Tissue‐Specific Differential Flux Analysis Reveals Metabolic Insights Into Pancreatic β‐Cell Dysfunction in Type 2 Diabetes

Type 2 diabetes (T2D) is a complex metabolic disorder characterized by impaired glucose homeostasis resulting from dysfunctional pancreatic β-cells. Understanding the fundamental mechanisms governing β-cell dysfunction can pave the way for novel therapeutic interventions. In this study, comprehensive context-specific genome-scale metabolic models for healthy and T2D pancreatic β-cells were reconstructed using high-throughput transcriptomics data. These models underscore substantial shifts in metabolic flux profile within pancreatic β-cells of diabetic patients compared to their healthy counterparts. Disruptions in glucose metabolism and compromised insulin biosynthesis were identified in β-cells, highlighting critical factors contributing to the onset of T2D. Further, a correlation was observed between reduced metabolic activity in amino sugar, amino acid, and peptide metabolism and diminished insulin production. Moreover, reduced ubiquinone synthesis and enhanced fatty acid oxidation in T2D patients were found to play a critical role in impaired β-cell function. These findings provide novel insights into the metabolic dysregulation underlying T2D pathogenesis. Furthermore, metabolically impacted reactions were leveraged to identify biomarker genes associated with β-cell failure. Drug repurposing analysis using the identified genes revealed 23 potential targets, seven of which have already been linked to the treatment of T2D. The most commonly used antidiabetic drugs, such as metformin, glyburide, nateglinide, and insulin, overlapped with our identified drug candidates, supporting the reliability of our predictions. Additionally, 341 FDA-approved drug candidates were identified that may serve as potential therapeutics targeting T2D biomarker genes. These results pave the way for developing targeted therapeutic interventions to restore healthy β-cell function and improve glucose homeostasis in T2D patients.