Unraveling the Mystery of Insulin Resistance: From Principle Mechanistic Insights and Consequences to Therapeutic Interventions
Abstract
1. Introduction
2. Definition and Clinical Relevance
3. Risk and Contributing Factors
4. Global Epidemiology of IR
5. Prevalence of IR in Specific Populations
6. Molecular Mechanisms of Insulin Signaling
6.1. Insulin Receptor: Structure and Function
6.2. Intracellular Signaling Pathways
6.3. Role of Kinases and Phosphatases
6.4. AKT Pathway of Insulin Action
6.5. Interplay of PKC Isoforms
6.6. Alternate Insulin Signaling: GRB2-SOS-RAS-MAPK Cascade
6.7. Modulation of Insulin Action
6.8. Role of Lipid Phosphatases
6.9. Regulatory Roles of Grb, SOCS, Trb3 and IP7
6.10. Role of Phosphorylation Cascade Induced Activated Serine—Threonine Kinases
7. Cellular and Tissue Specificity of Insulin Action
7.1. Adipose Tissue
7.2. Skeletal Muscle
7.3. Hepatic Insulin Action
8. Insulin Resistance
8.1. Factors Contributing to Insulin Resistance
8.1.1. Obesity and Adipose Tissue Dysfunction
8.1.2. Inflammatory Mechanisms in Insulin Resistance
8.1.3. Role of Oxidative Stress
8.1.4. Mitochondrial Distress
8.1.5. Lysosomal Distress
8.1.6. Dysfunction of Endoplasmic Reticulum
8.1.7. Genetic Factors in Insulin Resistance
8.1.8. Lifestyle and Nutritional Factors in Insulin Resistance Risk
8.1.9. Relationship Between Age and Insulin Resistance
9. Tissue Specific Insulin Resistance
9.1. Role of Skeletal Muscle in Insulin Resistance
9.2. Role of Liver in Insulin Resistance
9.3. Role of Adipose Tissue in Insulin Resistance
9.4. Role of Myocardial Tissue in Insulin Resistance
9.5. Role of Other Cell Types and Tissues in Insulin Resistance
9.5.1. Hypothalamic Neurons
9.5.2. Pancreatic β Cells
9.5.3. Vascular Endothelial Cells
9.5.4. Macrophages
10. Consequences of Insulin Resistance
11. Therapeutic Modalities Targeting Insulin Resistance
11.1. Lifestyle Modifications
11.2. Pharmacologic Interventions
11.2.1. Currently Used Medications
11.2.2. Recent Drug Targets for Insulin Resistance
11.2.3. Future Insulin Resistance Drug Targets
11β—Hydroxysteroid Dehydrogenase (11β-HSD)
ACRP-30 (Adiponectin)
Fetuin-A
Visfatin/NAMPT (Nicotinamide Phosphoribosyl Transferase)
Metrnl
PEDF (Pigment Epithelium-Derived Factor)
Vaspin (Serpin A12)
G Protein-Coupled Estrogen Receptor (GPER)
Gene Therapy
12. Personalized Therapies for Insulin Resistance
13. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
T1DM | Type-1 diabetes mellitus |
T2DM | Type-2 diabetes mellitus |
IR | Insulin resistance |
HOMA-IR | Homeostatic model assessment for insulin resistance |
IGF | Insulin like growth factor |
GRB | Growth factor receptor-bound protein |
SHC | Src homology 2 domain-containing adapter protein |
CETP | Cholesteryl ester transfer protein |
PH | Pleckstrin homology |
SH2 | Src homology -2 |
IRS | Insulin receptor substrate |
APS | Adapter protein with a PH and SH2 domain |
Ras | Rat sarcoma virus oncogene |
MAPK | Mitogen activated protein kinase |
IRR | Insulin related receptor |
IGF-1R | IGF-1 receptor |
mMRA | messenger RNA |
IR-A | Insulin receptor-A |
KO | knockout |
ERK | Extracellular signal-regulated kinase |
DOK4 | Docking protein4 |
GTP | Guanosine triphosphate |
GAB | Grb2-associated binder |
Cbl gene | Casitas B-lineage Lymphoma gene |
CAP | catabolite activator protein |
DOK | Docking protein |
PI3K | Phosphatidylinositol 3-kinase |
AKT | serine/threonine-protein kinase also known as protein kinase B |
Pik3r1 | Phosphoinositide-3-Kinase Regulatory Subunit 1 |
Src | Steroid receptor coactivator |
