Fig. 39.10A ). Binding of insulin to the receptor induces cross-phosphorylation of the subunits. These phosphotyrosine residues are then bound by the insulin receptor substrate (IRS) proteins (i.e., IRS proteins are “recruited” to the InsR). The IRS proteins themselves are phosphorylated by the InsR on specific tyrosines, which then recruits phosphoinositide-3-kinase (PI3K) to the IRS protein bound to the InsR (see
Fig. 39.10B ). PI3K converts phosphoinositol-4,5-bisphosphate (PIP2) to phosphoinositol-3,4,5-trisphosphate (PIP3). PIP3 is an informational lipid that recruits proteins to the membrane. In this pathway, PIP3 recruits Akt protein kinase to the cell membrane where it becomes activated. This pleiotropic Akt protein kinase signaling pathway orchestrates the numerous metabolic actions of insulin in hepatocytes, skeletal muscle, and adipocytes, including (see
Fig. 39.10C 1.
translocation of the GLUT4 glucose transporter to the cell membrane, thereby allowing import of glucose into skeletal myocytes and adipocytes; 2.
activation of protein phosphatases, which in turn regulate the activity of multiple metabolic enzymes in all insulin target cells; 3.
activation of the protein complex mechanistic target of rapamycin complex 1 (mTORC1), which promotes protein synthesis and may inhibit proteosomal-mediated protein degradation in insulin target cells; 4.
activation of the transcription factor sterol response element binding protein 1 (SREBP1).
SREBP1 is especially important for insulin effects on the liver, where it orchestrates glycolysis and de novo lipogenesis (DNL) for production of phospholipids, FAs, and TGs from excessive ingested glucose and fructose. InsR/Akt signaling stimulates SREBP1 directly as well as indirectly through activation of mTORC1, which also activates SREBP1. SREBP1 also induces the enzyme that catalyzes the first reaction in the oxidative arm of the pentose phosphate pathway (PPP). This reaction generates the coenzyme NADPH, which is required for DNL.
5. inactivation of the transcription factor FOXO1. Aktmediated phosphorylation of FOXO1 promotes nuclear exclusion of FOXO1. In the absence of insulin/Akt signaling, FOXO1 induces expression of genes encoding
VLDL assembly and export. All these actions of Akt will be discussed in more detail later. The InsR also promotes proliferation/renewal of some target cells through the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway (see
Fig. 39.10B ). The MAPK pathway also participates in some metabolic regulation.
Glucagon is the primary counterregulatory hormone that increases blood glucose levels, primarily through its effects on liver glucose output. Glucagon also enhances intramitochondrial fatty acid oxidation and ketogenesis in hepatocytes.
Glucagon is a member of the secretin gene family. The precursor preproglucagon harbors the AA sequences for glucagon, GLP-1, and GLP-2 (