Is central obesity a good predictor of carotid atherosclerosis in Japanese type 2 diabetes with metabolic syndrome?

Metabolic syndrome has been revealed to be a major risk factor for cardiovascular disease (CVD) and early mortality in non-diabetic and diabetic patients. In 2005, the International Diabetes Federation (IDF) and the Examination Committee of Criteria for Diagnosis of Metabolic Syndrome in Japan published new definitions of metabolic syndrome in which central obesity was an indispensable factor. However, the significance of this new definition to CVD in type 2 diabetes has not yet been clarified. A cross-sectional study was conducted with 294 Japanese type 2 diabetic patients without known cardiovascular disease to evaluate the association between metabolic syndrome defined by this new definition and carotid atherosclerosis, and the significance of central obesity for the prediction of the development of carotid atherosclerosis. In a multivariate regression analysis, metabolic syndrome but not central obesity was significantly associated with carotid intima-media thickness (IMT) independent of known cardiovascular risk factors (p<0.05). In addition, whereas carotid IMT was significantly increased according to the increase in the number of components of metabolic syndrome, it was not significantly different between the groups with the same number of components of metabolic syndrome with or without central obesity. These findings suggest that the prediction of the development of carotid atherosclerosis in Japanese type 2 diabetic patients could be improved by the assessment of aggregation of components of metabolic syndrome rather than with or without metabolic syndrome by this new definition.

PAX6 mutation as a genetic factor common to aniridia and glucose intolerance.

A paired homeodomain transcription factor, PAX6, is a well-known regulator of eye development, and its heterozygous mutations in humans cause congenital eye anomalies such as aniridia. Because it was recently shown that PAX6 also plays an indispensable role in islet cell development, a PAX6 gene mutation in humans may lead to a defect of the endocrine pancreas. Whereas heterozygous mutations in islet-cell transcription factors such as IPF1/IDX-1/STF-1/PDX-1 and NEUROD1/BETA2 serve as a genetic cause of diabetes or glucose intolerance, we investigated the possibility of PAX6 gene mutations being a genetic factor common to aniridia and diabetes. In five aniridia and one Peters' anomaly patients, all of the coding exons and their flanking exon-intron junctions of the PAX6 gene were surveyed for mutations. The results of direct DNA sequencing revealed three different mutations in four aniridia patients: one previously reported type of mutation and two unreported types. In agreement with polypeptide truncation and a lack of the carboxyl-terminal transactivation domain in all of the mutated PAX6 proteins, no transcriptional activity was found in the reporter gene analyses. Oral glucose tolerance tests revealed that all of the patients with a PAX6 gene mutation had glucose intolerance characterized by impaired insulin secretion. Although we did not detect a mutation within the characterized portion of the PAX6 gene in one of the five aniridia patients, diabetes was cosegregated with aniridia in her family, and a single nucleotide polymorphism in intron 9 of the PAX6 gene was correlated with the disorders, suggesting that a mutation, possibly located in an uncharacterized portion of the PAX6 gene, can explain both diabetes and aniridia in this family. In contrast, the patient with Peters' anomaly, for which a PAX6 gene mutation is a relatively rare cause, showed normal glucose tolerance (NGT) and did not show a Pax6 gene mutation. Taken together, our present observations suggest that heterozygous mutations in the PAX6 gene can induce eye anomaly and glucose intolerance in individuals harboring these mutations.