It is proposed that the impaired sympathoadrenal response to hypoglycemia induced by recurrent insulin-induced hypoglycemia (RH) is an adaptive phenomenon induced by specific changes in microRNA expression in the ventromedial hypothalamus (VMH). To test this hypothesis, genomewide microRNAomic profiling of the VMH by RNA-sequencing was performed in control rats and rats treated for RH. Differential expression analysis identified microRNA-7a-5p and microRNA-665 as potential mediators of this phenomenon. To further test this hypothesis, experiments were conducted consisting of targeted lentiviral-mediated overexpression of microRNA-7a-5p and downregulation of microRNA-665 in the VMH. Hyperinsulinemic hypoglycemic clamp experiments demonstrated that targeted overexpression of microRNA-7a-5p (but not downregulation of microRNA-665) in the VMH of RH rats restored the epinephrine response to hypoglycemia. This restored response to hypoglycemia was associated with a restoration of GABAA receptor gene expression. Finally, a direct interaction of microRNA-7a-5p with the 3′-UTR of GABAA receptor α1-subunit (Gabra1) gene was demonstrated in a luciferase assay. These findings indicate that (a) the impaired sympathoadrenal response RH induces is associated with changes in VMH microRNA expression and (b) microRNA-7a-5p, possibly via direct downregulation of GABA receptor gene expression, may serve as a mediator of the altered sympathoadrenal response to hypoglycemia.
|State||Published - Oct 3 2019|
Bibliographical noteFunding Information:
This work was supported by funding from National Institutes of Health R01 NS070235-01A1 (to SJF) and R01DK118082 (to SJF), the Juvenile Diabetes Research Foundation 2-SRA-2014-270-M-R (to SJF), and the University of Utah’s Diabetes and Metabolism Research Center. We are grateful for support from the High-throughput Genomics and Bioinformatic Analysis core facility of Huntsman Cancer Institute and the Genomics, DNA/Peptide Synthesis, and Fluorescence Microscopy core facilities of Heath Sciences cores at the University of Utah. The authors have declared that no conflict of interest exists.
© 2019, American Society for Clinical Investigation.
ASJC Scopus subject areas
- Medicine (all)