Dynamic Functional Relay between Insulin Receptor Substrate 1 and 2 in Hepatic Insulin Signaling during Fasting and Feeding

Abstract

Insulin receptor substrate (Irs) mediates metabolic actions of insulin. Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding.

Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance

“…The reverse-transcription reaction was carried out with a high-capacity cDNA reverse transcription kit (Applied Biosystems). Quantitative PCR analyses using TaqMan assays were performed as previously described (37). The relative expression levels were normalized by measurement of the amount of cyclophilin in each sample.…”

“…injections of glucose after an overnight fast. Blood glucose levels were measured using a Glutest sensor (Sanwa Chemical) at the indicated time points, and the plasma insulin levels were measured using a RIA kit (Biotrek), as previously described (37).…”

Development of novel cell lines of diabetic dysfunction model fit for cell-based screening tests of medicinal materials

“…This is thought to be compensation for the loss of Irs-1 function described e.g. in Kubota et al (2008) and Dobrzyn et al (2010). (iii) A decrease in the level of expression of Pdx-1 reduced Irs-2 expression, and this effect surpassed the reverse effect described above in (ii) as demonstrated in the double knockdown cells (double knockdown cell lines in Fig.…”

“…GSIS is a combination of glucose reception and insulin secretion functions. A number of studies have examined the genetic basis of diabetes and identified specific genes for insulin production (Melloul et al 2001), insulin reception (Kubota et al 2008;Guo et al 2009;Dobrzyn et al 2010), and GSIS (Pal 2009;Bennett et al 2010). It has been speculated that the genes for these various roles are functionally linked.…”

“…In these pathways, Irs-2 is of particular interest. Irs-2 expression is activated in compensation for the loss of Irs-1 function (Kubota et al 2008;Dobrzyn et al 2010;González-Rodríguez et al 2010;Yang et al 2010). Following its activation, Irs-2 stimulates expression of further downstream genes associated with insulin production.…”