The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered ...silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes-susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets.
The development of a successful lineage reprogramming strategy of liver to pancreas holds promises for the treatment and potential cure of diabetes. The liver is an ideal tissue source for generating ...pancreatic cells, because of its close developmental origin with the pancreas and its regenerative ability. Yet, the molecular bases of hepatic and pancreatic cellular plasticity are still poorly understood. Here, we report that the TALE homeoprotein TGIF2 acts as a developmental regulator of the pancreas versus liver fate decision and is sufficient to elicit liver-to-pancreas fate conversion both ex vivo and in vivo. Hepatocytes expressing Tgif2 undergo extensive transcriptional remodelling, which represses the original hepatic identity and, over time, induces a pancreatic progenitor-like phenotype. Consistently, in vivo forced expression of Tgif2 activates pancreatic progenitor genes in adult mouse hepatocytes. This study uncovers the reprogramming activity of TGIF2 and suggests a stepwise reprogramming paradigm, whereby a 'lineage-restricted' dedifferentiation step precedes the identity switch.
Type 1 diabetes (T1D) represents a hallmark of the fatal multiorgan autoimmune syndrome affecting humans with abrogated Foxp3
regulatory T (Treg) cell function due to
gene mutations, but whether the ...loss of Foxp3
Treg cell activity is indeed sufficient to promote β cell autoimmunity requires further scrutiny. As opposed to human Treg cell deficiency, β cell autoimmunity has not been observed in non-autoimmune-prone mice with constitutive
deficiency or after diphtheria toxin receptor (DTR)-mediated ablation of Foxp3
Treg cells. In the spontaneous nonobese diabetic (NOD) mouse model of T1D, constitutive Foxp3 deficiency did not result in invasive insulitis and hyperglycemia, and previous studies on Foxp3
Treg cell ablation focused on Foxp3
NOD mice, in which expression of a transgenic BDC2.5 T cell receptor (TCR) restricted the CD4
TCR repertoire to a single diabetogenic specificity. Here we revisited the effect of acute Foxp3
Treg cell ablation on β cell autoimmunity in NOD mice in the context of a polyclonal TCR repertoire. For this, we took advantage of the well-established DTR/GFP transgene of DEREG mice, which allows for specific ablation of Foxp3
Treg cells without promoting catastrophic autoimmune diseases. We show that the transient loss of Foxp3
Treg cells in prediabetic NOD.DEREG mice is sufficient to precipitate severe insulitis and persistent hyperglycemia within 5 days after DT administration. Importantly, DT-treated NOD.DEREG mice preserved many clinical features of spontaneous diabetes progression in the NOD model, including a prominent role of diabetogenic CD8
T cells in terminal β cell destruction. Despite the severity of destructive β cell autoimmunity, anti-CD3 mAb therapy of DT-treated mice interfered with the progression to overt diabetes, indicating that the novel NOD.DEREG model can be exploited for preclinical studies on T1D under experimental conditions of synchronized, advanced β cell autoimmunity. Overall, our studies highlight the continuous requirement of Foxp3
Treg cell activity for the control of genetically pre-installed autoimmune diabetes.
The IL-7/IL-7R pathway is essential for lymphocyte development and disturbances in the pathway can lead to immune deficiency or T cell mediated destruction. Here, the effect of transient ...hyperexpression of IL-7 was investigated on immune regulation and allograft rejection under immunosuppression. An experimental
immunosuppressive mouse model of IL-7 hyperexpression was developed using transgenic mice (C57BL/6 background) carrying a tetracycline inducible IL-7 expression cassette, which allowed the temporally controlled induction of IL-7 hyperexpression by Dexamethasone and Doxycycline treatment. Upon induction of IL-7, the B220
c-kit
Pro/Pre-B I compartment in the bone marrow increased as compared to control mice in a serum IL-7 concentration-correlated manner. IL-7 hyperexpression also preferentially increased the population size of memory CD8
T cells in secondary lymphoid organs, and reduced the proportion of CD4
Foxp3
T regulatory cells. Of relevance to disease, conventional CD4
T cells from an IL-7-rich milieu escaped T regulatory cell-mediated suppression
and in a model of autoimmune diabetes
. These findings were validated using an IL-7/anti-IL7 complex treatment mouse model to create an IL-7 rich environment. To study the effect of IL-7 on islet graft survival in a mismatched allograft model, BALB/c mice were rendered diabetic by streptozotocin und transplanted with IL-7-inducible or control islets from C57BL/6 mice. As expected, Dexamethasone and Doxycycline treatment prolonged graft median survival as compared to the untreated control group in this transplantation mouse model. However, upon induction of local IL-7 hyperexpression in the transplanted islets, graft survival time was decreased and this was accompanied by an increased CD4
and CD8
T cell infiltration in the islets. Altogether, the findings show that transient elevations of IL-7 can impair immune regulation and lead to graft loss also under immune suppression.
BackgroundVitamin D insufficiency (VDI) may be a factor in the development of type 1 diabetes (T1D). The aim of this study is to investigate the presence and persistence of VDI in a large cohort of ...infants with increased risk of developing T1D, in light of the differences in local supplementation guidelines.MethodsIn the POInT Study, a multicentre primary prevention study between February 2018 and March 2021 in Germany, Poland, Belgium, England and Sweden, including infants aged 4–7 months at high genetic risk of developing β-cell autoantibodies, vitamin D levels were analysed at each study visit from inclusion (4–7 months) until 3 years, with an interval of 2 months (first three visits) or 4–6 months (visits 4–8). The protocol actively promotes vitamin D sufficiency to optimise immune tolerance. VDI was defined as a concentration below 30 ng/mL and was treated according to local guidelines of participating centres. Recovery from VDI was defined as a concentration above or equal to 30 ng/mL on the subsequent visit after VDI.Results1050 infants were included, of which 5937 vitamin D levels were available for analyses. VDI was observed in 1464 (24.7%) visits and 507 (46.1%) of these were not resolved at the next visit. The risk of having VDI was independently associated with season (higher in winter), weight (higher with increased weight), age (higher with increased age) and country (higher in England). The risk of not recovering from VDI was independently associated with the season of the previously determined VDI, which was higher if VDI was identified in winter.ConclusionsVDI is frequent in infants with increased risk of developing T1D. Treatment guidelines for VDI do not seem effective. Increasing supplementation dosages in this patient population seems warranted, especially during winter, and increasing dosages more aggressively after VDI should be considered.
Zusammenfassung
Aktuell, 100 Jahre nach der Entdeckung des Insulins zur Behandlung des Typ-1-Diabetes, geben klinische Studien Anlass zur Hoffnung auf neue präventive Ansätze. Durch diese sollen das ...therapeutische Spektrum auf die präventive Behandlung des Typ-1-Diabetes erweitert und so eine Verhinderung bzw. Verzögerung des Krankheitsausbruchs oder eine Abmilderung des Verlaufs nach Manifestation erreicht werden. Neben dem deutschlandweit angelegten Screening auf ein genetisches Risiko (Freder1k) und auf ein Frühstadium (Fr1da) für Typ-1-Diabetes existieren mit POInT (oral gegebenes Insulin) und SINT1A (Beeinflussung des Mikrobioms durch Probiotika) klinische Studien, die auf eine Primärprävention zur Verhinderung oder Verzögerung von Typ-1-Diabetes abzielen. Ansätze der Immunmodulation zur Sekundär- oder Tertiärprävention werden mit oral zu verabreichendem Insulin (Fr1da-Insulin-Interventionsstudie), humanisierten Antikörpern (Teplizumab, Golimumab, Iscalimab), Erweiterung etablierter Medikamente (Antithymozytenglobulin, Verapamil) oder neuartigen immunmodulatorischen Ansätzen (IMPACT) durchgeführt. Die Einbettung der Studien in internationale, strukturierte wissenschaftliche Netzwerke (INNODIA „an innovative approach towards understanding and arresting type 1 diabetes“, GPPAD globale Plattform zur Prävention des autoimmunen Diabetes) lassen auf deren rasches Voranschreiten und einen hohen wissenschaftlichen Standard schließen. Im Folgenden werden die verschiedenen Wirkansätze zur Prävention des Diabetes mellitus Typ 1 beschrieben und Einblicke in die aktuell stattfindenden Studien gegeben.
The GTPase ADP-ribosylation factor related protein 1 (ARFRP1) controls the recruitment of proteins such as golgin-245 to the
trans-Golgi. ARFRP1 is highly expressed in adipose tissues in which the ...insulin-sensitive glucose transporter GLUT4 is processed through the Golgi to a specialized endosomal compartment, the insulin-responsive storage compartment from which it is translocated to the plasma membrane in response to a stimulation of cells by insulin. In order to examine the role of ARFRP1 for GLUT4 targeting, subcellular distribution of GLUT4 was investigated in adipose tissue specific
Arfrp1 knockout (
Arfrp1
ad
−/−) mice. Immunohistochemical and ultrastructural studies of brown adipocytes demonstrated an abnormal
trans-Golgi in
Arfrp1
ad
−/− adipocytes. In addition, in
Arfrp1
ad
−/− adipocytes GLUT4 protein accumulated at the plasma membrane rather than being sequestered in an intracellular compartment. A similar missorting of GLUT4 was produced by siRNA-mediated knockdown of
Arfrp1 in 3T3-L1 adipocytes which was associated with significantly elevated uptake of deoxyglucose under basal conditions. Thus,
Arfrp1 appears to be involved in sorting of GLUT4.
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