Table 2.
Pharmacological and physiological modulators of IR activation.
| Classification | Modulators | IR Modulation Mechanism | Model Organisms or Cells | Side Effects | References |
|---|---|---|---|---|---|
| Insulin and insulin analogs | insulin and IGFs, |
ligand-induced internalization and degradation of the IR | human | tissue irritation, abscesses, allergic edema, weight gain, risk of congestive heart failure | [3] |
| lispro, | [32,135] | ||||
| aspart, | |||||
| glulisine, | |||||
| aspb10, | |||||
| detemir, | |||||
| largine, | |||||
| degludec, | |||||
| ILPs | ligand | insects | - | [103] | |
| Insulin-mimetic peptides | S371, S446 | disrupts the primary insulin binding site of the IR | mice | - | [138] |
| - | |||||
| S519(agonist) | - | ||||
| S597 (partial agonist) |
receptor activation | IR-transfected L6 myoblasts | - | [138,177] | |
| S661 | antagonist of the IR | rat adipocytes | - | [140] | |
| S961(agonist/ antagonist) |
↓IR, blocks expression of the IR without insulin | breast cancer cells | - | [141,178] | |
| Antibodies | XMetA (partial agonist) | ↑IR autophosphorylation (EC50:1.3 nmol/L); ↑Akt phosphorylation (EC50: 1.1 nmol/L) |
CHO-hINSR cells (in vitro); diabetic mice (in vivo) | - | [144,145] |
| XmetS (agonist) | ↑binding affinity with IR; ↑IR autophosphorylation (insulin-dependent); ↑Akt phosphorylation |
MCF-7 human breast cancer (in vitro); mouse models of insulin-resistant diabetes (in vivo) | - | [146] | |
| XmetD (X358) (antagonist) |
↓autophosphorylation of IR (interacte with IR); ↓phosphorylation of Akt and Erk |
adult male CHO-hINSR cells; L6 muscle cells; COLO-205 human colon cancer cells; hyperinsulinemic hypoglycemia mice | - | [147] | |
| healthy adult | insulin resistance (3 d wherein X358-imparted) | [148] | |||
| IRAB-A (agonist/sensitizer) | ↓off-rate of insulin from the IR (stabilizes insulin binding) | diet-induced obese C57 mice | - | [132] | |
| IRAB-B (antagonist) | ↓IR phosphorylation (binds to IR) | C57BL/6N mice | - | [149] | |
| AK98 (antagonist) | competes with insulin (bind to IR) ↓IR expression levels | tumor cell (MCF-7) | - | [23] | |
| Aptamers | IR-A48 (partial agonist) (IR Tyr1150), | ↑IR autophosphorylation (allosteric binds and activates the IR, but not IGF-1R) | HEK293 and 3T3-L1 cells; Rat-1 cells overexpressing human IR (Rat-1/hIR) | - | [152] |
| IR-A43 (sensitizer) | binds to the allosteric site of IR; ↑insulin bind to IR |
- | - | [153] | |
| IR-A62 (agonist and activator) | ↑insulin binding and Y1150; monophosphorylation of the IR (low concentrations); ↓insulin binding and IR phosphorylation (high concentrations) |
C57BL/6 mice; Rat-1 cells overexpressing human IR (Rat-1/hIR); 3T3-L1 and MCF-7 breast cancer cells |
- | [154] | |
| GL56 (inhibitor) | specifically recognizes the IR; ↓IR phosphorylation; ↓phosphorylation of AKT, ERK1/2 and IRS1 |
U87MG; glioblastoma cancer cells |
- | [155] | |
| Proteins | GRB10/14, | ↓activity of the IR as a pseudosubstrate of the IR-TK | mice | - | [157] |
| SOCS1/3, | mice | - | [3] | ||
| GRP78 (IGF-1R) | ↑IGF-1R phosphorylation and activation | hepatoma cells | - | [158] | |
| SH2B1 | ↑IR and IRS1 phosphorylation;↑Akt and Erk activation | CHO–IR, 3T3L1, NIH3T3, and HEK293 cells; mice | - | [157] | |
| SORLA | ↑IR surface expression (redirects internalized IR from endosomes to PM) | mouse with loss of function/tissue -specific over- expression of SORLA; obese human subjects |
- | [70] | |
| Cav-2α | ↑IRS-1 recruitment and association with IR (a substrate of IR tyrosine kinase) | Hirc-B cells, HEK293T cells, 3T3L1 preadipocytes or adipocytes | - | [161] | |
| Cav-2β | desensitization of the IR; ↑IR-TK inactivation via dephospho-rylation by PTP1B and internalization via dynamin- 2-dependent endocytosis |
HEK293T cells, 3T3-L1 preadipocytes (ATCC, CL-173) |
- | [162] | |
| ApoE | interacts with the IR, interfering with insulin binding; ↓insulin–IR interaction and impairs IR trafficking |
human ApoE -targeted replacement mice | - | [164,165] | |
| Others | Glypican-4 | interacts with the IR, causing ↑IR signaling |
visceral and subcutaneous adipose tissue/3T3-L1 preadipocytes | - | [168] |
| mcIRBP-9 | ↑IR kinase activity; ↑phosphorylation of IR; ↑translocation of GLUT4; ↑uptake of glucose |
3T3-L1 preadipocytes; type 1 diabetic mice; type 2 diabetic mice (db/db mice) | - | [169] | |
| Visfatin | binds to the IR site | clonal mouse pancreatic β-cell; β-TC6 cell line (BTC) cells |
- | [170] | |
| SMPDL3b | interferes with the IR isoforms binding to caveolin1 in the PM | podocytes in DKD | - | [171] | |
| PTP1B | dephosphorylates the IR, causing deactivation |
mice | novel therapeutic strategy for T2DM | [172] | |
| PKCε | phosphorylates the IR, blocking IR autophosphorylation |
InsrT1150A mice | improves NAFLD diagnostic screening for the early identification of patients at risk for T2D | [174] | |
| Aroclor 1254 | inhibits the expression of the IR | male C57BL/6 mice/skeletal muscle & liver | _ | [175] | |
| Subetta | increases IR β-subunit phosphorylation | human preadipocytes | _ | [176] | |
| BACE1 | cleaves the IR ECD and decreases the amount of mature IR | mouse models of diabetes (db/db) and impaired glucose tolerance (HFD mice) | _ | [21] |
ILPs: insulin-like peptides; GRB: growth factor receptor-bound protein; SOCS: suppressor of cytokine signaling; SH2B1: SH2 domain-containing adaptor protein; SORLA protein, sorting-related receptor with type A repeats; Cav-2α: caveolin-2α; Cav-2β: caveolin-2β; ApoE: apolipoprotein E; mcIRBP-9: 9-amino-acid-residue peptide; SMPDL3b, sphingomyelin phosphodiesterase acid-like 3b; PTP1B: protein-tyrosine phosphatase 1B; PKCε: protein kinase Cε; NAFLD: nonalcoholic fatty liver disease; BACE1, β-site amyloid precursor protein cleaving enzyme 1; PM, plasma membrane; Hirc-B, human IR-overexpressed rat 1 fibroblast cells; CNS: central nervous system; DKD, diabetic kidney disease; CHO, Chinese hamster ovary; InsrT1150A mice, C57BL/6J mice harboring a threonine-to-alanine mutation at the homologous residue Thr1150.