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Etiology
Published in Varma H. Rambaran, Nalini K. Singh, Alternative Medicines for Diabetes Management, 2023
Varma H. Rambaran, Nalini K. Singh
As illustrated in Figure 1.3, after insulin enters the bloodstream it binds to the α-subunits of the INS-R and forms a receptor–ligand complex (Step 1). This, in turn, triggers the intracellular domain of the receptor's β-subunit to undergo phosphorylation by adenosine triphosphate (ATP) (Step 2). Now decorated with the phosphate groups, the INS-R becomes a suitable site for the transfer of these phosphate groups to other target proteins, such as the insulin receptor substrate (INR-S) (Step 3). The phosphorylated INR-S is now a target for insulin receptor tyrosine kinase (IRTK), which upon binding (Step 4) activates the enzyme phosphatidylinositol 3-kinase (PI3K) (Step 5). This domino effect continues as the activated PI3K binds to the membrane lipid, phosphatidylinositol (4,5)-bisphosphate (PIP2) (Step 6) and converts it to phosphatidylinositol (3,4,5)-triphosphate (PIP3) (Step 7). Next in the sequence is protein kinase-B (PKB/Akt), which binds to PIP3 via pleckstrin homology (Step 8). PKB is then phosphorylated on a threonine residue by phosphoinositide-dependent kinase-1 (PDK1) (Step 9), which in turn signals the translocation of the intracellular vesicle glucose transporter type-4 (GLUT-4) to the cell membrane (Step 10). The GLUT-4 finally fuses with the cell membrane (Step 11) and creates a portal through which glucose can enter (Step 12).
Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
One of the most well-described downstream pathways of the IR signaling cascade is the PI3K-AKT signaling pathway. The serine/threonine kinase PI3K is a heterodimer consisting of a regulatory (p85) and a catalytic subunit (p110). PI3K is recruited to the insulin receptor through an SH2 domain on p85, a process facilitated by activated IRS-1 (43). The formation of this complex is thought to release the inhibition of the catalytic p110 subunit by p85 (44). The p110 subunit, now in proximity to its lipid substrate, is free to catalyze the reaction of PIP2 to PIP3. PIP3 acts as a secondary messenger that recruits phosphatidylinositol-dependent protein kinase (PDK1) to the cell membrane. PDK1 subsequently binds AKT via its PH domain and activates it by phosphorylation at Thr308 (45, 46). However, for full AKT activation, further phosphorylation of AKT at Ser473 via mammalian target of rapamycin complex (mTORC) 2-itself activated and bound by PI3K- is necessary (47). AKT itself is known to act on a variety of pathways, though this is dependent on the affected tissue, including the translocation of GLUT4 vesicles to facilitate glucose uptake, the induction of glycogen synthesis, protein synthesis (via mTOR1), and the suppression of gluconeogenesis in peripheral tissues. In the CNS specifically, AKT is known to induce myelination (48), thereby affecting neuronal function, such as affective behavior and spatial memory (49) (Figure 1.1).
1,3-Diphenyl-2-Propene-1-One-Based Natural Product Antidiabetic Molecules as Inhibitors of Protein Tyrosine Phosphatase-1B (PTP-1B)
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Vivek Asati
The kinase enzyme, phosphoinositide 3-kinases (PI3K) downstream the metabolic signaling by phosphorylating the substrate PI to phosphatidylinositol biphosphate (PIP2), thereby activates the protein 3-phosphoinositide-dependent protein kinase-1 (PDK1).16 This cascade activates protein kinase-B (PKB) which is a sole component in the enrichment of glucose uptake by stimulating insulin-dependent GLUT4 translocation (Fig. 7.1).17
Endothelial function in obesity and effects of bariatric and metabolic surgery
Published in Expert Review of Cardiovascular Therapy, 2020
Elijah Sanches, Besir Topal, Monika Proczko, Pieter S. Stepaniak, Rich Severin, Shane A. Phillips, Ahmad Sabbahi, Juan Pujol Rafols, Sjaak Pouwels
Under normal conditions, insulin has both vasodilatory and vasoconstrictor effects. The net effect depends on the balance between the two effects but there is usually a neutral or overall vasodilatory effect. The vasodilatory effects of insulin work through the PI3 K/PDK1/Akt pathway mentioned above. The end result is phosphorylation of eNOS and production of NO. Insulin can also stimulate the mitogen-activated protein (MAP)-kinase signaling pathway leading to increased ET-1 production [78,80]. When insulin resistance is present, the phosphorylation of eNOS via the PI3 K/Akt is downregulated, causing reduced NO production. Moreover, hyperinsulinemia results in increased levels of the potent vasoconstrictor ET-1, disturbing physiological balance [82], and contributing further to obesity-induced endothelial dysfunction and increased CV risk.
Regulation of insulin resistance and glucose metabolism by interaction of PIM kinases and insulin receptor substrates
Published in Archives of Physiology and Biochemistry, 2020
Aziz ur Rehman Aziz, Sumbal Farid, Kairong Qin, Hanqin Wang, Bo Liu
The tyrosine kinase activity of an insulin receptor phosphorylates the IRS on tyrosine residues (DeFronzo and Tripathy 2009), which in turn produces binding sites for different SH2 proteins including PI3K,GRB2, and SHP2 (Hanke and Mann 2009). IRS binding with PI3K produces PIP3, which recruits AKT via PDK1 (Wu et al.2000). PDK1 activates the AKT via T308 phosphorylation, and also phosphorylates the other related kinases i.e. PKCs λ/ι and ζ leading to glucose uptake (Figure 2). AKT T308 phosphorylation by PDK1 is undetectable in IRS lacking tissues (Dong et al.2008, Long et al.2011); however, AKT S473 phosphorylation by mTORC2 is detected in these tissues. The most common variants of IRS-1 and -2 genes, Gly972Arg and Gly1057Asp, respectively, are linked with T2DM (Sir-Petermann et al.2004, Villuendas et al.2005). These results indicate that IRS proteins amplify and transduce the insulin signal downstream and activate different kinases, including PI3K, AKT, and mTOR. Here it is also noteworthy that interrelationships between PIM kinases and above mentioned kinases have been proved (Aziz et al.2018), which are described later in this review.
Myeloid deletion of phosphoinositide-dependent kinase-1 enhances NK cell-mediated antitumor immunity by mediating macrophage polarization
Published in OncoImmunology, 2020
Yuexi He, Juan Du, Zhongjun Dong
Mammalian target of rapamycin (mTOR) signaling is a key nutrient/energy sensor that links nutrient availability to downstream metabolic processes such as protein synthesis, glycolysis and de novo lipogenesis.39 Phosphoinositide-dependent kinase-1 (PDK1) is considered to be a major regulator of mTOR signaling through phosphorylating Akt, which indirectly activates mTOR complex1 (mTORC1) as a serine/threonine kinase. PDK1 is an important signaling molecule downstream of PI3Ks. Overexpression of PDK1 relates to the occurrence and development of tumors.40–43 PDK1 is ubiquitously expressed in all normal cells. Although many chemical inhibitors targeting PDK1 are developed, clinical use of these potential drugs has the risk of lethal toxicity, which hinders further use of these inhibitors. Moreover, PDK1 is also expressed in all immune cells and is essential for the regulation of the immune system. This kinase is indispensable for T lymphocyte activation.44,45 Cell-type specific PDK1 deletion revealed that the absence of PDK1 leads to stunted development of all lymphocytes, including T cells, B cells or NK cells. Therefore, targeting PDK1 very likely causes significant side effects from an immune perspective.