FUT2 non-secretor status is associated with Type 1 diabetes susceptibility in Japanese children.

AIM: To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children. METHODS: We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined. RESULTS: The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]. CONCLUSIONS: The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children.

Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age-specific effects of cis-regulatory haplotypes at 17q12-q21.

AIMS: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. METHODS: We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. RESULTS: Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. CONCLUSIONS: The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.

Association of postprandial hypertriglyceridemia and carotid intima-media thickness in patients with type 2 diabetes.

OBJECTIVE: Serum triglyceride levels are important in the development of atherosclerosis. Although triglyceride levels are generally increased in the postprandial periods, the association between postprandial triglyceride (pTG) levels and atherosclerosis has not been investigated in diabetic patients. To investigate the role of pTG levels in atherosclerosis, we examined the correlation between pTG levels and carotid intimal-medial thickness (IMT). RESEARCH DESIGN AND METHODS: Carotid IMT was measured by ultrasonography in 61 patients with type 2 diabetes. Plasma glucose (PG), insulin, total cholesterol, triglycerides, and HDL cholesterol levels were measured after overnight fasting and 4 h after a meal. RESULTS: Carotid IMT of the patients with fasting hypertriglyceridemia was greater than that of the patients with normal fasting triglyceride (fTG) levels (0.85+/-0.12 vs. 0.76+/-0.14 mm; P = 0.02). The carotid IMT was increased in the patients with pTG levels >2.27 mmol/l. The normo-normo (NN) and normo-hyper (NH) groups consisted of patients with normal fTG levels but with pTG levels <2.27 and >2.27 mmol/l, respectively. Patients with both hypertriglyceridemia and pTG levels >2.27 mmol/l formed the hyper-hyper (HH) group. Carotid IMT was significantly increased in the NH (0.86+/-0.13 mm) and HH (0.85+/-0.12 mm) groups compared with the NN group (0.73+/-0.13 mm; P<0.01). Although postprandial PG, pTG, and fasting LDL cholesterol levels were all independently correlated with carotid IMT, pTG levels had the strongest statistical influence (P = 0.002). CONCLUSIONS: Postprandial hypertriglyceridemia despite normal fTG levels may be an independent risk factor for early atherosclerosis in type 2 diabetes.

Serum leptin level as an indicator to predict the clinical efficacy of troglitazone in patients with type 2 diabetes mellitus.

Troglitazone is effective in approximately 50% in patients with type 2 diabetes (NIDDM). In this study, we investigated the relations between serum leptin levels and clinical efficacy of troglitazone. Forty-five type 2 diabetic patients (23 men and 22 women) from our outpatient clinic were treated with troglitazone 400 mg daily for 12 weeks. Fasting plasma glucose (FPG), HbA1c, body weight, serum insulin and leptin concentrations were measured before and after troglitazone treatment. After 12 weeks of troglitazone treatment, FPG (before versus after, 179+/-33 vs. 138+/-26 mg/dl, mean+/-SD), HbA1c (7.8+/-1.3 vs. 6.9+/-1.0%), IRI (8.3+/-4.3 vs. 6.3+/-3.4 microU/ml) and HOMA-R index (homeostasis model assessment of insulin resistance) (3.8+/-2.4 vs. 2.2+/-1.3) decreased significantly, while body mass index (BMI) slightly increased (26.3+/-3.5 vs. 26.6+/- 3.6 kg/m(2)), and serum leptin remained unchanged (8.5+/-7.2 vs. 9.1+/-8.7 ng/ml). Reduction in FPG (DeltaFPG) after troglitazone treatment were correlated with reduction in HOMA-R (DeltaHOMA-R) (r=0.721, P<0.0001). DeltaFPG was correlated with serum leptin (r=0.441, P<0.01), HOMA-R (r=0.460, P<0.01) and FPG (r=-0.781, P<0.0001) at baseline, but not with BMI and serum IRI at baseline. Furthermore, serum leptin at baseline was significantly correlated with DeltaHOMA-R (r=0.634, P<0.01). Leptin concentration before treatment therefore, can be used as an predictor for clinical efficacy of troglitazone in patients with type 2 diabetes.

