Sex-specific metabolic differences may explain why some populations develop diabetes without obesity, particularly among East Asian women who show distinct glucose regulation patterns compared to men. This finding challenges assumptions about universal fructose toxicity and suggests female metabolic resilience deserves greater research attention. Female mice consuming high-fructose corn syrup under calorie-controlled conditions maintained normal glucose tolerance despite significant pancreatic adaptations. Over 16 weeks, these mice showed reduced insulin secretion capacity and smaller pancreatic mass, yet preserved blood sugar control through compensatory mechanisms. The animals exhibited elevated ketohexokinase expression, suggesting enhanced fructose metabolism, while maintaining stable insulin sensitivity markers. Crucially, islet architecture remained intact, indicating functional pancreatic reserves. This research fills a critical gap in diabetes prevention science, where male-dominated studies have shaped dietary recommendations for decades. The metabolic flexibility demonstrated here may explain epidemiological observations of lean diabetes phenotypes, particularly in women. However, the long-term sustainability of these adaptations remains questionable—reduced pancreatic capacity could represent early-stage metabolic stress rather than benign adaptation. The calorie-controlled design also limits real-world applicability, since fructose consumption typically occurs alongside caloric excess. While these findings suggest females may tolerate moderate fructose exposure better than males, they shouldn't encourage complacency about added sugar intake. The pancreatic changes observed could represent subclinical dysfunction that manifests as overt diabetes under additional metabolic stressors like aging, pregnancy, or illness.