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 carboxylterminal 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. Diabetes 51:224 -230, 2002

OBJECTIVE -To evaluate whether low-grade inflammation contributes to early-stage advanced carotid atherosclerosis in young subjects with type 1 diabetes.RESEARCH DESIGN AND METHODS -The mean and maximum (max) intimamedia thicknesses (IMT) of the carotid artery were assessed using ultrasound B-mode imaging in 55 patients with type 1 diabetes (22 men and 33 women, aged 22.1 Ϯ 3.6 years (Ϯ SD), duration of diabetes 14.2 Ϯ 5.7 years) and 75 age-matched healthy nondiabetic subjects (28 men and 47 women). High-sensitive C-reactive protein (hs-CRP) levels were measured with a latex-enhanced immunonephelometer.RESULTS -The patients with type 1 diabetes had significantly higher hs-CRP levels (median 0.35, range 0.05-1.47 mg/l vs. median 0.14, range 0.05-1.44 mg/l; P ϭ 0.001) as well as significantly higher mean IMT and max IMT than the nondiabetic subjects (mean IMT 0.76 Ϯ 0.09 vs. 0.72 Ϯ 0.04 mm, P ϭ 0.003; max IMT 0.84 Ϯ 0.11 vs. 0.77 Ϯ 0.06 mm, P Ͻ 0.0001). Hs-CRP levels were significantly correlated with the mean and max IMT of patients with type 1 diabetes and with the max IMT of nondiabetic patients. Multivariate regression analyses for both diabetic and nondiabetic subjects as a single group showed that hs-CRP levels are independently correlated with the mean IMT and max IMT levels (P ϭ 0.002 and P ϭ 0.023, respectively) as well as with diastolic blood pressure, sex, and duration of diabetes.CONCLUSIONS -Our data indicate that hs-CRP levels are elevated in young patients with type 1 diabetes, possibly corresponding with early-stage advanced carotid atherosclerosis.

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OBJECTIVETo reveal the influence of preoperative factors on the prognosis of patients undergoing percutaneous transluminal angioplasty (PTA) for critical limb ischemia (CLI).RESEACH DESIGN AND METHODSWe recruited 278 Japanese patients who underwent PTA for CLI between 2003 and 2009. The outcome measures were mortality and major amputation. Cox proportional hazards regression analyses were performed.RESULTSThe prevalence of diabetes was 71%, and A1C was 7.0 ± 1.4%. The follow-up period was 90 ± 72 weeks, and 48 patients underwent major amputations and 89 died. The presence of diabetes in the whole population and A1C level in the diabetic population had no influence on morality; rather, mortality was associated with age (P = 0.007), impaired activities of daily living (P < 0.001), hemodialysis (P < 0.001), and albumin level (P = 0.010). In contrast, the presence of diabetes and A1C level had significant association with major amputation (P = 0.012 and P = 0.007, respectively). The quartile analysis showed that diabetic subjects with an A1C ≥6.8%, but not <6.8%, had a significantly higher risk of major amputation than nondiabetic subjects. The adjusted hazard ratio of diabetes with A1C ≥6.8% was 2.907 (95% CI 1.606–5.264) (P < 0.001).CONCLUSIONSDiabetes with poor glycemic control is associated with major amputation, but not mortality, in CLI patients undergoing PTA. Prognostic indicators seem somewhat different between survival and limb salvage in the population.

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