Insulin Signal Transduction Perturbations in Insulin Resistance.

Mariyam Khalid,Juma Alkaabi,Moien A B Khan,Abdu Adem

doi:10.3390/ijms22168590

Abstract

Type 2 diabetes mellitus is a widespread medical condition, characterized by high blood glucose and inadequate insulin action, which leads to insulin resistance. Insulin resistance in insulin-responsive tissues precedes the onset of pancreatic β-cell dysfunction. Multiple molecular and pathophysiological mechanisms are involved in insulin resistance. Insulin resistance is a consequence of a complex combination of metabolic disorders, lipotoxicity, glucotoxicity, and inflammation. There is ample evidence linking different mechanistic approaches as the cause of insulin resistance, but no central mechanism is yet described as an underlying reason behind this condition. This review combines and interlinks the defects in the insulin signal transduction pathway of the insulin resistance state with special emphasis on the AGE-RAGE-NF-κB axis. Here, we describe important factors that play a crucial role in the pathogenesis of insulin resistance to provide directionality for the events. The interplay of inflammation and oxidative stress that leads to β-cell decline through the IAPP-RAGE induced β-cell toxicity is also addressed. Overall, by generating a comprehensive overview of the plethora of mechanisms involved in insulin resistance, we focus on the establishment of unifying mechanisms to provide new insights for the future interventions of type 2 diabetes mellitus.

Highlights

Type 2 diabetes mellitus (T2DM) is a serious medical challenge of the 21st century.Persistently elevated glucose concentrations above the physiological range result in the manifestation of diabetes
advanced glycation end products (AGE): Advanced glycation end products; AGER1: AGE receptor 1 encoded by diphosphooligosaccharide protein glycosyltransferase (DDOST) gene; AMPK: AMP-activated protein kinase; AS160: Akt substrate of 160 kDa; FoxO: Forkhead family of transcription factors; GLUT4: Glucose transporter protein 4; GEF: GLUT4 enhancer factor; glycogen synthase kinase 3 (GSK3): Glycogen synthase kinase 3; IKK: IκB kinase; insulin receptor substrate (IRS): Insulin receptor substrate1; MEF: Myocyte enhancer factor; mammalian target of rapamycin (mTOR): Mammalian target of rapamycin
Both in rodents and humans, free fatty acids (FFAs) are crucial for glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells through to the activation of G-protein coupled receptors GPR40 [32]

Summary

Introduction

Type 2 diabetes mellitus (T2DM) is a serious medical challenge of the 21st century. Persistently elevated glucose concentrations above the physiological range result in the manifestation of diabetes. Insulin resistance is the condition in which a cell, tissue, or body of an organism cannot adequately respond to normal levels of insulin This in turn hinders insulin’s function of maintaining glucose and lipid homeostasis [4]. The acquired causes of insulin resistance include obesity, physical inactivity, advanced glycation end products (AGE), excess free fatty acids (FFAs), psychological stress, smoking, alcohol intake, or certain medications [8,9,10]. All these factors are linked to constant low-grade inflammatory conditions [11,12]. We hope that a more sophisticated understanding of the mechanistic link between insulin resistance and its associated key pathophysiological processes presents the molecular basis to facilitate the development of novel therapies for type 2 diabetes mellitus

Insulin Receptor and Insulin Signaling Pathway

Mechanisms Involved in Insulin Resistance

Insulin Receptor Substrate

Phosphatidylinositol 3-Kinase

Concluding Remarks