Analysis of over 300,000 males demonstrates that Y chromosome loss—a common age-related phenomenon—creates ancestry-specific type 2 diabetes risks, with distinct patterns emerging between East Asian and European populations. Multi-omics profiling reveals compromised glucose metabolism in pancreatic β cells lacking the Y chromosome. This discovery illuminates why diabetes susceptibility varies dramatically across populations and suggests that chromosomal instability, rather than just genetic variants, may drive metabolic disease. The finding challenges the traditional focus on autosomal genetics in diabetes research, highlighting how sex chromosome dynamics contribute to disease risk. For aging males, this research suggests that Y chromosome loss could serve as an early biomarker for diabetes development, though the ancestry-specific effects mean risk assessment tools would need population-tailored approaches. The work represents a paradigm shift toward understanding how chromosomal mosaicism—the presence of cells with different genetic compositions—influences metabolic health throughout aging.