DLL1- and DLL4-Mediated Notch Signaling Is Essential for Adult Pancreatic Islet Homeostasis

Abstract

Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Deltalike 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of Dll1 leads to premature endocrine differentiation. However, the role of Delta-Notch signaling in adult tissue homeostasis is not well understood. Here, we describe the spatial expression pattern of Notch pathway components in adult murine pancreatic islets and show that DLL1 and -4 are specifically expressed in β-cells, whereas JAGGED1 is expressed in α-cells. We show that mice lacking both DLL1 and DLL4 in adult -cells display improved glucose tolerance, increased glucosestimulated insulin secretion and hyperglucagonemia. In contrast, overexpression of the intracellular domain of DLL1 in adult murine pancreatic β-cells results in impaired glucose tolerance and reduced insulin secretion, both in vitro and in vivo. These results suggest that NOTCH ligands play specific roles in the adult pancreas and highlight a novel function of the Delta-Notch pathway in β-cell insulin secretion.

Association of DLL1 with type 1 diabetes in patients characterized by low polygenic risk score

“…FAM120B showed nominal statistical significance, lacking genome-wide significance in the two low PRS cohorts (Supplementary Tables 1 and 2). In conclusion, this study highlights the role of genetic variants of DLL1 in low PRS T1D, which is less dependent on autoimmune mechanisms, as further supported by the functional study on DLL1 in diabetes by Rubey et al [15]. The genetic effects of DLL1 in low PRS T1D was further supported by the decile analysis in this study.…”

“…A recent study by Rubey et al suggests that the DLL1 signaling is essential for adult pancreatic islet homeostasis and overexpression of DLL1 causes impaired glucose tolerance and reduced insulin secretion [15]. In our previous large-scale meta-analysis, the DLL1/FAM120B locus showed association with T1D in Caucasian; however, this analysis included additional samples genotyped by an Affymetrix genotyping array [3], whereas those samples could not be included in the current study as limited by the performance of the PRS modeling.…”

Insights into non-autoimmune type 1 diabetes with 13 novel loci in low polygenic risk score patients

“…LocusZoom plots for genetic association signals within each locus are shown in Supplementary Figures 8 – 25 . Among the 18 loci, 16 loci are novel, while the Notch ligand Delta-like 1 ( DLL1 ) locus, with the gene function essential for pancreatic islet homeostasis 23 , have been identified by our gene-based association study on low PRS T1D 24 . The other locus, containing the UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 2 gene ( B3GNT2 ) and transmembrane protein 17 gene ( TMEM17 ), is ~ 200 kb from the Eps15 homology domain binding protein 1 locus ( EHBP1 ) that has been identified of genome-wide significance in our study on low T1D GRS patients 21 .…”

Whole-Slide Image Analysis of Human Pancreas Samples to Elucidate the Immunopathogenesis of Type 1 Diabetes Using the QuPath Software

“…Interestingly, whole-slide image analysis is widely used in pancreatic malignancies for the detection of infiltrating immune cells or for annotation of tumor areas (Carstens et al, 2021;Zacarías-Fluck et al, 2021;Bulle et al, 2020), yet in the T1D research field this is still not a common practice. To date, out of the 552 publications citing QuPath (Bankhead, 2021), 27 used it for analysis of images from the pancreas or from isolated pancreatic islets (human or rodent): 24 were found related to pancreatic cancer, 3 to diabetes (Rajendran et al, 2020;Rubey et al, 2020;Apaolaza et al, 2021) and, to our knowledge, only 2 of them describe results from whole-image analysis of donors with T1D (Rajendran et al, 2020;Apaolaza et al, 2021).…”