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Under insulin-resistant conditions such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. A liver–brain–pancreas neuronal relay plays an important role in this process. Here, we show the molecular mechanism underlying this compensatory β-cell proliferation. We identify FoxM1 activation in islets from neuronal relay-stimulated mice. Blockade of this relay, including vagotomy, inhibits obesity-induced activation of the β-cell FoxM1 pathway and suppresses β-cell expansion. Inducible β-cell-specific FoxM1 deficiency also blocks compensatory β-cell proliferation. In isolated islets, carbachol and PACAP/VIP synergistically promote β-cell proliferation through a FoxM1-dependent mechanism. These findings indicate that vagal nerves that release several neurotransmitters may allow simultaneous activation of multiple pathways in β-cells selectively, thereby efficiently promoting β-cell proliferation and maintaining glucose homeostasis during obesity development. This neuronal signal-mediated mechanism holds potential for developing novel approaches to regenerating pancreatic β-cells.

BackgroundImpaired glucose metabolism is an established risk factor for coronary artery disease. Previous studies revealed that glycemic variability (GV) is also important for glucose metabolism in patients with acute coronary syndrome (ACS). We explored the association between GV and prognosis in patients with ACS.MethodsA total of 417 patients with ACS who received reperfusion wore a continuous glucose monitoring system (CGMS) in a stable phase after admission and were monitored for at least 24 consecutive h. The mean amplitude of glycemic excursion (MAGE) was calculated as a marker of GV. We divided into two groups based on the highest tertile levels of MAGE (MAGE = 52 mg/dl). The groups were followed up for a median of 39 months [IQR 24–50 months]. The primary endpoint was the incidence of major adverse cardiovascular and cerebrovascular events (MACCE).ResultDuring follow-up, 66 patients experienced MACCE (5 patients had cardiovascular death, 14 had recurrence of ACS, 27 had angina requiring revascularization, 8 had acute decompensated heart failure, and 16 had a stroke). MACCE was more frequently observed in the high MAGE group (23.5% vs. 11.6%, p = 0.002). In multivariate analysis, high MAGE was an independent predictive factor of poor prognosis for MACCE (odds ratio, 1.84; 95% confidence interval, 1.01–3.36; p = 0.045).ConclusionGlycemic variability determined with a CGMS is a predictor of prognosis in patients with ACS without severe DM.Trial registration UMIN 000010620. Registered April 1st 2012

An intensive combination chemotherapy regimen supported by granulocyte colony-stimulating factor (G-CSF) was evaluated in adult T-cell leukemia/lymphoma (ATLL) patients in a multiinstitutional, cooperative study. Vincristine 1 mg/m2 i.v. day 1, Adriamycin 40 mg/m2 i.v. day 1, cyclophosphamide 400 mg/m2 i.v. day 1, prednisolone 40 mg/m2 i.v. days 1 to 3 and 8 to 10, etoposide 35 mg/m2 i.v. days 1 to 8, vindesine 2 mg/m2 i.v. day 8, ranimustine 50 mg/m2 i.v. day 8, mitoxantrone 7 mg/m2 i.v. day 8, and G-CSF 50 mg/m2 s.c. days 9 to 21 were given for 2 to 4 courses every 3 weeks to 83 patients with ATLL. Complete remission (CR) and partial remission (PR) were achieved in 35.8 and 38.3 percent, respectively, of 81 evaluable patients. The median survival of all patients was 8.5 months, with a predicted 3-year survival of 13.5 percent by the Kaplan-Meier method. The median duration of response was 7.6 months (range 0.2-42.7), and 13 patients were alive. Their median survival time was 29.1 months (range 19.2-44.7). In 67.6 percent of courses, white blood cell (WBC) nadirs were < 1.0 x 10(9)/L. Days required for the recovery of WBC from the nadir to > 1.0 x 10(9)/L were <5 days in 71.4 percent of the treatment courses. The G-CSF supported an intensified chemotherapy regimen for ATLL and yielded better response rate and longer survival compared to previous reports in Japan. Because duration of remission is still short, further studies of postremission therapy or other strategies are warranted.

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Aims/hypothesis It is difficult to use HbA 1c as an indicator of glycaemic control in patients with neonatal diabetes mellitus (NDM) because of high levels of fetal haemoglobin (HbF) remaining in the blood. In this study, glycated albumin (GA), which is not affected by HbF, and HbA 1c were compared to evaluate whether they reflect glycaemic control in patients with NDM. Methods This study included five patients with NDM. Age at diagnosis was 38±20 days. Insulin therapy was started in all patients, and levels of GA, HbA 1c and HbF were measured monthly for 6 months. One-month average preprandial plasma glucose (aPPG) was calculated using self-monitoring of blood glucose. Results Plasma glucose and GA were elevated (29.7± 13.1 mmol/l [n=5] and 33.3±6.9% [n=3], respectively) but HbA 1c was within normal limits (5.4±2.6% [35.5± 4.9 mmol/mol]; n=4) at diagnosis. With diabetes treatment, aPPG (r=−0.565, p=0.002), GA (r=−0.552, p=0.003) and HbF (r=−0.855, p<0.0001) decreased with age, whereas HbA 1c increased (r=0.449, p=0.004). GA was strongly positively correlated with aPPG (r=0.784, p<0.0001), while HbA 1c showed no correlation with aPPG (r=0.221, p=0.257) and was significantly inversely correlated with HbF (r=−0.539, p=0.004). Conclusions/interpretation GA is a useful indicator of glycaemic control in patients with NDM, whereas HbA 1c is influenced by age-related changes in HbF and does not accurately reflect glycaemic control.

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Background Glycated albumin (GA) reflects glycemic control in patients with neonatal diabetes mellitus (NDM). However, GA in NDM patients is apparently low in relation to glycemia. Objective To establish the reference intervals for GA in healthy infants. Subjects and Methods Fifty‐eight healthy, full‐term newborn infants were used to define the GA reference values and to investigate its relationship to plasma glucose (PG) and serum albumin. The infants were categorized into three groups according to age: group A, 5 (4–6) median (range) d: n = 18; group B, 33 (30–38) d: n = 19; and group C, 181 (50–352) d: n = 21. We also studied 212 non‐diabetic adults [group D, 53 (28–78) yr old] and the 5 NDM patients previously reported for GA comparisons. Results In the infants, GA was strongly positively correlated with logarithmic transformation of age [log (age)] (p = 0.831, p < 0.0001). The GA in groups A, B, C, and D were 7.3 ± 1.0%, 8.6 ± 1.1%, 10.9 ± 0.8%, and 14.0 ± 1.1%, respectively. The GA was more strongly positively correlated with serum albumin (r = 0.768, p < 0.0001) than with PG (r = 0.596, p < 0.0001). When GA levels were compared with the age‐dependent reference values, GA in the transient NDM patient was normalized although GA in the four permanent NDM patients decreased but remained high after insulin therapy. Conclusions This study showed that the reference range for GA in infants is lower than that of adults and increases with age, with which we confirmed that GA in the NDM patients reflected the clinical course. Consequently, GA in NDM patients should be compared with the age‐based reference values to assess the accurate glycemic status.