Endocrine Abstracts

Prolonged increases in foetal plasma noradrenaline occur in pathologies, including intrauterine growth restriction (IUGR). Infusion of noradrenaline into healthy sheep foetuses showed continuous suppression of insulin secretion but produced a compensatory beta-cell response after noradrenaline infusion was terminated, similar to findings with adrenergic antagonists in IUGR foetuses. Hyper-insulin secretion responsiveness was confirmed in isolated foetal islets. To identify molecular mechanisms that explain islet programing from chronically elevated noradrenaline, we performed high throughput mRNA sequencing. Noradrenaline (1–4 μg/min per kg) or vehicle was intravenously infused into foetal sheep for 7 days beginning at 131 days of gestation. Islets (n=4/group) were isolated with collagenase procedures. The extracted RNA was sequenced with the Illumina hiseq2500 and analysed with Tuxedo Software using the sheep genome (Oarv3.1). Differentially expressed transcripts were queried for enrichment and modeled to functional pathways. Plasma noradrenaline was increased tenfold in noradrenaline-infused foetuses compared to vehicle-infused controls. In noradrenaline-islets, 321 genes were differentially expressed. These genes were involved in an array of biological processes including: cell death, signal transduction, inflammation, adhesion, and growth. Molecular functions and cellular locations of differentially expressed genes were related to neuronal development, hormone activity, calcium binding, and transcription factor binding. Noradrenaline increased expression of genes that regulate pancreatic endocrine cell function: including; somatostatin (2.9-fold) and death associated protein like 1 (DAPL1, 5.8-fold). Gene shifts that explain insulin hypersecretion include: increases in glycolytic genes aldolase (ALDOB, 2.2-fold) and fructose-1,6-bisphosphatase (FBP, 1.7-fold), as well as NK6 homeobox 3 (NKX6-3, 2.8-fold), phosphatase 2A inhibitor (PP2A, 2.5-fold) and inward rectifying potassium channel (KCNJ8, 3.2-fold) with decreases in synaptic regulatory genes (RIMS4, −1.9-fold). Noradrenaline-induced gene expression describes proximal and distal mechanisms for the observed insulin hyper-secretion. The specific pathways promote glucose metabolism and potassium transport, consistent with better glucose sensitivity, as well as calcium regulation and exocytosis, consistent with more efficient insulin release.