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Context: Staging and monitoring of pre-symptomatic type 1 diabetes includes the assessment for dysglycemia., Objective: To assess the ability of Continuous Glucose Monitoring (CGM) to differentiate between islet autoantibody-negative controls and early-stage type 1 diabetes and explore whether CGM classifiers predict progression to clinical diabetes., Research Design and Methods: Children and adolescents participating in public health screening for islet autoantibodies in Bavaria, Germany were invited to undergo CGM with Dexcom G6. In total, 118 participated and valid data was obtained from 97 (57 female; median age 10 [range 3-17] years), including 46 with stage 1, 18 with stage 2, and 33 with no islet autoantibodies., Results: Mean glucose during CGM in islet autoantibody-negative controls was high (median, 115.3 mg/dl) and varied substantially (IQR, 106.8-124.4). Eleven (33%) of the controls had more than 10% of glucose values above 140 mg/dl (TA140). Using thresholds corresponding to 100% specificity in controls, differences between controls and stage 1 and stage 2 were obtained for glucose standard deviation, TA140, TA160 and TA180. Elevations in any two of these parameters identified 12 (67%) with stage 2 and 9 (82%) of 11 participants who developed clinical diabetes within one year. However, there was marked variation within groups for all parameters and poor consistency observed in a second CGM performed in 18 participants., Conclusion: This study demonstrated the potential of integrating CGM into staging and monitoring of early-stage type 1 diabetes. However, substantial improvement in the precision of CGM is required for its application in routine monitoring practices., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Foam formulations are safe and effective therapy options for the treatment of chronic skin conditions that require the application of a topical formulation to delicate skin areas, such as scalp psoriasis or seborrheic dermatitis. This study focused on the development of foamable emulsions based on aqueous phospholipid blends. The effects of cosurfactants (nonionic Lauryglucoside (LG); zwitterionic Lauramidopropyl betaine (LAPB)), as well as of oil phases of different polarities, namely paraffin oil (PO), medium-chain triglycerides (MCT) and castor oil (CO), were investigated. The foaming experiments showed that both the type of cosurfactant, as well as the type of oil phase, affects the quality of the resulting foam. Emulsions that were based on a combination of hydrogenated lysophosphatidylcholine (hLPC) and a non-hydrogenated phospholipid, as well as LG as a cosurfactant and MCT as an oil phase, yielded the most satisfactory results. Furthermore, profile analysis tensiometry (PAT), polarization microscopy and laser diffraction analysis were used to characterize the developed formulations. These experiments suggest that the employed phospholipids predominantly stabilize the emulsions, while the cosurfactants are mainly responsible for the formation and stabilization of the foams. However, it appears that both sets of excipients are needed in order to acquire stable emulsions with satisfactory foaming properties.

Aims/hypothesis: Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and immune response actions on immunity and the gut microbiome., Methods: A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6 months to 2.99 years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory., Results: Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes., Conclusions/interpretation: The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells., Trial Registration: Clinicaltrials.gov NCT02547519 FUNDING: The main funding source was the German Center for Diabetes Research (DZD e.V.).

Background: Research evidence indicates that vitamin D deficiency is involved in the pathogenesis of insulin resistance (IR) and associated metabolic disorders including hyperglycemia and dyslipidemia. It also suggested that vitamin D deficiency is associated with elevated levels of oxidative stress and its complications. Therefore, the aim of our study was to determine the effect of vitamin D supplementation on DNA damage and metabolic parameters in vitamin D deficient individuals aged >45 with metabolic disorders. Material and Methods: Of 98 initially screened participants, 92 subjects deficient in vitamin D were included in the study. They were randomly assigned to the following group: with vitamin D supplementation (intervention group, n = 48) and without supplementation (comparative group, n = 44). The patients from both groups were divided into two subgroups according to the presence or absence of type 2 diabetes (T2DM). The intervention group was treated with 2000 International Unit (IU) cholecalciferol/day between October and March for three months. At baseline and after three-month supplementation vitamin D concentration (25-OH)D3 and endogenous and oxidative DNA damage were determined. In addition, fast plasma glucose (FPG), fasting insulin, HbA1c and lipid fraction (total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglyceride (TG)), as well as anthropometric measurements (weight, height) were gathered. The following IR-related parameters were calculated Homeostatic Model Assesment - Insulin Resistance (HOMA-IR) and TG/HDL ratio. Results: Three-month vitamin D supplementation increased the mean vitamin D concentration to generally accepted physiological level independently of T2DM presence. Importantly, vitamin D exposure decreased the level of oxidative DNA damage in lymphocytes of patients of intervention group. Among studied metabolic parameters, vitamin D markedly increased HDL level, decreased HOMA-IR, TG/HDL ratio. Furthermore, we found that HbA1c percentage diminished about 0.5% in T2DM patients supplemented with vitamin D. Conclusion: The current study demonstrated that daily 2000I U intake of vitamin D for three months decreased the level of oxidative DNA damage, a marker of oxidative stress, independently on T2DM presence. Furthermore, vitamin D reduced metabolic parameters connected with IR and improved glucose and lipid metabolism. Therefore, our results support the assertion that vitamin D, by reducing oxidative stress and improving of metabolic profile, may decrease IR and related diseases., Competing Interests: The authors declare no conflict of interest.

