Insulin-regulated gene expression

Abstract

Insulin regulates the expression of more than 150 genes, indicating that this is a major action of this hormone. At least eight distinct consensus insulin response sequence (IRSs) have been defined through which insulin can regulate gene transcription. These include the serum response element, the activator protein 1 ('AP-1') motif, the Ets motif, the E-box motif and the thyroid transcription factor 2 ('TTF-2') motif. All of these IRSs mediate stimulatory effects of insulin on gene transcription. In contrast, an element with the consensus sequence T(G/A)TTT(T/G)(G/T), which we refer to as the phosphoenolpyruvate carboxykinase (PEPCK)-like motif, mediates the inhibitory effect of insulin on transcription of the genes encoding PEPCK, insulin-like-growth-factor-binding protein 1 (IGFBP-1), tyrosine aminotransferase and the glucose-6-phosphatase (G6Pase) catalytic subunit. The forkhead transcription factor FKHR has recently been shown to bind this PEPCK-like IRS motif and a model has been proposed in which insulin inhibits gene transcription by stimulating the phosphorylation and nuclear export of FKHR. Our results suggest that this model is consistent with the action of insulin on transcription of the gene encoding IGFBP-1 but not that of the G6Pase catalytic subunit. Thus, even though the IRSs in both promoters seem identical, they are functionally distinct. In addition, in the G6Pase catalytic subunit promoter, hepatocyte nuclear factor 1 ('HNF-1'), acts as an accessory factor to enhance the effect of insulin mediated through the IRS.

Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

“…Interestingly, activation of ERK1/2 is unchanged, consistent with similar observations in muscles of insulin-resistant subject and a greater role for the IGF1R signals in ERK activation and sustained IGF1 signaling in IR-Mut cells (30)(31)(32)(33). As a result of these upstream alterations in insulin signaling, we also observed impaired insulin stimulation of early growth-related genes, such as EGR1, cFOS, and cJUN, as well as reduced expression of insulindependent metabolic genes such as RAD1, HK2, and GLUT4 (18,19). RAD1 encodes a protein that belongs to a class of small GTP binding proteins related to Ras, which was first identified as being overexpressed in skeletal muscle of patients with T2D (18).…”

“…Both insulin and diabetes also exert potent effects on transcription of metabolic and growth-regulatory genes in skeletal muscle, including ras-related associated with diabetes (RAD1), hexokinase 2 (HK2), and glucose transporter type 4 (GLUT4) (18)(19)(20)(21). Basal expression of these genes was significantly reduced in IR-Mut myotubes compared with controls ( Fig.…”

Liver-specific mRNA for Insig-2 down-regulated by insulin: Implications for fatty acid synthesis

“…In marked contrast, the Insig-2a mRNA rose 6-fold upon STZ treatment and was repressed with insulin. This change was in the same direction, although not as profound, as the changes in four classic insulin-repressed genes, namely, PEPCK, glucose-6-phosphatase, IGFBP-1, and IRS-2 (7,19,21). In contrast, SREBP-1c mRNA levels fell dramatically upon STZ treatment and rose when insulin was injected.…”

The role of inflammation and macrophage accumulation in the development of obesity-induced type 2 diabetes mellitus and the possible therapeutic effects of long-chainn-3 PUFA

“…During association with IRS proteins phosphatidylinositol 3-kinase is activated and its phospholipid products promote the recruitment of various serine kinases such as protein kinases B and C to the plasma membrane, where they are activated by phosphorylation (20) . Protein kinases B and C phosphorylate multiple downstream effectors that promote diverse biological responses including: GLUT4 translocation at the plasma membrane (21) ; glycogen synthesis via protein kinase B-mediated inhibitory phosphorylation of glycogen synthase kinase-3, which negatively regulates glycogen synthase (22) ; lipogenesis via up-regulation of the expression of the fatty acid synthase gene (23) ; more general control of gene expression patterns (24) . GLUT4 is the predominant GLUT isoform expressed in mature muscle and fat tissues and is primarily responsible for enhanced glucose uptake in response to insulin (25) .…”