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We previously reported that administration of a streptococcal preparation (OK432) inhibited insulitis and development of autoimmune diabetes in nonobese diabetic (NOD) mice and BB rats as animal models of insulin-dependent diabetes mellitus. In this study, we screened various cytokines that could be induced by OK432 in vivo, for their preventive effect against diabetes in NOD mice. Among recombinant mouse IFN'y, human ILla, human IL2, mouse granulocyte-macrophage colony-stimulating factor and human TNFa, only human TNFa suppressed insulitis and significantly (P < 0.001) inhibited development of diabetes. NOD mice were the lowest producers of the mRNA of TNF and serum TNF on stimulation with OK432 or with IFNy plus LPS, compared with C57BL/6, C3H/He, and Balb/c mice. The results imply a role for low productivity of TNF in the pathogenesis of autoimmune diabetes in NOD mice. IntroductionDiabetes develops spontaneously in the nonobese diabetic

abstract. Fulminant type 1 diabetes, established in 2000, is defined as a novel subtype of diabetes mellitus that results from remarkably acute and almost complete destruction of pancreatic beta cells at the disease onset. In this study, we aimed to clarify the pathogenesis of fulminant type 1 diabetes with special reference to insulitis and viral infection. We examined pancreatic autopsy samples from three patients who had died soon after the onset of disease and analyzed these by immunohistochemistry and in situ hybridization. The results were that both beta and alpha cell areas were significantly decreased in comparison with those of normal controls. Mean beta cell area of the patients just after the onset was only 0.00256 % while that of normal control was 1.745 %. Macrophages and T cells-but no natural killer cells-had infiltrated the islets and the exocrine pancreas. Although both of them had massively infiltrated, macrophages dominated islet infiltration and were detected in 92.6 % of the patients' islets. Toll-like receptor (TLR) 3, a sensor of viral components, was detected in 84.7±7.0 % of macrophages and 62.7±32.3 % of T cells (mean±SD) in all three patients. TLR7 and TLR9 were also detected in the pancreas of all three patients. enterovirus RNa was detected in beta-cell positive islets in one of the three patients by in situ hybridization. In conclusion, our results suggest that macrophage-dominated insulitis rather than T cell autoimmunity contributes to beta cell destruction in fulminant type 1 diabetes.

AimsThe efficacy and safety of insulin degludec (IDeg) was compared with insulin detemir (IDet), both administered once daily (OD) as basal treatment in participants with type 1 diabetes mellitus (T1DM). The primary outcome was non-inferiority of IDeg to IDet in glycated haemoglobin (HbA1c) reduction after 26 weeks.MethodsThis multinational, 26-week, controlled, open-label, parallel-group trial randomized adults with T1DM to IDeg or IDet as OD basal insulin treatment combined with mealtime bolus insulin aspart (IAsp). Participants with T1DM treated with any basal–bolus insulin regimen for ≥12 months prior to the trial, a mean HbA1c ≤ 10.0% (85.8 mmol/mol) and body mass index (BMI) ≤35.0 kg/m2 at screening participated in the trial (IDeg: N = 302; IDet: N = 153).ResultsAfter 26 weeks, HbA1c decreased 0.73% (8.0 mmol/mol) (IDeg) and 0.65% (7.1 mmol/mol) (IDet) [estimated treatment difference (ETD) IDeg–IDet: −0.09% (−0.23; 0.05)95%CI (−10.0 mmol/mol [−2.6; 0.6]95% CI); confirming non-inferiority]. Mean fasting plasma glucose improved in both groups, and was lower with IDeg than IDet [ETD IDeg–IDet: −1.66 mmol/l (−2.37; −0.95)95% CI, p < 0.0001]. The rate of confirmed hypoglycaemia was similar with IDeg and IDet [45.83 vs. 45.69 episodes per patient-year of exposure (PYE); estimated rate ratio (RR) IDeg/IDet: 0.98 (0.80; 1.20)95% CI, p = 0.86]. The rate of nocturnal confirmed hypoglycaemia was lower with IDeg than IDet [4.14 vs. 5.93 episodes per PYE; RR IDeg/IDet: 0.66 (0.49; 0.88)95% CI, p = 0.0049]. Adverse event profiles were similar between groups.ConclusionIDeg administered OD in basal–bolus therapy effectively improved long-term glycaemic control in participants with T1DM with a lower risk of nocturnal confirmed hypoglycaemia than IDet.

Aims/hypothesis Our aim was to clarify the association between leisure-time physical activity (LTPA) and cardiovascular events and total mortality in a nationwide cohort of Japanese diabetic patients.Methods Eligible patients (1,702) with type 2 diabetes (mean age, 58.5 years; 47% women) from 59 institutes were followed for a median of 8.05 years. A comprehensive lifestyle survey including LTPA and occupation was performed using standardised questionnaires. Outcome was A complete list of members of the JDCS group can be found in the electronic supplementary material (ESM). occurrence of coronary heart disease (CHD), stroke and total mortality. The adjusted HR and 95% CI were calculated by Cox regression analysis. Results A significant reduction in HR in patients in the top (≥15.4 metabolic equivalents [MET] h/week) vs the bottom tertile (≤3.7 MET h/week) of LTPA, adjusted by age, sex and diabetes duration, was observed in stroke (HR 0.55, 95% CI 0.32, 0.94) and total mortality (HR 0.49, 95% CI 0.26, 0.91) but not in CHD (HR 0.77, 95% CI 0.48, 1.25). The HR for stroke became borderline significant or nonsignificant after adjustment for lifestyle or clinical variables including diet or serum lipids. The significantly reduced total mortality by LTPA was independent of these variables and seemed not to be, at least mainly, attributed to reduced cardiovascular disease. Conclusions/interpretation In Japanese persons with type 2 diabetes, LTPA of 15.4 MET h/week or more was associated with a significantly lower risk of stroke partly through ameliorating combinations of cardiovascular risk factors. It was also associated with significantly reduced total mortality but independently of cardiovascular risk factors or events. These findings, implying differences from Western diabetic populations, should be considered in the clinical management of East Asians with diabetes. Electronic supplementary material