Research ArticlesPhysiology

Selective control of up-regulated and down-regulated genes by temporal patterns and doses of insulin

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Sci. Signal.  22 Nov 2016:
Vol. 9, Issue 455, pp. ra112
DOI: 10.1126/scisignal.aaf3739

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Insulin highs and lows

Insulin is released by the pancreas and enables tissues such as skeletal muscle, fat, and liver to take up glucose. The pancreas secretes a basal amount of insulin, and eating triggers a rapid, transient increase in insulin release. Sano et al. identified a set of genes that increased in expression and a set that decreased in expression in response to insulin in hepatoma cells. Stimulating the cells with different doses and temporal patterns of insulin revealed that the up-regulated genes responded more rapidly than did the down-regulated genes to transient high concentrations of insulin stimulation; the down-regulated genes responded to lower concentrations of insulin than did the up-regulated genes. Simple mathematical modeling of the insulin-stimulated transcriptional pathway in two parts [(i) insulin to nucleus and (ii) transcription and mRNA degradation] suggested that the suppression of down-regulated genes occurred at steps before transcription and that transcription and transcript degradation rates were higher for the up-regulated genes. Livers from rats receiving a single dose of insulin exhibited increased or decreased expression of a subset of the regulated genes identified in the hepatoma cells. In particular, a gene involved in cholesterol biosynthesis was stimulated by insulin in culture and in vivo, and genes involved in gluconeogenesis were suppressed.