Novel Urinary Glycan Biomarkers Predict Cardiovascular Events in Patients With Type 2 Diabetes: A Multicenter Prospective Study With 5-Year Follow Up (U-CARE Study 2)

Background: Although various biomarkers predict cardiovascular event (CVE) in patients with diabetes, the relationship of urinary glycan profile with CVE in patients with diabetes remains unclear. Methods: Among 680 patients with type 2 diabetes, we examined the baseline urinary glycan signals binding to 45 lectins with different specificities. Primary outcome was defined as CVE including cardiovascular disease, stroke, and peripheral arterial disease. Results: During approximately a 5-year follow-up period, 62 patients reached the endpoint. Cox proportional hazards analysis revealed that urinary glycan signals binding to two lectins were significantly associated with the outcome after adjustment for known indicators of CVE and for false discovery rate, as well as increased model fitness. Hazard ratios for these lectins (+1 SD for the glycan index) were UDA (recognizing glycan: mixture of Man5 to Man9): 1.78 (95% CI: 1.24-2.55, P = 0.002) and Calsepa [High-Man (Man2-6)]: 1.56 (1.19-2.04, P = 0.001). Common glycan binding to these lectins was high-mannose type of N-glycans. Moreover, adding glycan index for UDA to a model including known confounders improved the outcome prediction [Difference of Harrel's C-index: 0.028 (95% CI: 0.001-0.055, P = 0.044), net reclassification improvement at 5-year risk increased by 0.368 (0.045-0.692, P = 0.026), and the Akaike information criterion and Bayesian information criterion decreased from 725.7 to 716.5, and 761.8 to 757.2, respectively]. Conclusion: The urinary excretion of high-mannose glycan may be a valuable biomarker for improving prediction of CVE in patients with type 2 diabetes, and provides the rationale to explore the mechanism underlying abnormal N-glycosylation occurring in patients with diabetes at higher risk of CVE

Diagnostic criteria for acute-onset type 1 diabetes mellitus (2012): Report of the Committee of Japan Diabetes Society on the Research of Fulminant and Acute-onset Type 1 Diabetes Mellitus

Type 1 diabetes is a disease characterized by destruction of pancreatic β-cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute-onset or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute-onset type 1 diabetes mellitus. Among the patients who develop ketosis or diabetic ketoacidosis within 3 months after the onset of hyperglycemic symptoms and require insulin treatment continuously after the diagnosis of diabetes, those with anti-islet autoantibodies are diagnosed with \u27acute-onset type 1 diabetes mellitus (autoimmune)\u27. In contrast, those whose endogenous insulin secretion is exhausted (fasting serum C-peptide immunoreactivity <0.6 ng/mL) without verifiable anti-islet autoantibodies are diagnosed simply with \u27acute-onset type 1 diabetes mellitus\u27. Patients should be reevaluated after certain periods in case their statuses of anti-islet autoantibodies and/or endogenous insulin secretory capacity are unknown

The glycated albumin to HbA1c ratio is elevated in patients with fulminant type 1 diabetes mellitus with onset during pregnancy

Fulminant type 1 diabetes mellitus (FT1DM) develops as a result of very rapid and almost complete destruction of pancreatic β cell. The most common form of type 1 diabetes mellitus with onset during pregnancy has been shown to be FT1DM at least in Japan. We previously reported that the ratio of glycated albumin (GA) to HbA1c (GA/HbA1c ratio) is elevated in FT1DM patients at the diagnosis. In the present study, we investigated whether the GA/HbA1c ratio is also elevated in FT1DM with onset during pregnancy (P-FT1DM). The study subjects consisted of 7 patients with P-FT1DM. Ten patients with untreated type 2 diabetes mellitus (T2DM) discovered during pregnancy (P-T2DM) and 9 non-pregnant women with untreated T2DM (NP-T2DM) were used as controls. All study patients satisfied HbA1c<8.7%, the diagnostic criteria for FT1DM. The GA/HbA1c ratio in the P-FT1DM patients at the diagnosis was significantly higher than that in the P-T2DM patients and the NP-T2DM patients. The GA/HbA1c ratio was ≥3.0 in all P-FT1DM patients, whereas it was <3.0 in 8 of 10 P-T2DM patients and all NP-T2DM patients. The GA/HbA1c ratio was also elevated in P-FT1DM patients at the diagnosis compared with T2DM with or without pregnancy

