Human islets were transplanted into immunodeficient mice (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ; abbreviated as NOD-scid IL2rγnull or NSG) that expressed the diphtheria toxin receptor (DTR) on native mouse β-cells (NSG-DTR). Exposure to neither chronic hyperglycemia (induced by DT injection into NSG-DTR mice with human islets); A), nor chronic insulin resistance (induced by placing mice on a high-fat diet; NSG-HFD; B–C), nor acute hyperglycemia and insulin resistance (induced by administration of insulin receptor antagonist, S961; H–I) elicited β-cell proliferation in human islet grafts. In contrast, the same metabolic stressors increased β-cell proliferation rates in mouse islet grafts (E–G; J). Reproduced from Dai et al (JCI, 2016, in press).