Post-Translational Modifications as Molecular Mediators in the Pathogenesis and Complications of Diabetes

Abstract

Diabetes mellitus is a multifactorial metabolic disorder marked by chronic hyperglycemia and associated complications that affect millions globally. Recent advances in molecular biology have highlighted the central role of post-translational modifications (PTMs) in the pathogenesis and progression of all major types of diabetes, including type 1, type 2 and gestational diabetes. This review focuses on three pivotal PTMs- glycation, phosphorylation, and acetylation, along with their interrelated roles in disrupting insulin signaling, promoting inflammation and driving diabetic complications. Glycation leads to the formation of advanced glycation end-products (AGEs) that impair protein function and trigger the RAGE-mediated inflammatory cascade. Phosphorylation, when dysregulated by nutrient excess and stress-activated kinases, disrupts insulin signal transduction and exacerbates insulin resistance. Acetylation, particularly of histones and metabolic regulators, modulates gene expression patterns linked to the metabolic memory of prior hyperglycemic insults. We explore how these PTMs influence molecular and cellular mechanisms contribute to long-term complications, and offer novel diagnostic and therapeutic opportunities. By understanding the intricate crosstalk between these PTMs, this review advocates for integrated strategies targeting glycation, kinase signaling and epigenetic modulation to improve diabetes management and outcomes.