Prevention of hypoglycemia by intermittent-scanning continuous glucose monitoring device combined with structured education in patients with type 1 diabetes mellitus : A randomized, crossover trial

Aims: We conducted a randomized, crossover trial to compare intermittent-scanning continuous glucose monitoring (isCGM) device with structured education (Intervention) to self-monitoring of blood glucose (SMBG) (Control) in the reduction of time below range. Methods: This crossover trial involved 104 adults with type 1 diabetes mellitus (T1DM) using multiple daily injections. Participants were randomly allocated to either sequence Intervention/Control or sequence Control/Intervention. During the Intervention period which lasted 84 days, participants used the first-generation FreeStyle Libre (Abbott Diabetes Care, Alameda, CA, USA) and received structured education on how to prevent hypoglycemia based on the trend arrow and by frequent sensor scanning (≥10 times a day). Confirmatory SMBG was conducted before dosing insulin. The Control period lasted 84 days. The primary endpoint was the decrease in the time below range (TBR; <70 mg/dL). Results: The time below range was significantly reduced in the Intervention arm compared to the Control arm (2.42 ± 1.68 h/day [10.1 %±7.0 %] vs 3.10 ± 2.28 h/day [12.9 %±9.5 %], P = 0.012). The ratio of high-risk participants with low blood glucose index >5 was significantly reduced (8.6 % vs 23.7 %, P < 0.001). Conclusions: The use of isCGM combined with structured education significantly reduced the time below range in patients with T1DM

Studies on the role of neutrophils in intractable asthma Part 1. Leukotriene and superoxide production of neutrophils

The role of neutrophils migrated in the sputum and bronchoalveolar lavage fluid of intractable asthmatics is not difficult to understand. The production of leukotrienes (LTs) and superoxide stimulated by the calcium ionophores (CaI) from neutrophil-rich fraction of 29 intractable, 70 non-intractable asthmatics and 18 healthy subjects was examined by high performance liquid chromatography and a cytochrome C reduction method. Significantly larger amounts of LTC(4) and LTB(4) were produced by CaI in the neutrophil-rich fraction from asthematics, than in that from the healthy subjects (p<0.01). Moreover, a significantly larger amounts of LTC(4) was producted in the fraction obtained from the intractable asthmatics than in that from the non-intractable asthmatics (p<0.05). However, there was no significant difference in LTB(4) production between the two groups of asthmatics. The production of superoxide by concanavalin A was significantly increased in the neutrophil-rich fraction from prednisolone-within-10mg-dependent asthmatics than in those from prednisolone-over-10mg-dependent patients (p<0.01). There were correlations between the LTC(4) and LTB(4) production, and also between LTB(4) and superoxide production. LTs and superoxide released from inflammatory cells, especially neutrophils, may play an important role in the pathgenesis of intractable asthma

Studies on the role of neutrophils in intractable asthma Part 2. Leukotriene production of neutrophils by immunological stimulation

Previously, I reported that more leukotrienes (LTs) and superoxides were produced from the neutrophil-rich fraction by non-immunological stimulation with CaI in intractable asthmatics than in non-intractable asthmatics. This suggested that neutrophils are involved in the pathogenesis of intractable asthma. To investigate the process of neutrophil activation in intractable asthma, the LTs production from neutrophils by immunological stimulation was measured by high performance liquid chromatography (HPLC). LTs were produced from neutrophils by stimulation of anti-IgG and zymosan activated serum (ZAS), but not anti-IgE. However, there was no significant difference with each disease severity of asthma. The production from neutrophils was also detected by Candida antigen stimulation. Moreover, the production of LTC4 from neutrophils by this stimulation was higher in intractable asthmatics than in non-intractable asthmatics. These findings suggested that neutrophils are produced LTs by immunological stimulation such as by Candida antigen based on the IgG mediated allergy reaction, and play an important role in the pathogenesis of intractable asthma