Csk | C-Terminal Src Kinase |
DOCK | Dedicator of cytokinesis protein |
Crk | Proto-oncogene c-Crk protein |
PKB | Protein kinase B |
mTORC | Mammalian target of rapamycin complex 1 |
DNAPK | DNA-dependent protein kinase |
FOXO1 | Forkhead box protein O1 |
TBC1D4 | TBC1D4 (TBC1 Domain Family Member 4) |
PGC | Peroxisome proliferator-activated receptor-gamma coactivator |
PDE3B | PDE3B phosphodiesterase 3B |
c-AMP | Cyclic adenosine monophosphate |
Cip 1 | Cdk-interacting protein-1 |
WAF 1 | wildtype p53-activated fragment 1 |
p27Kip1 | Cyclin-dependent kinase inhibitor 1B |
IKK | IκB kinase |
PKC | Protein Kinase C |
nPKCs | Novel protein kinases |
aPKCs | atypical protein kinases |
SREBP1 | Sterol regulatory element-binding protein 1 |
SOS | Son of Sevenless (a set of genes) |
MEK | Mitogen-activated protein kinase kinas |
PTP1B | Protein tyrosine phosphatase 1B |
LAR | leukocyte common antigen-related protein |
PP2A | Protein Phosphatase 2A |
PP2B | Protein Phosphatase 2B |
S6K | S6 kinase p70 |
PHLPP-1 | PH domain leucine-rich repeat protein phosphatase 1 |
PTEN | Phosphatase and tensin homolog |
SHIP | SH2 domain-containing inositol 5-phosphatases |
SOCS | Suppressor of Cytokine Signaling |
IP7 | Inositol pyrophosphate |
IP6K1 | Inositol hexakisphosphate kinase 1 |
Trb3 | Tribbles homolog 3 |
JNK | c-Jun N-terminal kinase |
Ser-307 | Serine residue at position 307 |
DAG | Diacylglycerol |
PKA | Protein kinase A |
PPARγ | Peroxisome proliferator-activated receptor-γ |
GLUT | Glucose transporter |
GAP | GTPase-activating protein |
RAC-1 | Ras-related C3 botulinum toxin substrate 1 |
GYS | Glycogen synthase |
GSK | Glycogen synthase kinase |
IRTK | Insulin-Induced Receptor Tyrosine Kinase |
HGP | Hepatic glucose production |
G6PC1 | Glucose-6-phosphatase catalytic subunit 1 |
PEPCK | Phosphoenolpyruvate carboxylase |
SREBP-1 | Sterol regulatory element-binding protein |
ACC1 | Acetyl-CoA carboxylase 1 |
GPAT1 | Glycerol-3-phosphate acyltransferase |
NAFLD | Non-alcoholic fatty liver disease |
ROS | Reactive oxygen species |
ER | Endoplasmic reticulum |
NFκB | Nuclear factor kappa B |
TLR4 | Toll-like receptor 4 |
CerS | Ceramide synthase |
FFA | Free fatty acids |
MCP-1 | Monocyte chemoattractant protein-1 |
TNF- α | Tumor necrosis factor alpha |
IL | Interleukin |
CLS | Crown like structure |
JAK-STAT | Janus kinase signal transducer and activator of transcription |
NOX | NADPH oxidase |
GPX | Glutathione peroxidase |
Mfn1 | Mitofusin1 |
Drp1 | Dynamin-related protein 1 |
VLDL | Very low-density lipoprotein |
DAMP | Damage-associated molecular patterns |
ULK1 | Unc-51 like autophagy activating kinase 1 |
SERCA | Sarcoendoplasmic reticulum calcium transport ATPase |
TFEB | Transcription factor EB |
PC | Phosphatidylcholine |
PERK | Protein kinase R like protein kinase |
ATF | Activating transcription factor |
IRE-1 | Inositol-requiring enzyme type 1 |
XBP1 | X-box binding protein 1 |
F25BS | Los Angeles insulin |
F25BL | Chicago insulin |
PTPN1 | Protein tyrosine phosphatase N1 |
LDLR | Low density lipoprotein receptor |
IGF1R | Insulin-like growth factor receptor-1 |
AgRP | Agouti-related protein |
POMC | Pro-opiomelanocortin |
Ins1 | Insulin 1 gene |
VEC | Vascular endothelial cell |
VCAM | Vascular cell adhesion molecule |
eNOS | endothelial nitric-oxide synthase |
iNOS | Inducible nitric-oxide synthase |
CVD | Cardiovascular disease |
SLI | silent lacunar infarction |
Ty-G | Triglyceride-glucose index |
END | Early neurological degeneration |
PCOS | Polycystic ovarian syndrome |
