Pioglitazone-reduced insulin resistance in patient with Werner syndrome

Abstract

Werner syndrome is a rare disorder that has provided a useful model for the study of human ageing. Patients with Werner syndrome usually display an aged appearance with various features including loss of hair, cataracts, atrophy of skin and peripheral fat, and diabetes. Mutations in the DNA helicase gene have been shown to be responsible for this disorder. One common feature of Werner syndrome is insulin resistance. However, as is the case in most patients with non-insulin-dependent diabetes mellitus (NIDDM), the precise mechanism underlying the disease is not known. As a step toward understanding the molecular mechanism of insulin resistance in Werner syndrome, we used pioglitazone, a new antidiabetic drug classified as a thiazolidinedione derivative, in a patient with Werner syndrome. Thiazolidinediones improve hyperglycaemia by enhancing insulin sensitivity without stimulating insulin secretion. These drugs have been shown to bind peroxisome proliferator-activated receptor (PPAR ), a dominant activator of fat-cell differentiation. This receptor is likely to mediate the antidiabetic effects of thiazolidinediones, since their affinity to PPAR correlates well with the strength of their effect as insulin sensitisers. A 53-year-old man with Werner syndrome was admitted for glycaemic control. The diagnosis was based on his clinical features and the reduced life-span of cultured fibroblasts. Although he was thin (body-mass index 14·2 kg/m) and had only a small amount of subcutaneous fat (%fat 4·9%), he had a moderate degree of insulin resistance as judged by the exogenous glucose infusion rate (GIR) during euglycaemic hyperinsulinaemic clamp (3·7 mg/kg per min, normal value 10·5 [SD 2·2]). His glycaemia was poorly controlled with a sulfonylurea agent, gliclazide. Written informed consent was obtained and the study was approved by the Institutional Ethical Committee. After 1 week of treatment by dietary restriction alone, pioglitazone 30 mg daily was initiated. After 12 weeks, the GIR had improved to 5·2 mg/kg per min (figure). This effect on the insulin sensitivity was similar to those observed in obese NIDDM patients; according to our data, the average GIR values for NIDDM patients (body-mass index 23 [SD 1·8]%, HbA1c 8·4 [1·4]%) before and after pioglitazone treatment was 8·2 [2·2] and 9·2 [2·0] mg/kg per min, respectively [p=0·003]; Kawamori R, Yamasaki Y, unpublished data). After 12 weeks of pioglitazone treatment, the patient’s fasting plasma glucose had decreased from 187 mg/dL (10·4 mmol/L) to 105 mg/dL (5·8 mmol/L) and glycated haemoglobin from 8·3% to 7·8%. All these glycaemic values deteriorated immediately after discontinuation of pioglitazone (figure). The fasting plasma insulin remained unchanged. These results suggest that pioglitazone was effective in ameliorating impaired insulin sensitivity and thus improved the glycaemic control in our patient. Recently, it was suggested that thiazolidinedione derivatives have direct effects on some tissues other than the adipose tissue, which has been considered to be the target organ of thiazolidinedione derivatives. Among the two isoforms of PPAR , PPAR 1, and PPAR 2, which can be activated to the same extent by a thiazolidinedione derivative, PPAR 1 (and maybe PPAR 2 also) seems to be weakly expressed in skeletal muscle. Also, a weak expression of PPAR 1 can be observed in liver, which seems to increase glucose uptake in response to pioglitazone. Thus, especially for this patient with Werner syndrome whose %fat was as low as 4·9%, the effects of pioglitazone on those non-adipose tissues may have had a role in improving the insulin sensitivity.