Background: Although detection of children at high risk of developing type 1 diabetes and diagnosis of early stages is possible, up to now there exists no approved therapy to delay or prevent type 1 diabetes. Thus it is vital to develop evidence-based interventions. For this a sufficient number of trial participants is crucial but difficult to obtain especially in asymptomatic children., Aim: Identifying family characteristics that lead to or impede trial participation and analyze reasons stated by families for non-participation., Methods: Participants for the Fr1da Insulin Intervention study are recruited from the Fr1da study, a population based screening for early stage type 1 diabetes in Bavaria. Families with eligible children were invited to enroll. We analyzed sex and age of the child, distance of the family to the study center in Munich and the existence of a first degree family member with type 1 as possible influential factors for study participation. We also analyzed reasons stated by families who declined study participation in a phone interview., Results: Of 146 eligible children 77 (53%) were enrolled into the trial. None of the tested family characteristics differed significantly between the enrolling and the families not participating, but in general enrolling families lived closer to the study site than families not participating. This is also reflected in the reasons given by non-participating families. The most frequent reason stated were time restrictions. The second most frequent reason was the venous blood draw., Conclusion: The factors for non-participation identified in this project need be taken into account for the design of future trials in young children to ensure proper recruitment and thus to generate valid results for medical treatment of children. More research on the reason of participation and non-participation in clinical trials is needed.

Objective: Women with insulin-requiring gestational diabetes mellitus (GDM) are at high risk of developing diabetes within a few years postpartum. We implemented this phase II study to test the hypothesis that vildagliptin, a dipeptidyl peptidase-4 inhibitor, is superior to placebo in terms of reducing the risk of postpartum diabetes., Methods: Women with insulin-requiring GDM were randomized to either placebo or 50 mg vildagliptin twice daily for 24 months followed by a 12-month observation period (EudraCT: 2007-000634-39). Both groups received lifestyle counseling. The primary efficacy outcomes were the diagnosis of diabetes (American Diabetes Association (ADA) criteria) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT)., Results: Between 2008 and 2015, 113 patients (58 vildagliptin, 55 placebo) were randomized within 2.2-10.4 (median 8.6) months after delivery. At the interim analysis, nine diabetic events and 28 IFG/IGT events had occurred. Fifty-two women withdrew before completing the treatment phase. Because of the low diabetes rate, the study was terminated. Lifestyle adherence was similar in both groups. At 24 months, the cumulative probability of postpartum diabetes was 3% and 5% (hazard ratio: 1.03; 95% confidence interval: 0.15-7.36) and IFG/IGT was 43% and 22% (hazard ratio: 0.55; 95% confidence interval: 0.26-1.19) in the placebo and vildagliptin groups, respectively. Vildagliptin was well tolerated with no unexpected adverse events., Conclusions: The study did not show significant superiority of vildagliptin over placebo in terms of reducing the risk of postpartum diabetes. However, treatment was safe and suggested some improvements in glycemic control, insulin resistance, and β-cell function. The study identified critical issues in performing clinical trials in the early postpartum period in women with GDM hampering efficacy assessments. With this knowledge, we have set a basis for which properly powered trials could be performed in women with recent GDM. TRIAL REGISTRATION NUMBER AT CLINICALTRIALS.GOV: NCT01018602., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Aberrant immune activation mediated by T effector cell populations is pivotal in the onset of autoimmunity in type 1 diabetes (T1D). T follicular helper (TFH) cells are essential in the induction of high-affinity antibodies, and their precursor memory compartment circulates in the blood. The role of TFH precursors in the onset of islet autoimmunity and signaling pathways regulating their differentiation is incompletely understood. Here, we provide direct evidence that during onset of islet autoimmunity, the insulin-specific target T-cell population is enriched with a C-X-C chemokine receptor type 5 (CXCR5) + CD4 + TFH precursor phenotype. During onset of islet autoimmunity, the frequency of TFH precursors was controlled by high expression of microRNA92a (miRNA92a). miRNA92a-mediated TFH precursor induction was regulated by phosphatase and tension homolog (PTEN) - phosphoinositol-3-kinase (PI3K) signaling involving PTEN and forkhead box protein O1 (Foxo1), supporting autoantibody generation and triggering the onset of islet autoimmunity. Moreover, we identify Krueppel-like factor 2 (KLF2) as a target of miRNA92a in regulating human TFH precursor induction. Importantly, a miRNA92a antagomir completely blocked induction of human TFH precursors in vitro. More importantly, in vivo application of a miRNA92a antagomir to nonobese diabetic (NOD) mice with ongoing islet autoimmunity resulted in a significant reduction of TFH precursors in peripheral blood and pancreatic lymph nodes. Moreover, miRNA92a antagomir application reduced immune infiltration and activation in pancreata of NOD mice as well as humanized NOD Scid IL2 receptor gamma chain knockout (NSG) human leucocyte antigen (HLA)-DQ8 transgenic animals. We therefore propose that miRNA92a and the PTEN-PI3K-KLF2 signaling network could function as targets for innovative precision medicines to reduce T1D islet autoimmunity., Competing Interests: The authors declare no conflict of interest.