INSR | Insulin receptor |
NALP3 | Nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 |
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Role | Drug Class | Examples | Mechanism | Citation |
---|---|---|---|---|
Decrease Hepatic glucose production | Biguanides | Metformin | The precise mechanism of metformin is still elusive and is thought to reduce HGP, a process that is facilitated by the stimulation of mitochondrial activity or the suppression of glucagon signaling via AMPK activation and increased expression of the GLUT4 glucose transporter. | [268] |
Increase insulin sensitivity | Thiazolidinediones | Rosiglitazone Pioglitazone | Thiazolidinediones function through their interaction with the PPAR-γ to enhance the sensitivity of adipose muscle and liver to insulin. | [268] |
Inhibit renal glucose reabsorption | Sodium-Glucose Cotransporter Inhibitors (SGLT-2i) | Empagliflozin Dapagliflozin | SGLT-2is facilitate insulin-independent glucose reduction by inhibiting glucose reabsorption in the proximal renal tubules, thereby decreasing blood glucose levels. Additionally, These medications are linked to reliable and well documented weight loss and decreases in blood pressure | [268,269] |
Increase insulin sensitivity | Glucagon-like Peptide-1 Receptor Agonists (GLP 1 RA) | Semaglutide Dulaglutide Liraglutide Exenatide | GLP 1RAs increase insulin sensitivity in peripheral tissues and also have notable anti-inflammatory and anti-obesity effects, protective benefits for lung health, and favorable impact on gut microbiome composition. However, GLP-1RAs are linked to prevalent gastrointestinal adverse effects, impacting over one-third of patients and other complications. | [268,270] |
Increase insulin secretion | Dipeptidyl Peptidase-4 Inhibitors (DPP-4i) | Vildagliptin Alogliptin Linagliptin Gemigliptin Teneligliptin Trelagliptin Saxagliptin | DPP-4is inhibit incretin degradation and facilitates postprandial insulin secretion. Their advantages include the reduction in HbA1c levels, renal microalbuminuria, and inflammation. | [268,271] |
Increase insulin secretion | Sulfonylureas | Glimepiride Gliclazide | Sulfonylureas reduce blood glucose levels by enhancing insulin secretion from beta cells through the inhibition of KATP channels. They also inhibit gluconeogenesis and lipid breakdown into fatty acids. They also promote insulin sensitivity. | [268,272] |
Role | Drug Target | Examples | Mechanism | Citation |
---|---|---|---|---|
Increase insulin secretion | Glucose-dependent insulinotropic polypeptide (GIP) | Tirzepatide | GIP is present in β-cells, adipose tissue, and the brain and increases intracellular cAMP by binding to its receptor. High cAMP levels activate PKA, and exchange protein-activated cAMP2. Depolarizing voltage-gated calcium channels raises intracellular Ca2+ and promotes insulin release from β-cells. Recently, Tirzepatide, a novel dual GIP/GLP 1 receptor agonist, not only achieved significantly improved glycemic control but also allowed the majority of participants to attain a mean weight reduction exceeding 10% from baseline, which is a notable outcome in the realm of current pharmacotherapy. Its safety profile is being investigated, and it offers a lot of promise as of now. | [273,274] |
↑ Insulin release ↓ HGP | G-Protein coupled receptor (GPCR 119) |
