RNA Sequencing Exposes Adaptive and Immune Responses to Intrauterine Growth Restriction in Fetal Sheep Islets
| Autor: | Miranda J. Anderson, Leticia E. Camacho, David J. Taska, Amy C. Kelly, Fiona M. McCarthy, Christopher A. Bidwell, Sean W. Limesand |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Intrauterine growth restriction Type 2 diabetes Placental insufficiency Adaptive Immunity Biology Transcriptome Islets of Langerhans 03 medical and health sciences Fetus Endocrinology Immune system Pregnancy Diabetes mellitus Internal medicine medicine Animals Research Articles reproductive and urinary physiology geography Fetal Growth Retardation Sheep geography.geographical_feature_category Sequence Analysis RNA Placental Insufficiency medicine.disease Islet 030104 developmental biology embryonic structures Female Signal Transduction |
| Zdroj: | Endocrinology. 158:743-755 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2016-1901 |
| Popis: | The risk of type 2 diabetes is increased in children and adults who exhibited fetal growth restriction. Placental insufficiency and intrauterine growth restriction (IUGR) are common obstetrical complications associated with fetal hypoglycemia and hypoxia that reduce the β-cell mass and insulin secretion. In the present study, we have defined the underlying mechanisms of reduced growth and proliferation, impaired metabolism, and defective insulin secretion previously established as complications in islets from IUGR fetuses. In an IUGR sheep model that recapitulates human IUGR, high-throughput RNA sequencing showed the transcriptome of islets isolated from IUGR and control sheep fetuses and identified the transcripts that underlie β-cell dysfunction. Functional analysis expanded mechanisms involved in reduced proliferation and dysregulated metabolism that include specific cell cycle regulators and growth factors and mitochondrial, antioxidant, and exocytotic genes. These data also identified immune responses, wnt signaling, adaptive stress responses, and the proteasome as mechanisms of β-cell dysfunction. The reduction of immune-related gene expression did not reflect a change in macrophage density within IUGR islets. The present study reports the islet transcriptome in fetal sheep and established processes that limit insulin secretion and β-cell growth in fetuses with IUGR, which could explain the susceptibility to premature islet failure in adulthood. Islet dysfunction formed by intrauterine growth restriction increases the risk for diabetes. |
| Databáze: | OpenAIRE |
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