Shin-ichi Gorogawa

Probucol preserves pancreatic β-cell function through reduction of oxidative stress in type 2 diabetes

Oxidative stress is induced under diabetic conditions and causes various forms of tissue damage in patients with diabetes. Recently, pancreatic beta-cells have emerged as a putative target of oxidative stress-induced tissue damage and this seems to explain in part the progressive deterioration of beta-cell function in type 2 diabetes. As a step toward clinical trial of antioxidant for type 2 diabetes, we investigated the possible anti-diabetic effects of probucol, an antioxidant widely used as an anti-hyperlipidemic agent, on preservation of beta-cell function in diabetic C57BL/KsJ-db/db mice. Probucol-containing diet was given to mice from 6 to 16 weeks of age. Immunostaining for oxidative stress markers such as 4-hydroxy-2-nonenal (HNE)-modified proteins and heme oxygenase-1 revealed that probucol treatment decreased reactive oxygen species (ROS) in pancreatic islets of diabetic animals. Oxidative stress is known to enhance apoptosis of beta-cells and to suppress insulin biosynthesis, but probucol treatment led to preservation of beta-cell mass and the insulin content. According to intraperitoneal glucose tolerance tests, the probucol treatment preserved glucose-stimulated insulin secretion and improved glucose tolerance at 10 and 16 weeks: insulin, 280+/-82 vs. 914+/-238 pmol/l (120 min, at 16 weeks; P<0.05); glucose, 44.6+/-2.4 vs. 35.2+/-2.6 mmol/l (120 min, at 16 weeks; P<0.05). Thus, our present observations demonstrate the potential usefulness of probucol for treatment of type 2 diabetes.

Association of -786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

Abstract Aims/hypothesis. Endothelial derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with abnormal vasomotility and impaired local blood flow. A decrease in local blood flow has been reported to cause insulin resistance. The aim of this study was to examine a possible association of two eNOS polymorphisms, Glu298Asp (G894T) in exon 7 and -786T-C mutation with insulin resistance. Methods. Genotypes of both Glu298Asp and -786T-C mutation were examined by the PCR-RFLP method. Plasma nitrate and nitrite concentrations were also measured. Results. The allele frequencies of both polymorphisms showed no considerable differences in 233 non-diabetic subjects and 301 patients with Type II (non-insulin-dependent) diabetes mellitus. Non-diabetic subjects with the -786C allele had (p<0.05) higher fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the -786T/ -786T genotype. Diabetic subjects with -786C allele showed higher HbA1c than those with the -786T/-786T genotype. A euglycaemic hyperinsulinemic clamp study done on 71 of the 301 patients showed a lower glucose infusion rate in diabetic patients with the -786C allele than those without it. In diabetic patients with the -786C allele, plasma nitrate and nitrite concentrations were lower than in subjects without it (p=0.026). No differences were observed between mutant carriers of Glu298Asp and non-carriers among both non-diabetic subjects and Type II diabetic patients. Conclusions/interpretation. The -786T-C mutation of the eNOS gene is associated with insulin resistance in both Japanese non-diabetic subjects and Type II diabetic patients.

The Influence of Glycemic Control on the Prognosis of Japanese Patients Undergoing Percutaneous Transluminal Angioplasty for Critical Limb Ischemia

OBJECTIVE To reveal the influence of preoperative factors on the prognosis of patients undergoing percutaneous transluminal angioplasty (PTA) for critical limb ischemia (CLI). RESEACH DESIGN AND METHODS We 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. RESULTS The 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). CONCLUSIONS Diabetes 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.

