INTEGRATED COMPARATIVE ANALYSIS OF METABOLOMICS AND PROTEOMIC PROFILES ACROSS HEALTHY, PREDIABETES, AND DIABETES STATES

Abstract

Type 2 diabetes (T2D) is a global health problem with an estimated 537 million cases, nearly half undiagnosed. Prediabetes, the key precursor, affects 7.5% of the global population and progresses to T2D at a rate of 5–10% per year. In the Middle East and North Africa, prediabetes prevalence ranges from 20% to 40%; in Qatar, 22% of the population is affected, emphasizing the need for early intervention. The molecular mechanisms driving progression from healthy to prediabetic and diabetic states remain poorly understood. This cross-sectional study uses an omics-based approach to explore metabolic and signaling alterations in T2D development. Metabolomic and proteomic data from 600 Qatari participants—classified as healthy, prediabetic, or diabetic based on HbA1c levels—were analyzed using MetaboAnalyst and IPA software. Metabolomic profiling revealed significant alterations in carbohydrate, lipid, and amino acid metabolism. Glucose, fructose, pyruvate, and mannose increased with disease progression, reflecting disruptions in glycolysis, gluconeogenesis, and glucose homeostasis. Elevated acylcarnitines and phospholipids indicated mitochondrial dysfunction and impaired fatty acid oxidation. Amino acid metabolism was also affected, suggesting metabolic inflexibility and insulin resistance. Enrichment analysis highlighted disrupted solute carrier-mediated transmembrane transport, essential for nutrient uptake. Proteomic analysis revealed changes in insulin signaling, inflammation, and oxidative stress. Dysregulated proteins such as angiopoietin-4, epidermal growth factor, interleukin-6, and interferon-gamma showed links between metabolic alterations and chronic inflammation. Canonical pathway analysis indicated enrichment in synaptogenesis and cardiac hypertrophy signaling, processes also implicated in T2D. Receiver operating characteristic analysis identified glucose and 1,5-anhydroglucitol as key metabolite biomarkers distinguishing diabetic from healthy individuals, while angiopoietin-4 and BMP-10 were protein markers differentiating diabetes and prediabetes. This study highlights early molecular changes and potential biomarkers for T2D detection and intervention in the Qatari population.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences