Biology subjects

Ilegems, E.

Publications and source records attributed to Ilegems, E..

5 recordsLinked to original sources

bioRxiv2026

Targeting PFKFB3 Metabolic Gatekeeping of β-Cell Dysfunctional States Enables Durable Glucose Tolerance in Type 2 Diabetes

Progressive {beta}-cell dysfunction underlies type 2 diabetes (T2D), yet existing therapies fail to correct the dysfunctional cellular states that accumulate during disease progression. We show that pharmacological inhibition of PFKFB3 markedly reduced the population of PFKFB3 dysfunctional {beta}-cells while preserving functional islet mass, consistent with selective depletion or phenotypic reprogramming of compromised {beta}-cells. In transgenic diabetic mice expressing human IAPP, PFKFB3 inhibitor AZ67 improved glucose-stimulated insulin secretion and glucose tolerance through a mechanism consistent with direct restoration of {beta}-cell function and distinct from incretin-based therapy. Critically, glycemic improvement persisted after treatment withdrawal, consistent with durable remodeling of islet functional states rather than transient pharmacological suppression. In human islet microtissues under glucotoxic and cytokine stress, AZ67 and its analogue AZ26 improved insulin secretion and proinsulin processing in a stress- and compound-dependent manner while reducing PFKFB3 dysfunctional endocrine populations. Transcriptomic profiling identified suppression of inflammatory programs and activation of cholesterol homeostasis and adaptive metabolic pathways. These findings establish PFKFB3 inhibition as a potential disease-modifying therapeutic strategy for T2D.

cell biology↗

bioRxiv2026

From bats to humans: uncovering ISG15 as a new resistance factor in type 1 diabetes

Viral infections are one of the main environmental factors triggering type 1 diabetes (T1D). Pancreatic alpha cells are more resistant than beta cells to diabetogenic viruses, partially explaining their survival in T1D. Similarly, bats have enhanced viral resistance, suggesting putative convergent evolution in antiviral mechanisms. Herein, we compared global gene expression in bat fibroblasts under basal conditions or exposed to double-stranded RNA to human alpha and beta cells and found that alpha cells exhibit greater similarity than beta cells to the antiviral responses of bat cells, as well as stronger intrinsic resistance to viral infection. Interferon-stimulated gene 15 (ISG15), a key regulator of antiviral responses in humans and bats, has higher expression in alpha compared to beta cells in five single-cell RNASeq datasets from human islet cells and in human induced pluripotent stem cell (hiPSC)-derived alpha-like cells. ISG15 knockdown in human insulin-producing EndoC-{beta}H1 cells and human islets increases apoptosis under basal conditions and after IFN exposure, exacerbates IFN responses and increases cell death and viral production after infection with the diabetogenic virus coxsackievirus B1, while its overexpression protects EndoC-{beta}H1 cells from the virus. Collectively, the present results demonstrate that alpha cells but not beta cells have similarities with the virus resistance gene program present in bats and identify ISG15 as an important factor for islet cells to cope with viral and diabetogenic stresses.

immunology↗

bioRxiv2025

Differential immune- and apoptosis-related gene signatures in pancreatic alpha and beta cells contribute to their fate in type 1 diabetes

Both alpha and beta cells are dysfunctional in type 1 diabetes (T1D), but beta cells die while alpha cells survive the immune attack. Understanding the mechanisms underlying alpha-cell resistance could identify new approaches to protect beta cells. Herein, we analysed single-cell datasets from human alpha and beta cells under basal/unstimulated conditions and under immune-mediated stress. Alpha cells exhibit enhanced immune-like gene expression compared to beta cells. We also found that the tumour suppressor Maternally Expressed Gene 3 (MEG3), a T1D risk gene, is highly expressed in beta cells while almost undetectable in alpha cells. These observations were confirmed by analysing bulk RNA-sequencing data from fluorescence-activated cell-sorted alpha and beta cells isolated from primary human islets from non-diabetic donors. Additionally, MEG3 knockdown in human insulin-producing EndoC-{beta}H1 cells and human islets microtissues decreased cytokine-induced damage and apoptosis, preserving beta-cell function under inflammatory conditions. The fact that alpha cells exhibit increased immune-like and anti-apoptotic activity as compared to beta cells suggests that they are better equipped to endure the autoimmune assault in T1D. In addition, the marked difference in the expression of the pro-apoptotic factor MEG3 in beta cells compared to alpha cells may explain, at least in part, why beta cells are more susceptible to damage and cell death in a diabetogenic environment than neighbour alpha cells within the same islet.