Detailed knowledge about online brain processing during the execution of complex motor tasks with a high motion range still remains elusive. The aim of the present study was to investigate the hemodynamic responses within sensorimotor networks as well as in visual motion area during the execution of a complex visuomotor task such as juggling. More specifically, we were interested in how far the hemodynamic response as measured with functional near infrared spectroscopy (fNIRS) adapts as a function of task complexity and the level of the juggling expertise. We asked expert jugglers to perform different juggling tasks with different levels of complexity such as a 2-ball juggling, 3- and 5-ball juggling cascades. We here demonstrate that expert jugglers show an altered neurovascular response with increasing task complexity, since a 5-ball juggling cascade showed enhanced hemodynamic responses for oxygenated hemoglobin as compared to less complex tasks such as a 3- or 2-ball juggling pattern. Moreover, correlations between the hemodynamic response and the level of the juggling expertise during the 5-ball juggling cascade, acquired by cinematographic video analysis, revealed only a non-significant trend in primary motor cortex, indicating that a higher level of expertise might be associated with lower hemodynamic responses.

The NOD mouse spontaneously develops autoimmune diabetes. Dendritic cells (DC) play a crucial role in the autoimmune response. Previous studies have reported a defective DC generation in vitro from the NOD mouse bone marrow (BM), but a deviated development of myeloid precursors into non-DC in response to GM-CSF was not considered. In this study, we demonstrate several abnormalities during myeloid differentiation of NOD BM precursors using GM-CSF in vitro. 1) We found reduced proliferation and increased cell death in NOD cultures, which explain the previously reported low yield of DC progeny in NOD. Cell yield in NOR cultures was normal. 2) In a detailed analysis GM-CSF-stimulated cultures, we observed in both NOD and NOR mice an increased frequency of macrophages, identified as CD11c(+)/MHCII(-) cells with typical macrophage morphology, phenotype, and acid phosphatase activity. This points to a preferential maturation of BM precursors into macrophages in mice with the NOD background. 3) The few CD11c(+)/MHCII(high) cells that we obtained from NOD and NOR cultures, which resembled prototypic mature DC, appeared to be defective in stimulating allogeneic T cells. These DC had also strong acid phosphatase activity and elevated expression of monocyte/macrophage markers. In conclusion, in this study we describe a deviated development of myeloid BM precursors of NOD and NOR mice into macrophages and macrophage-like DC in vitro. Potentially, these anomalies contribute to the dysfunctional regulation of tolerance in NOD mice yet are insufficient to induce autoimmune diabetes because they occurred partly in NOR mice.

