serum level of TNF-α, a mediator of insulin resistance, was significantly elevated in WS regardless of having diabetes (21.8 ± 8.7 pg/ml, P < 0.0001 by Mann-Whitney test) or not having diabetes (14.0 ± 3.2 pg/ml, P = 0.002) compared with the healthy control group (6.05 ± 3.0 pg/ml). Adiponectin levels in diabetic WS patients (3.1 ± 2.9 μg/ml) was significantly lower than in nondiabetic WS patients (11.6 ± 9.2 μg/ml, P = 0.006) or control subjects (14.4 ± 8.8 μg/ml, P < 0.0001). The growing evidence indicates insulin sensitizing as well as antiatherogenic actions of adiponectin and the association of decreased serum adiponectin with insulin resistance, obesity, and type 2 diabetes (2,4). Although WS patients are usually not obese by the definition of BMI, the visceral fat specifically accumulated by an unknown mechanism (3) might cause high TNF-α and low adiponectin levels, characteristics similar to morbid obesity.

We recently reported the successful improvement of glycemic control and insulin sensitivity by pioglitazone in diabetic WS patients (5). Therefore, we next assessed adipocytokines before and after 16 weeks on pioglitazone (15 mg/day) in three diabetic WS patients. The treatment significantly elevated adiponectin levels from 2.57 ± 1.36 to 7.07 ± 2.48 μg/ml (P = 0.03 by paired t test). TNF-α and HbA1c levels showed a tendency to decline from 16.1 ± 4.75 to 3.53 ± 0.58 pg/ml (P = 0.052) and from 7.7 ± 0.6 to 6.4 ± 0.5% (P = 0.17), respectively.

To our knowledge, this is the first study to examine serum adipocytokine levels in WS patients. Reduced insulin sensitivity with increased visceral adiposity is the hallmark of both WS and normal aging. Because pioglitazone achieved improvement of glycemic control as well as correction of adiponectin and TNF-α levels, these cytokines are likely to be at least in part responsible for insulin resistance in WS. Adipocyte function may be a key element linking WRN mutation and the metabolic abnormalities observed in WS. It is also of our interest to know whether pioglitazone and other thiazolidinediones can prevent or delay the onset of diabetes in WS by modulating adipocytokines. Our present findings raise a possibility that pioglitazone could extend the lifespan of WS patients by improving metabolism and preventing early cardiovascular death.

We thank Dr. R.W. Miller (National Cancer Institute) for helpful comments. This work was supported in part by the grants from the Japanese Ministry of Education, Science and Sports and the Ministry of Health, Labor and Welfare.

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