Biology subjects

Engin, F.

Publications and source records attributed to Engin, F..

4 recordsLinked to original sources

bioRxiv2023

Ormdl3 regulation of specific ceramides is dispensable for β-cell function and glucose homeostasis under obesogenic conditions

Chronic elevation of sphingolipids contributes to {beta}-cell failure. ORMDL3 has been identified as a key regulator of sphingolipid homeostasis, however, its function in pancreatic {beta}-cell pathophysiology remains unclear. Here, we generated a mouse model lacking Ormdl3 within pancreatic {beta}-cells (Ormdl3{beta}-/-). We show that loss of {beta}-cell Ormdl3 does not alter glucose tolerance, insulin sensitivity, insulin secretion, islet morphology, or cellular ceramide levels on standard chow diet. When challenged with a high fat diet, while Ormdl3{beta}-/- mice did not exhibit any alteration in metabolic parameters or islet architecture, lipidomics analysis revealed significantly higher levels of very long chain ceramides in their islets. Taken together, our results reveal that loss of Ormdl3 alone is not sufficient to impinge upon {beta}-cell function or whole-body glucose and insulin homeostasis, but loss of Ormdl3 does alter specific sphingolipid levels.

cell biology↗

bioRxiv2021

Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Pancreatic {beta}-cells undergo high levels of endoplasmic reticulum (ER) stress due to their role in insulin secretion. Hence, they require sustainable and efficient adaptive stress responses to cope with the stress. Whether duration and episodes of chronic ER stress directly compromises {beta}-cell identity is largely unknown. We show that under reversible, chronic ER stress, {beta}-cells undergo a distinct transcriptional and translational reprogramming. During reprogramming, expression of master regulators of {beta}-cell function and identity and proinsulin processing is impaired. Upon recovery from stress, {beta}-cells regain their identity, highlighting a high-degree of adaptive {beta}-cell plasticity. Remarkably, when stress episodes exceed a certain threshold, {beta}-cell identity is gradually lost. Single cell RNA-seq analysis of islets from type 1 diabetes (T1D) patients, identifies the severe deregulation of the chronic stress-adaptation program, and reveals novel biomarkers for progression of T1D. Our results suggest {beta}-cell adaptive exhaustion ({beta}EAR) is a significant component of the pathogenesis of T1D.

systems biology↗

bioRxiv2021

Machine learning algorithms in big data analyses identify determinants of insulin gene transcription

Machine learning (ML)-workflows enable unprejudiced/robust evaluation of complex datasets. Here, we analyzed over 490,000,000 data points to compare 10 different ML-workflows in a large (N=11,652) training dataset of human pancreatic single-cell (sc-)transcriptomes to identify genes associated with the presence or absence of insulin transcript(s). Prediction accuracy/sensitivity of each ML-workflow were tested in a separate validation dataset (N=2,913). Ensemble ML-workflows, in particular Random Forest ML-algorithm delivered high predictive power (AUC=0.83) and sensitivity (0.98), compared to other algorithms. The transcripts identified through these analyses also demonstrated significant correlation with insulin in bulk RNA-seq data from human islets. The top-10 features, (including IAPP, ADCYAP1, LDHA and SST) common to the three Ensemble ML-workflows were significantly dysregulated in scRNA-seq datasets from Ire-1{beta}-/- mice that demonstrate dedifferentiation of pancreatic {beta}-cells in a model of type 1 diabetes (T1D) and in pancreatic single cells from individuals with type 2 Diabetes (T2D). Our findings provide direct comparison of ML-workflows in big data analyses, identify key determinants of insulin transcription and provide workflows for future analyses.

genetics↗

bioRxiv2019

Differential expression of Ormdl genes in the islets of mice and humans with obesity

The orosomucoid-like proteins (Ormdl1-3) are emerging as the critical regulators of sphingolipid homeostasis, inflammation and ER stress. However, their roles in {beta}-cells and obesity remain unknown. Here, we showed that islets isolated from overweight/obese human donors displayed marginally reduced ORMDL1-2 expression while ORMDL3 expression was significantly reduced as compared to islets from lean donors. In contrast, Ormdl3 expression was significantly upregulated in the islets of leptin-deficient obese (ob/ob) mice compared to lean mice. We identified that the difference in expression of Ormdl3 between mouse and human islets was leptin-dependent, as treatment of ob/ob mice with leptin significantly reduced Ormld3 expression. Furthermore, Ormdl1-3 were significantly upregulated upon chemically-induced ER stress, but they showed differential responsiveness to cytokines in a {beta}-cell line. Knockdown of Ormdl3 substantially increased expression of apoptotic markers, which was rescued by a pharmacological inhibitor of ceramide synthase. Taken together we demonstrate leptin-dependent regulation of Ormdl3 expression in ob/ob islets, highlight the possible importance of {beta}-cell stress conditions in differential Ormdl expression and identify a critical role for Ormdl3 in {beta}-cell survival.

molecular biology↗