Type 2 diabetes is driven by the inability of pancreatic islet β-cells to secrete sufficient insulin to maintain normal blood glucose. Intracellular Ca 2 + homeostasis is essential for β-cell health and function, with Ca 2 + compartmentalized within organelles such as the ER and mitochondria to coordinate insulin synthesis and secretion. Mitochondria are dynamic organelles that integrate nutrient and extracellular cues to regulate cellular energy and redox balance, and their function is closely linked to Ca 2 + flux. The mitochondrial calcium uniporter (MCU) is the primary channel that transports Ca 2 + into the mitochondrial matrix. Although β-cell-specific MCU deletion impairs β-cell mass and function, elevated islet MCU expression is observed in diabetic mouse models and in palmitate-treated islets. Whether this increase represents an adaptive response or contributes to β-cell dysfunction remains unknown. We hypothesized that elevated MCU expression leads to mitochondrial Ca 2 + overload, promoting β-cell apoptosis and failure and ultimately impairing glucose homeostasis. To investigate the consequences of elevated MCU, we generated a pancreatic β-cell-specific MCU-overexpression mouse model (Ins1-Cre; CAG-CAT-MCU, βMCUOE). Statistical analyses were performed using Student’s t-test for single-variable comparisons and one- or two-way ANOVA with Bonferroni correction for multiple comparisons. Statistical significance was defined as p< 0.05. Both male and female mice were tested. Male βMCUOE mice maintained normal glucose metabolism at early ages (8-15 weeks old) but developed glucose intolerance with aging (30 weeks old), whereas female βMCUOE mice exhibited persistent glucose intolerance from 8 to 30 weeks of age. In both sexes, glucose intolerance was accompanied by reduced in vivo glucose-stimulated insulin secretion (GSIS). To identify mechanisms underlying impaired GSIS, we assessed pancreatic β-cell mass and function. β-cell mass was preserved in female βMCUOE mice but reduced in males. In vitro, female βMCUOE islets displayed diminished GSIS, whereas male islets exhibited no functional impairment, indicating distinct sex-specific modes of β-cell dysfunction. Bulk RNA sequencing revealed only 26.1% overlap in differentially expressed genes between male and female βMCUOE islets, with most DEGs unique to each sex. Male βMCUOE islets showed dysregulation of cell survival pathways, whereas female βMCUOE islets exhibited increased acinar/exocrine-like gene signatures. These data indicate that MCU overexpression differentially modulate β-cell survival and identity in each sex. In summary, elevated MCU expression in β-cells impairs glucose homeostasis through sex-specific mechanisms. These findings identify mitochondrial Ca 2 + handling as a critical regulator of β-cell function and highlight its potential contribution to diabetes pathophysiology. This research is supported by NIH-funded grants (R01DK136237 and R25DK140753) and Integrative Biology & Physiology (IBP) department (Land Grant in Diabetes & Marvin and Hadassah Bacaner Endowment in Cardiovascular Physiology). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Jo et al. (Fri,) studied this question.