Single-cell gene expression profile of cultured mouse islet cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE255447 | GEO | 2025/07/29
REPOSITORIES: GEO
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Project description:Dysfunction of pancreatic alpha cells contributes to the pathophysiology of diabetes. Features of diabetic alpha cell dysfunction include glucagon hypersecretion, defects in proglucagon processing, and altered transcriptomic profile. The lack of an in vitro human alpha cell model has prevented the investigation, and potential correction, of these dysfunctional phenotypes. Here, we show that induction of endoplasmic reticulum stress in stem cell-derived alpha (SC-α) cells induces hypersecretion of glucagon. ER stress also increases the secretion of glicentin and expression of GLP-1, peptides produced by alternate cleavage of proglucagon by the prohormone convertase 1 (PC1/3) enzyme. Additionally, ER stress establishes a diabetic transcriptional state in SC-α cells characterized by downregulation of MAFB, as well as glycolysis and oxidative phosphorylation pathways. We show that sunitinib, a tyrosine kinase inhibitor, protects SC-α cells against the ER stress-induced glucagon hypersecretion phenotype. Thus, SC-α cell model can advance our knowledge of islets in health and diabetes.
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Project description:This a model from the article:
Pancreatic network control of glucagon secretion and counterregulation.
Farhy LS, McCall AL. Methods Enzymol.
2009;467:547-81. 19897107
,
Abstract:
Glucagon counterregulation (GCR) is a key protection against hypoglycemia compromised in insulinopenic diabetes by an unknown mechanism. In this work, we present an interdisciplinary approach to the analysis of the GCR control mechanisms. Our results indicate that a pancreatic network which unifies a few explicit interactions between the major islet peptides and blood glucose (BG) can replicate the normal GCR axis and explain its impairment in diabetes. A key and novel component of this network is an alpha-cell auto-feedback, which drives glucagon pulsatility and mediates triggering of pulsatile GCR by hypoglycemia via a switch-off of the beta-cell suppression of the alpha-cells. We have performed simulations based on our models of the endocrine pancreas which explain the in vivo GCR response to hypoglycemia of the normal pancreas and the enhancement of defective pulsatile GCR in beta-cell deficiency by switch-off of intrapancreatic alpha-cell suppressing signals. The models also predicted that reduced insulin secretion decreases and delays the GCR. In conclusion, based on experimental data we have developed and validated a model of the normal GCR control mechanisms and their dysregulation in insulin deficient diabetes. One advantage of this construct is that all model components are clinically measurable, thereby permitting its transfer, validation, and application to the study of the GCR abnormalities of the human endocrine pancreas in vivo.
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2005-01-01 | MODEL1112110002 | BioModels
Project description:Diabetes is characterized by hyperglycemia, loss of functional islet beta cell mass, deficiency of glucose-lowering insulin, and persistent alpha cell secretion of gluconeogenic glucagon. Still, no therapies that target these underlying processes are available. We therefore performed high-throughput screening of 300,000 compounds and extensive medicinal chemistry optimization and here report the discovery of SRI-37330, an orally bioavailable, non-toxic small molecule, which effectively rescued mice from streptozotocin- and obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and human islets, SRI-37330 inhibited expression and signaling of thioredoxin-interacting protein, which we have previously found to be elevated in diabetes and to have detrimental effects on islet function. In addition, SRI-37330 treatment inhibited glucagon secretion and function, reduced hepatic glucose production, and reversed hepatic steatosis. Thus, these studies describe a newly designed chemical compound that, compared to currently available therapies, may provide a distinct and effective approach to treating diabetes.
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