Unraveling the Mystery of Insulin Resistance: From Principle Mechanistic Insights and Consequences to Therapeutic Interventions

Abstract

Insulin resistance (IR) is a significant factor in the development and progression of metabolic-related diseases like dyslipidemia, T2DM, hypertension, nonalcoholic fatty liver disease, cardiovascular and cerebrovascular disorders, and cancer. The pathogenesis of IR depends on multiple factors, including age, genetic predisposition, obesity, oxidative stress, among others. Abnormalities in the insulin-signaling cascade lead to IR in the host, including insulin receptor abnormalities, internal environment disturbances, and metabolic alterations in the muscle, liver, and cellular organelles. The complex and multifaceted characteristics of insulin signaling and insulin resistance envisage their thorough and comprehensive understanding at the cellular and molecular level. Therapeutic strategies for IR include exercise, dietary interventions, and pharmacotherapy. However, there are still gaps to be addressed, and more precise biomarkers for associated chronic diseases and lifestyle interventions are needed. Understanding these pathways is essential for developing effective treatments for IR, reducing healthcare costs, and improving quality of patient life.

Keywords: T2DM; dyslipidemia; inflammasome; insulin resistance; insulin signaling; lipotoxicity; metabolic disease; signal transduction.

Figure 1

Global impact of insulin resistance research, tanking the top ten nations in terms of overall number of publications related to IR research during the period between 2002 and 2021. The numbers on the Y axis represent the number of total publications; the US is on top with 7360 publications, while France, in last place, has 858.

Figure 2

A schematic illustration of the insulin-signaling mechanism. The initiation of a chain reaction of phosphorylation events is triggered when insulin and IGF-1 receptors are activated by their respective ligand (insulin). During the process of ligand binding, the receptors undergo a conformational change and autophosphorylation. This results in the recruitment and phosphorylation of receptor substrates, such as IRS and Shc proteins. The Ras-MAPK pathway is activated by Shc, whereas the PI3K-Akt route is primarily activated by IRS proteins. This is accomplished by the recruitment and activation of PI3K, ultimately resulting in the production of the second messenger PIP3. PIP3, linked to the membrane, has the ability to recruit and activate PDK-1, which then phosphorylates and activates Akt as well as atypical PKCs. In addition to regulating glucose transport, lipid synthesis, gluconeogenesis, and glycogen synthesis, Akt is responsible for mediating the majority of insulin’s metabolic actions. Akt also regulates the cell cycle and the survival behavior of cells. The Shc-Grb2-SosRas-Raf-MAPK pathway is responsible for controlling the transcription of genes and the proliferation of cells. This image was drawn using BioRender software (https://app.biorender.com/illustrations/66fe49992ddf61bf4d5a35f6, accessed on 14 February 2025) (Science Suite Inc., Toronto, ON, Canada, DBA BioRender #2827-9028).

Figure 3

A schematic illustration of the activation of Ser/Thr kinases leading to the phosphorylation cascade on insulin receptors, insulin receptor substrates, and Akt, culminating in insulin resistance. 1—dyslipidemia; 2—inflammatory processes; 3—hyperglycemia; 4—reactive oxygen/mitochondrial stress; 5—endoplasmic reticulum stress; 6—protein kinases C and A phosphorylating insulin receptor; 7—IRS-1 phosphorylation by multiple kinases, including classical and novel PKC, JNK, IKK, S6K1, GSK3, SIK2, MAPK, and mPLK1; 8—iRS-2 phosphorylation involving JNK and GSK3; 9—Akt phosphorylation involving atypical PKC. The letter “P” in the pink circles represents phosphorylation status. This image was drawn using BioRender software (Science Suite Inc. DBA BioRender #2827-9028).

Figure 4

A pictorial representation of the consequences of insulin resistance.

Figure 5

Graphic illustration of therapeutic strategies targeting insulin resistance and T2DM. The currently used modalities are shown in green. The future therapeutic options are summarized in blue. Drugs like sulfonylureas, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptide-4 (DPP-4) inhibitors augment insulin secretion. Thiazolidinediones (TZDs) and metformin are insulin-sensitizing agents, targeting fat storage capacity of adipose tissue and HGP (hepatic glucose production). The potential agents targeting enhancement of ß oxidation in liver and skeletal muscle and stimulation of muscle quality. Mit—Mitochondria; ER—Endoplasmic reticulum; FFA—free fatty acid; ACC—Acetyl-CoA carboxylase; GPAT-Glycerol-3-phosphate acyltransferase; DGAT2—diacylglycerol acyl transferase 2; UCP3—Uncoupling proetein3; MSTN—Myostatin; PPARγ—Peroxisome proliferator-activated receptor-γ; SGLT2—Sodium glucose cotransporter2.

Figure 6

A schematic view of future drug targets aiming at insulin resistance: 11β-DH—1β Hydroxysteroid dehydrogenase; PEDF—Pigment epithelium-derived factor); GPER—(G protein-coupled estrogen receptor); METRNL—Meteorin-like.