cell biology↗

bioRxiv2023

Diet-induced obesity results in endothelial cell desensitization to VEGF-A and permanent islet vascular dysfunction

BackgroundPancreatic islet microvasculature is essential for optimal islet function and glucose homeostasis. However, islet vessel pathogenesis and its role in the manifestation of metabolic disorders remain understudied. Here we depict a time-resolved decline of intra-islet endothelial cell sensitivity to vascular endothelial cell growth factor A (VEGF-A) in a mouse model of diet-induced obesity. MethodsMice were transplanted with reporter islets in their eyes and put on different diet schemes for 48 weeks. Islet vascular morphology, VEGF-A signaling activity in islet endothelial cells and vessel function were longitudinally monitored by in vivo imaging, while the metabolic implication of islet vessel alterations was measured by glucose tolerance tests and insulin secretion assays. ResultsIn parallel with substantial islet vasculature remodeling, diminished VEGF-A response in islet endothelial cells emerged after 12 weeks of western diet feeding. This led to vessel barrier dysfunction and hemodynamic dysregulation, which delayed transportation of secreted insulin into the blood. Islet vessels also exhibited a remarkable metabolic memory long after the removal of western diet. Neither islet endothelial cell VEGF-A sensitivity nor the vascular damage elicited by 24 weeks of western diet feeding was restored by switching to control diet for another 24 weeks. As a result, these refed mice still exhibited mild but significant impairment in glucose clearance, despite a complete normalization of body weight and insulin sensitivity. While plasma levels of soluble VEGF receptor 1 - the natural VEGF-A trap - were similar in all diet groups, increased activity of atypical protein kinase C (aPKC) was observed under both western diet and recovery conditions, which inhibited VEGF receptor 2 (VEGFR2) internalization and dampened VEGF-A triggered signal transduction in vivo and in human endothelial cells cultured under diet-mimicking conditions. ConclusionsLong-term western diet feeding causes irreversible VEGF-A desensitization in islet endothelial cells and islet vessel dysfunction which undermines glucose homeostasis.

physiology↗

bioRxiv2022

An MR-based brain template and atlas for optical projection tomography and light sheet fluorescence microscopy

Optical projection tomography (OPT) and light sheet fluorescence microscopy (LSFM) are high-resolution optical imaging techniques operating in the mm-cm range, ideally suited for ex vivo 3D whole mouse brain imaging. Although these techniques exhibit high sensitivity and specificity for antibody-labeled targets, the provided anatomical information remains limited. To allow anatomical mapping of fluorescent signal in whole brain, we developed a novel magnetic resonance (MR) - based template with its associated tissue priors and atlas labels, specifically designed for brains subjected to tissue processing protocols required for 3D optical imaging. We investigated the effect of tissue pre-processing and clearing on brain size and morphology and developed optimized templates for BABB/Murrays clear (OCUM) and DBE/iDISCO (iOCUM) cleared brains. By creating optical-(i)OCUM fusion images using our mapping procedure, we localized dopamine transporter and translocator protein expression and tracer innervation from the eye to the lateral geniculate nucleus of thalamus and superior colliculus. These fusion images allowed for precise anatomical identification of fluorescent signal in discrete brain areas. As such, these templates enable applications in a broad range of research areas integrating optical 3D brain imaging by providing an MR template for cleared brains.

neuroscience↗