In this study, we provide evidence that SWELL1-mediated currents and SWELL1 protein are reduced in murine and human adipocytes and pancreatic β-cells in the setting of T2D and hyperglycemia suggesting that dysfunctional SWELL1-mediated signaling could contribute to T2D pathogenesis by impairing insulin sensitivity and insulin secretion. This evidence concerns the gene INS and type 2 diabetes mellitus.