GSK1292263, MBX-2982 DS-8500a APD668 BMS-903452 | GPR119, a Class-I G protein coupled receptor, is found in muscles, liver, and pancreatic β-cells. Similar to incretin hormones, GPR119 activation may enhance insulin synthesis and secretion when agonists bind to its binding site. GPR119 enhances glucose homeostasis via direct β-cell insulin release and indirect GLP-1 and GIP release in enteroendocrine cells. More than 40 GPR 119 agonists have been reported to show promising effects on glucoses homeostasis by depressing HGP and increasing insulin synthesis in both humans and/or animal models. The efficacy and the safety profile of these agonists is under continuous scrutiny. | [275,276] |
↑Incretin hormone Release ↑ Insulin release | Free-fatty acid receptor-1 agonists | TAK-875 TSL1806 | G-protein-coupled receptor-40 (FFA1) is a Class-A receptor and is expressed in the mammalian pancreas, gut, taste buds, and CNS. FFA1 affects blood glucose levels by increasing incretin hormones and promoting insulin release from pancreatic β-cells. Synthetic GPR40/FFA1 receptor agonists, such as TAK-875 and TSL1806, have been tried in the last many years, but their side effects, including hepatotoxicity, are a matter of concern, which is being investigated. | [277,278] |
Target Fatty acid oxidation | PPAR full agonists | Chiglitazar Sodium | Chiglitazar Sodium is a peroxisome proliferator-activated receptor (PPAR) full agonist simultaneously activates three subtypes of PPAR receptors (α, γ, and δ). It can induce the expression of downstream target genes related to insulin sensitivity, fatty acid oxidation, energy conversion and lipid transport, and inhibit the phosphorylation of PPARγ receptors associated with insulin resistance. | [279] |
↑ Insulin release | Melatonin (neuroendocrine hormone) | Melatonin | Melatonin modulates glucose levels via its melatonin receptors MT1 and MT2 in diverse cells. Melatonin supplementation has been reported to ameliorate hyperinsulinemia, insulin resistance, and insulin sensitivity by many investigators and there is enough evidence to use it as an adjuvant therapy. | [280] |
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Mir, M.M.; Jeelani, M.; Alharthi, M.H.; Rizvi, S.F.; Sohail, S.K.; Wani, J.I.; Sabah, Z.U.; BinAfif, W.F.; Nandi, P.; Alshahrani, A.M.; et al. Unraveling the Mystery of Insulin Resistance: From Principle Mechanistic Insights and Consequences to Therapeutic Interventions. Int. J. Mol. Sci. 2025, 26, 2770. https://doi.org/10.3390/ijms26062770
Mir MM, Jeelani M, Alharthi MH, Rizvi SF, Sohail SK, Wani JI, Sabah ZU, BinAfif WF, Nandi P, Alshahrani AM, et al. Unraveling the Mystery of Insulin Resistance: From Principle Mechanistic Insights and Consequences to Therapeutic Interventions. International Journal of Molecular Sciences. 2025; 26(6):2770. https://doi.org/10.3390/ijms26062770
Chicago/Turabian StyleMir, Mohammad Muzaffar, Mohammed Jeelani, Muffarah Hamid Alharthi, Syeda Fatima Rizvi, Shahzada Khalid Sohail, Javed Iqbal Wani, Zia Ul Sabah, Waad Fuad BinAfif, Partha Nandi, Abdullah M. Alshahrani, and et al. 2025. "Unraveling the Mystery of Insulin Resistance: From Principle Mechanistic Insights and Consequences to Therapeutic Interventions" International Journal of Molecular Sciences 26, no. 6: 2770. https://doi.org/10.3390/ijms26062770
APA StyleMir, M. M., Jeelani, M., Alharthi, M. H., Rizvi, S. F., Sohail, S. K., Wani, J. I., Sabah, Z. U., BinAfif, W. F., Nandi, P., Alshahrani, A. M., Alfaifi, J., Jehangir, A., & Mir, R. (2025). Unraveling the Mystery of Insulin Resistance: From Principle Mechanistic Insights and Consequences to Therapeutic Interventions. International Journal of Molecular Sciences, 26(6), 2770. https://doi.org/10.3390/ijms26062770