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

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.

In Vivo Decoding Mechanisms of the Temporal Patterns of Blood Insulin by the Insulin-AKT Pathway in the Liver

“…We have found that insulin selectively regulates not only a signaling pathway but also metabolites and gene expression via its temporal patterns using rat hepatoma Fao cells (Kubota et al, 2012;Noguchi et al, 2013;Sano et al, 2016). Therefore, metabolites and gene expression might also be selectively regulated in vivo.…”

“…Among them, metabolic regulation, such as gluconeogenesis, glycogenesis, protein synthesis, and lipid synthesis, is a major target of insulin action and is regulated through the insulin-AKT (also known as protein kinase B [PKB]) signaling pathway and gene regulation in vivo (Whiteman et al, 2002;Yugi et al, 2014). Using rat hepatoma Fao cells, we have revealed that insulin selectively regulates the AKT pathway molecules, metabolism, and gene expression, via its temporal patterns (Kubota et al, 2012;Noguchi et al, 2013;Sano et al, 2016). However, as these results came from a cultured cell line, it remains unknown whether selective regulation by insulin exists in the liver or not.…”

Trans-omic Analysis Reveals Selective Responses to Induced and Basal Insulin across Signaling, Transcriptional, and Metabolic Networks

“…To respond properly to insulin, cells must detect both induced and basal insulin signals and properly interpret each type of insulin signal. We previously showed that signaling proteins, such as Akt ( Kubota et al., 2012 , Kubota et al., 2018 ); metabolites, such as glycogen ( Noguchi et al., 2013 ); and genes, such as glucose-6-phosphatase ( G6Pase ) and phosphoenolpyruvate carboxykinase1 ( Pck1 ) ( Sano et al., 2016 ), show distinct changes in the activity, abundance, or expression in response to a transient high dose or a sustained low dose of insulin. However, the pathways that selectively transmit the induced and basal insulin signals to regulate selective functions have yet to be analyzed.…”

Logical design of oral glucose ingestion pattern minimizing blood glucose in humans

“…The ingestion method was rapid within a minute (bolus ingestion), and continuous over the course of 2 hours (2 h-continuous ingestion). For continuous ingestion, we connected the tube to noncontact microdispenser robot (Mr. MJ; MECT Corporation) (Sano et al, 2016) and glucose solution was ingested from tube. To equalize the volume of ingested glucose solution, glucose solution, TRELAN-G75 (AJINOMOTO), was diluted with distilled water into a total volume 225 ml.…”