High prevalence of glucose intolerance in Japanese patients with peripheral arterial disease

Recent studies revealed that patients with coronary artery disease and stroke have an increased prevalence of glucose intolerance [1,2]. No corresponding data are, however, available in patients with peripheral arterial disease (PAD). In this study we examined glucose tolerance in patients with PAD, using 75-g oral glucose tolerance test (OGTT). We recruited 329 consecutive patients who underwent percutaneous transluminal angioplasty (PTA) for PAD between 2005 and 2006 in Kansai Rosai Hospital, Hyogo, Japan. As shown in Fig. 1a, 210 patients (64%) were diagnosed with overt diabetes mellitus (ODM) which included people already treated for diabetes mellitus (DM) or met the following criteria: fasting plasma glucose (FPG) level 7 mmol/l, casual plasma glucose level 11.1 mmol/l, or haemoglobin A1c (HbA1c) level 6.5%. They were 70 9 years old and for those with established diabetes their duration was 18 12 years, HbA1c level

Characteristics of peripheral arterial disease in Japanese type 2 diabetic patients

To the Editor: It is well known that diabetes is an important factor in the progression of peripheral arterial disease [1, 2]. Indeed, peripheral arterial disease in diabetic patients often leads to extremity amputation and has a poorer prognosis and higher mortality [3, 4], suggesting that vessel lesions are even worse in diabetes. There have been few reports, however, that directly compare the characteristics of peripheral arterial disease in type 2 diabetic and nondiabetic subjects as observed by angiography. The aim of this study was to directly compare the characteristics of peripheral arterial disease in type 2 diabetic and nondiabetic subjects according to the TransAtlantic InterSociety Consensus (TASC) [1, 5], which is thought to provide strong worldwide consensus. The TASC classifies vessel lesions into four categories based on severity of the lesions from a therapeutic point of view. The categories are as follows: A, an intravascular intervention is recommended; B, an intravascular intervention tends to be recommended; C, a surgical operation tends to be recommended; D, a surgical operation is recommended. To examine the characteristics of peripheral arterial disease in type 2 diabetic subjects, we screened patients in Kansai Rosai Hospital from January 2000 to July 2004, and recruited 211 patients who had significant stenosis in the lower limb arteries upon observation by aortography and who were thought to need revascularisation. We believe that revascularisation is necessary when patients meet the following criteria: (1) patients have symptoms such as rest pain, foot ulcer, foot gangrene (Fontaine classification III or IV) and significant stenosis upon observation by aortography; or (2) subjects have symptoms such as psychroesthesia, numbness, intermittent claudication (Fontaine classification I or II), significant stenosis, and are resistant to 6-month exercise and internal medication. Clinical characteristics and features of the vessel lesions such as severity, length, calcification, and distribution were compared between type 2 diabetic (n=122) and nondiabetic subjects (n=89). Coronary artery disease was diagnosed when there was clinical evidence of angina or myocardial infarction, abnormalities on electrocardiography, or significant stenosis or obstruction of the coronary artery on angiography. Diabetes was diagnosed when the fasting glucose level was 7 mmol/l or higher, HbA1c was 6.5% or greater, or the patient was currently on antidiabetic treatment. In this study, hypertension was provisionally diagnosed when systolic blood pressure was 140 mmHg or higher and/or diastolic blood pressure was 90 mmHg or higher, or when the patient was taking anti-hypertensive medication. Hyperlipidaemia was provisionally diagnosed when total cholesterol was 5.7 mmol/l or more, or when the patient was taking anti-hyperlipidaemic medication. The criteria for diagnosis of nephropathy were continuous macro-albuminuria or a serum creatinine level of 140 μmol/l or higher. We evaluated the results of aortography according to TASC. A total of 122 subjects (58%) had diabetes with a duration of 15.±12.5 years (mean±SD). Type 2 diabetic and non-diabetic subjects showed similar age (68.2±8.5 and 69.7±9.9 years) and sex distribution (male: 74.6 and 84.3%). There was no difference in the proportion of patients with a smoking habit (41.7 and 46.4%), hypertenS. Gorogawa . O. Iida . M. Ikeda . S. Nanto Department of Internal Medicine, Kansai Rosai Hospital, 3-1-69 Inabasco, Amagasaki, Hyogo, Japan