Sphingomonas herbicidovorans MH was able to completely degrade both enantiomers of the chiral herbicide dichlorprop [(RS)-2-(2,4-dichlorophenoxy)propanoic acid], with preferential degradation of the (S) enantiomer over the (R) enantiomer. These results are in agreement with the recently reported enantioselective degradation of mecoprop [(RS)-2-(4-chloro-2-methylphenoxy)propanoic acid] by this bacterium (C. Zipper, K. Nickel, W. Angst, and H.-P. E. Kohler, Appl. Environ. Microbiol. 62:4318-4322, 1996). Uptake of (R)-dichlorprop, (S)-dichlorporp, and 2,4-D (2,4-dichlorophenoxyacetic acid) was inducible. Initial uptake rates of cells grown on the respective substrate showed substrate saturation kinetics with apparent affinity constants (Kt) of 108, 93, and 117 microM and maximal velocities (Vmax) of 19, 10, and 21 nmol min-1 mg of protein-1 for (R)-dichlorprop, (S)-dichlorprop, and 2,4-D, respectively. Transport of (R)-dichlorprop, (S)-dichlorprop, and 2,4-D was completely inhibited by various uncouplers and by nigericin but was only marginally inhibited by valinomycin and by the ATPase inhibitor N,N'-dicyclohexylcarbodiimine. Experiments on the substrate specificity of the putative transport systems revealed that (R)-dichlorprop uptake was inhibited by (R)-mecoprop but not by (S)-mecoprop, (S)-dichlorprop, or 2,4-D. On the other hand, the (S)-dichlorprop transport was inhibited by (S)-mecoprop but not by (R)-mecoprop, (R)-dichlorprop, or 2,4-D. These results provide evidence that the first step in the degradation of dichlorprop, mecoprop, and 2,4-D by S. herbicidovorans is active transport and that three inducible, proton gradient-driven uptake systems exist: one for (R)-dichlorprop and (R)-mecoprop, another for (S)-dichlorprop and (S)-mecoprop, and a third for 2,4-D.

The biotransformation of N-(4-hydroxyphenyl)retinamide (HPR), and interactions of parent compound and/or metabolites with the cellular retinoid binding proteins (CRBPs) and cellular retinoic acid binding proteins (CRABPs) were examined in murine mammary tumor virus (MuMTV)-induced murine mammary tumor cells (GR-3A) grown in monolayer cell culture. Soluble fractions (cytosols) obtained from the extracts of GR-3A cells after high speed centrifugation were found to contain proteins of approx. 15,000 daltons which bound retinol and retinoic acid, but did not bind HPR or HPR metabolites. Moreover, HPLC analysis of GR-3A cell extracts demonstrated that [3H]retinol and [3H]retinoic acid were not detected in cells that had been exposed to [3H]HPR for 48 h. These findings, that under in vitro conditions there is no appreciable enzymatic hydrolysis of HPR to retinoic acid or conversion to retinol, suggests that the metabolism and cytological effects of HPR may be distinct from those of retinol or retinoic acid within murine mammary epithelial cells.

Experiments were conducted to examine the effects of dietary zinc (Zn) upon plasma vitamin E (E) concentrations to test the hypothesis that there may be a significant dietary interaction between these two nutrients. Weanling female Sprague-Dawley rats were fed diets that were (i) Zn-deficient (less than 0.9 micrograms Zn/g diet) ad libitum; (ii) Zn-adequate (50.9 micrograms Zn/g diet), pair-fed to the Zn-deficient group; and (iii) Zn-adequate (50.9 micrograms Zn/g diet) ad libitum. Plasma E in Zn-deficient animals (4.02 +/- 1.20 micrograms/ml) was significantly reduced (P less than or equal to 0.05) compared with results in both Zn-adequate pair-fed (9.21 +/- 0.70 micrograms/ml) and Zn-adequate ad libitum-fed (9.47 +/- 0.90 micrograms/ml) animals. Zn deficiency in this model system also resulted in significant (P less than or equal to 0.05) reductions in femur and plasma Zn concentrations as well as in plasma retinol, plasma triglyceride, and plasma cholesterol concentrations. Plasma albumin and total plasma protein concentrations were normal in Zn-deficient animals. With dietary Zn deficiency, the decrease in plasma E appeared to be out of proportion to associated decreases in plasma triglyceride and plasma cholesterol concentrations. Since E is associated with plasma lipoproteins, these data suggest that lipid and/or E malabsorption may be a consequence of Zn deficiency. In response to increased dietary intake of E, increments of plasma E were lower in Zn-depleted than in Zn-adequate, pair-fed animals. These findings suggest that dietary Zn deficiency possibly may increase the nutritional requirement for E necessary to maintain adequate plasma concentrations.