Increased activity of membrane glycoprotein PC-1 in the fibroblasts from non-insulin-dependent diabetes mellitus patients with insulin resistance.

Although most of patients with non-insulin-dependent diabetes mellitus (NIDDM) have insulin resistance, it is unknown whether a molecule might interfere with insulin action. Membrane glycoprotein PC-1 (plasma cell antigen-1), which inhibits insulin receptor tyrosine kinase activity, was isolated from fibroblasts of NIDDM patients. Because PC-1 content in skeletal muscle and adipose tissue correlated with whole body insulin sensitivity, PC-1 might play a role in insulin resistance. In order to know whether PC-1 activity of fibroblasts is also elevated in Japanese NIDDM patients, and whether PC-1 activity correlates with the parameters of insulin resistance in vivo or not, we measured PC-1 activity of cultured fibroblasts from 17 patients with NIDDM and seven healthy controls. PC-1 activity of the NIDDM patients was 85.2 +/- 33.1 nmol/mg per min (mean +/- S.D.), and was higher than that of healthy controls (42.6 +/- 12.7 nmol/mg per min, P = 0.0002). Insulin sensitivity was measured in 11 of 17 NIDDM patients by the artificial pancreas. PC-1 activity of the patients with insulin resistance (glucose infusion rate < 3.0 mg/kg per min, n = 7) was elevated to 99.9 +/- 31.9 nmol/mg per min, while that of the other patients (n = 4) was 55.3 +/- 7.5 nmol/mg per min (P = 0.003). In conclusion, glycoprotein PC-1 activity of dermal fibroblasts is correlated with insulin resistance in patients with NIDDM.

Acutely exacerbated hypertension and increased inflammatory signs due to radiation treatment for metastatic pheochromocytoma.

Hypertension and norepinephrine hypersecretion in a 59-year-old woman suffering from malignant pheochromocytoma with multiple metastases were appropriately controlled with alpha- and beta- blockers, and alpha-methyltyrosine (alpha-MT), a catecholamine-synthesis inhibitor. Metastasized vertebrae were treated with external radiation to relieve pain, but this treatment had to be interrupted at a total dose of 20 Gy because the patient suffered acutely exacerbated hypertension (200/110 mmHg), tachycardia (160 beats/min) and a low-grade fever. Simultaneously her serum levels of LDH, potassium, urea nitrogen, creatinine, white blood cell count, CRP and norepinephrine were significantly increased, suggesting that this episode was due to radiation-induced tissue destruction and the leakage of catecholamines and possibly interleukin-6, a cytokine mediating inflammation which is reportedly present in pheochromocytoma. The marked hypertension was controlled by continuous i.v. administration of phentolamine and propranolol. Although radiation therapy effectively relieves pain due to neoplasmic metastasis to the bone, physicians should be aware that life-threatening complications such as the above occur in malignant pheochromocytoma. Sufficient pretreatment with adrenergic blocking agents and/or alpha-MT and careful monitoring of the patient's general condition during radiation therapy, even at a low dose, are highly recommended.

Treatment with alpha-glucosidase inhibitor for severe reactive hypoglycemia: a case report.

Gastrectomy or vagotomy may result in reactive hypoglycemia, which, in some cases, can reduce the plasma glucose levels to 30-40 mg/dl due to rapid digestion and absorption of food, especially carbohydrates. It also occurs sometimes in patients on hemodialysis, where it is a potentially lethal complication. Because insulin has a longer half-life due to lack of renal degradation, hypoglycemia can be induced by insulin in patients with renal failure. We treated a patient with frequent episodes of severe hypoglycemia, that were sometimes accompanied by convulsions. He had undergone total gastrectomy 8 years before and had been maintained on hemodialysis for 3 years. Hyperinsulinemia caused by oxyhyperglycemia associated with post-gastrectomy led to severe hypoglycemia in this patient because of the lack of renal insulin degradation. Since nutritional treatment did not successfully manage his reactive hypoglycemia, an alpha-glucosidase inhibitor, acarbose, was administered to treat his oxyhyperglycemia. This therapy was very effective and he has not had any recurrence of reactive hypoglycemia since the initiation of the therapy.