Research ArticlePhysiology

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

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.

Abstract

Secretion of insulin transiently increases after eating, resulting in a high circulating concentration. Fasting limits insulin secretion, resulting in a low concentration of insulin in the circulation. We analyzed transcriptional responses to different temporal patterns and doses of insulin in the hepatoma FAO cells and identified 13 up-regulated and 16 down-regulated insulin-responsive genes (IRGs). The up-regulated IRGs responded more rapidly than did the down-regulated IRGs to transient stepwise or pulsatile increases in insulin concentration, whereas the down-regulated IRGs were repressed at lower concentrations of insulin than those required to stimulate the up-regulated IRGs. Mathematical modeling of the insulin response as two stages—(i) insulin signaling to transcription and (ii)transcription and mRNA stability—indicated that the first stage was the more rapid stage for the down-regulated IRGs, whereas the second stage of transcription was the more rapid stage for the up-regulated IRGs. A subset of the IRGs that were up-regulated or down-regulated in the FAO cells was similarly regulated in the livers of rats injected with a single dose of insulin. Thus, not only can cells respond to insulin but they can also interpret the intensity and pattern of signal to produce distinct transcriptional responses. These results provide insight that may be useful in treating obesity and type 2 diabetes associated with aberrant insulin production or tissue responsiveness.

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