144. Patel S, Doble BW, MacAulay K, Sinclair EM, Drucker DJ, Woodgett JR. Tissue-specific role of glycogen synthase kinase 3beta in glucose homeostasis and insulin action. 2008;28:6314-28
23. Cross DA, Alessi DR, Vandenheede JR, McDowell HE, Hundal HS, Cohen P. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. 1994;303:21-6
2. Summers SA, Kao AW, Kohn AD, Backus GS, Roth RA, Pessin JE. . The role of glycogen synthase kinase 3beta in insulin-stimulated glucose metabolism. 1999;274:17934-40
Gebhardt et al. showed application of emodin (82) and its ethylenediamine analog 83 as non-ATP competitive inhibitors of GSK-3 (Table ). Addition of the ethylenediamine group on the emodin nucleus increased potency of inhibition (IC50 0.56±0.02 µM, 83), reduced cytotoxicity and generated an insulin sensitizing effect mediated by increasing hepatocellular glycogen and fatty acid biosynthesis. Selectivity's of compounds 82 and 83 were evaluated against twelve protein kinases including eleven of human protein kinases. Compound 83 showed high selectivity towards GSK-3β but 82 failed to do so.
PTPase (Protein Tyrosine Phosphatases) catalyze the dephosphorylation of insulin receptor and its substrates, leading to attenuation of insulin action. A number of PTPases have been implicated as the negative regulator of insulin signaling. Among them, the intracellular PTPase, PTP1B, has been shown to function as the insulin receptor phosphatase. PTEN (Phosphatase and Tensin Homolog Deleted On Chromosome-10) negatively regulates insulin signaling. SHIP2 (SH2-containing Inositol Phosphatase-2) is another negative regulator of insulin signaling and such negative regulation depends on its 5'-phopshatase activity. Overexpression of SHIP2 protein decreases Insulin-dependent PIP3 production as well as insulin-stimulated Akt activation, GSK3 inactivation, and glycogen synthetase activation. Insulin increases glucose uptake in muscle and fat, and inhibits hepatic glucose production, thus serving as the primary regulator of blood glucose concentration. Insulin also stimulates cell growth and differentiation, and promotes the storage of substrates in fat, liver and muscle by stimulating lipogenesis, glycogen and protein synthesis, and inhibiting lipolysis, glycogenolysis and protein breakdown. Insulin resistance or deficiency results in profound dysregulation of these processes, and produces elevations in fasting and postprandial glucose and lipid levels.
6. Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L, Henry RR. Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. 2000;49:263-71
Tyrosine-phosphorylated IRS then displays binding sites for numerous signaling partners. PI3K has a major role in insulin functions. It regulates three main classes of signaling molecules: the AGC family of serine/threonine protein kinases, guanine nucleotide-exchange proteins of the Rho family of GTPases, and the Tec family of tyrosine kinases. The best characterized of the AGC kinases is PDK-1 (Phosphoinositide-Dependent Kinase-1), one of the serine kinases that phosphorylates and activates the serine/threonine kinase Akt/PKB (Protein Kinase-B). Akt possesses a PH domain that also interacts directly with PIP3 (Phosphatidylinositol -3, 4, 5-Triphosphate), promoting membrane targeting of the protein and catalytic activation. Akt has been suggested to be important in transmission of the insulin signal, by phosphorylation of the enzyme GSK3 (Glycogen Synthase Kinase-3), the FKHRL1 (Forkhead-Related Family of Mammalian Transcription Factor) and cAMP (Cyclic Adenosine Monophosphate) response element-binding protein. Akt inhibits apoptosis by phosphorylating the BAD (BCL2 Antagonist of Cell Death) component of the BAD/BCLXL complex. Phosphorylated BAD binds to 14-3-3 causing dissociation of the BAD/BCLXL complex and allowing cell survival, and Akt activates IKK, which ultimately leads to NF-KappaB (Nuclear Factor-KappaB) activation and cell survival. Akt also activates the mTOR (Mammalian Target of Rapamycin)/FRAP pathway. Activation of mTOR results in the phosphorylation of ribosomal protein S6 kinase, p70S6K, which is also regulated by phosphorylation by PDK-1. Rapamycin (FRAP) interactions with mTOR also regulate the activity of p70S6K, the kinase that phosphorylates the 40S ribosomal protein S6. S6 is thought to be the only p70S6K substrate, and by controlling S6 phosphorylation, p70S6K regulates the translation of an essential family of mRNAs that contain an oligopyrimidine tract at their transcriptional start site. Activation of mTOR also results in phosphorylation and inactivation of eIF4EBP (Eukaryotic Initiation Factor 4EBinding Protein), also known as PHAS, an inhibitor of the translation initiation factor eIF4E (Eukaryotic Initiation Factor-4E). Insulin induces dephosphorylation of eEF2 (Eukaryotic Elongation Factor-2) and inactivation of eEF2K (Eukaryotic Elongation Factor-2 Kinase), and these effects are blocked by rapamycin, which inhibits the mammalian target of rapamycin, mTOR.