High glucose alters fetal rat islet transcriptome and induces progeny islet dysfunction

Jose Casasnovas, Yunhee Jo, Xi Rao, Xiaoling Xuei, Mary E. Brown, Kok Lim Kua

Research output: Contribution to journalArticle

Abstract

Offspring of diabetic mothers are susceptible to developing type 2 diabetes due to pancreatic islet dysfunction. However, the initiating molecular pathways leading to offspring pancreatic islet dysfunction are unknown. We hypothesized that maternal hyperglycemia alters offspring pancreatic islet transcriptome and negatively impacts offspring islet function. We employed an infusion model capable of inducing localized hyperglycemia in fetal rats residing in the left uterine horn, thus avoiding other factors involved in programming offspring pancreatic islet health. While maintaining euglycemia in maternal dams and right uterine horn control fetuses, hyperglycemic fetuses in the left uterine horn had higher serum insulin and pancreatic beta cell area. Upon completing infusion from GD20 to 22, RNA sequencing was performed on GD22 islets to identify the hyperglycemia-induced altered gene expression. Ingenuity pathway analysis of the altered transcriptome found that diabetes mellitus and inflammation/cell death pathways were enriched. Interestingly, the downregulated genes modulate more diverse biological processes, which includes responses to stimuli and developmental processes. Next, we performed ex and in vivo studies to evaluate islet cell viability and insulin secretory function in weanling and adult offspring. Pancreatic islets of weanlings exposed to late gestation hyperglycemia had decreased cell viability in basal state and glucose-induced insulin secretion. Lastly, adult offspring exposed to in utero hyperglycemia also exhibited glucose intolerance and insulin secretory dysfunction. Together, our results demonstrate that late gestational hyperglycemia alters the fetal pancreatic islet transcriptome and increases offspring susceptibility to developing pancreatic islet dysfunction.

Original languageEnglish (US)
Pages (from-to)309-323
Number of pages15
JournalJournal of Endocrinology
Volume240
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Islets of Langerhans
Transcriptome
Hyperglycemia
Glucose
Insulin
Cell Survival
Fetus
Mothers
RNA Sequence Analysis
Biological Phenomena
Glucose Intolerance
Insulin-Secreting Cells
Gene Expression Profiling
Type 2 Diabetes Mellitus
Diabetes Mellitus
Cell Death
Down-Regulation
Inflammation
Gene Expression
Pregnancy

Keywords

  • Fetal hyperglycemia f late gestation hyperglycemia
  • Fetal islet transcriptome
  • Maternal hyperglycemia
  • Offspring of diabetic mothers
  • Pancreatic islet programming

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

High glucose alters fetal rat islet transcriptome and induces progeny islet dysfunction. / Casasnovas, Jose; Jo, Yunhee; Rao, Xi; Xuei, Xiaoling; Brown, Mary E.; Kua, Kok Lim.

In: Journal of Endocrinology, Vol. 240, No. 2, 01.02.2019, p. 309-323.

Research output: Contribution to journalArticle

Casasnovas, Jose ; Jo, Yunhee ; Rao, Xi ; Xuei, Xiaoling ; Brown, Mary E. ; Kua, Kok Lim. / High glucose alters fetal rat islet transcriptome and induces progeny islet dysfunction. In: Journal of Endocrinology. 2019 ; Vol. 240, No. 2. pp. 309-323.
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