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 postnatal 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-computer tomography 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 type 1 diabetes. 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.NEW & NOTEWORTHY Early-life undernutrition plays a critical role in the development of undernutrition-related diabetes. Undernourished mice exhibited a metabolic shift from the glucose metabolism toward the fatty acid metabolism, leading to bone fragility and hepatic steatosis. Paradoxically, undernutrition-related diabetes emerged after transition to a regular diet due to a persistent compromised insulin production and impaired pancreatic catch-up growth. Early-life undernutrition is a pivotal contributor to metabolic disorders and comorbidities in populations facing the double burden of malnutrition.