The Molecular Basis of Insulin Resistance in Type 2 Diabetes Mellitus: A Chemical and Pathophysiological Perspective

Document Type : Review Articles

Authors

Ministry of National Guard, Saudi Arabia

Abstract

Type 2 Diabetes Mellitus (T2DM) constitutes a global health epidemic, characterized by hyperglycemia caused by peripheral insulin resistance and deteriorating pancreatic β-cell failure. Insulin resistance, the reduced responsiveness of target cells to physiological levels of insulin, is the prevalent defect in the overwhelming majority of T2DM. This review examines the intricate molecular and chemical origin of insulin resistance, from beyond the classic clinical presentation to the subcellular dysregulation that typifies the disease. We first define the elementary chemistry and biology of typical insulin signaling as a point of reference from which pathogenic deviations can be sensed. The review's center methodically dissects the major mechanistic hypotheses of insulin resistance, such as the roles of chronic low-grade inflammation, lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. Detailed analysis is given on the chemical nature of major inhibitors, such as Ser/Thr phosphorylation of insulin receptor substrates (IRS) by several kinases (JNK, IKK, PKCθ), and bioactive lipid metabolite formation like diacylglycerols (DAG) and ceramides. Furthermore, we explore the action of adipose tissue as an endocrine organ, gut microbiota, and potential genetic/epigenetic mechanisms. The review also discusses the ensuing hyperglycemia-mediated molecular damage by advanced glycation end-products (AGEs) production and oxidative stress that constitute a vicious cycle to perpetuate insulin resistance. By integration of current knowledge, the current review aims to provide a chemically-based paradigm for the explanation of insulin resistance, identifying potential molecular targets for therapeutic intervention and new areas of research, of particular interest given the rising burden of T2DM in North African and Middle Eastern regions.

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Egyptian Journal of Chemistry
Volume 68, Issue 13 - Serial Number 13
In Loving Memory of Late Professor Doctor”Zeinab M. Nofal”
December 2025
Pages 1357-1363

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History

  • Receive Date: 02 September 2025
  • Revise Date: 21 October 2025
  • Accept Date: 25 October 2025

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