Metabolic traits and adaptations of mice lacking Slc12a5 in insulin-secreting β-cells

Abstract Pancreatic β-cells integrate metabolic and electrical signals to couple nutrient sensing with insulin secretion, yet the physiological contribution of the neuronal K+Cl− cotransporter-2, Kcc2 (Slc12a5) to β-cell function and whole-body metabolic regulation remains incompletely understood. To define its role in vivo, we generated mice lacking Kcc2 selectively in insulin-secreting β-cells (Kcc2βKO) and evaluated growth, body composition, feeding behavior, glucose homeostasis and islet function from weaning through early adulthood. Kcc2βKO mice developed sex- and age-dependent metabolic phenotypes. Females exhibited lower body weight at weaning and increased lean mass during adulthood, whereas males displayed reduced body-weight gain despite increased food intake. Feeding microstructure analyses identified age-dependent alterations in meal patterning in male Kcc2βKO mice. Morphometric analysis demonstrated increased mean islet area without changes in endocrine cell composition, and isolated islets exhibited enhanced glucose-stimulated insulin secretion at younger ages. Male, but not female, Kcc2βKO mice showed improved glucose tolerance and age-dependent differences in glycemic responses to exogenous insulin, whereas both sexes exhibited attenuated glycemic responses to alanine challenge. Fasting blood glucose remained largely preserved across genotypes, although fasting plasma insulin concentrations varied according to sex, age and fasting duration. These findings identify β-cell Kcc2 as a physiological contributor to nutrient-stimulated insulin secretion and demonstrate that disruption of β-cell chloride homeostasis is accompanied by integrated, age- and sex-dependent adaptations in body-weight regulation, feeding behavior and glucose homeostasis.