Undernutrition-Related Diabetes in Mice is Linked to Early Undernutrition

The classification of undernutrition-related diabetes as a distinct entity separate from Type 1 and Type 2 diabetes, remains under debate. Here, we show that post-natal undernutrition induces coordinated transcriptional, metabolic, and pathophysiological alterations that mediate the development of undernutrition-related diabetes in young animals. Undernourished mice exhibited hypoglycemia, reduced insulin (p<0.01) and impaired glucose tolerance (p<0.05), consistent with pancreatic insufficiency. Micro-CT analysis revealed skeletal fragility, with significant reductions in bone mineralization (p< 0.01), trabecular integrity (p < 0.05), and increased porosity (p<0.001), as commonly reported in T1D. Liver tissue histology revealed substantial triglyceride accumulation (p<0.001) and histopathological features consistent with hepatic steatosis, including hepatocyte ballooning (p< 0.001). RNA sequencing of liver tissue revealed a gene expression pattern hallmarked by upregulated fatty acid metabolism (p=0.031), and downregulation of the PI3K/AKT/mTOR signaling pathway (p=0.05). This metabolic shift was associated with PPARG activation (Z=2.3) and increased fatty acid oxidation (p<0.01). Conversely, genes involved in insulin secretion (Z=-3.6) and glucose metabolism (Z<-1.6) were downregulated. Strikingly, transitioning from early undernutrition to a standard diet for 28 days resulted in mild hyperglycemia (p<0.05), accompanied by persistent hypoinsulinemia due to impaired pancreatic catch-up growth. These findings suggest that early undernutrition fosters a distinct trajectory toward insulin deficiency and undernutrition-related diabetes, while also increasing susceptibility to metabolic comorbidities. These mechanisms could serve as foundational drivers of the double burden of malnutrition, with consequences for both metabolic and skeletal health.