Diabetes is a growing global health concern and an enormous burden on healthcare systems. There are several types of diabetes, but all converge on dysregulated blood glucose and chronic hyperglycemia, that if left unmanaged, can result in permanent disability and death. Central to blood glucose regulation is the pancreatic Islet of Langerhans (islet) and specifically the β-cell and its secretion of insulin in response to elevated blood glucose. While there is no cure for diabetes, there are several useful therapeutics strategies, including enhancing β-cell insulin secretion, improving insulin sensitivity, enhancing glucose excretion, or islet cell replacement to help patients manage their chronic hyperglycemia and minimize complications. Currently available anti-diabetic medications do not work for all patients and cutting-edge β-cell replacement therapy is not available to the vast majority. Here I describe two new mouse models that can be employed to discover and evaluate novel therapies for diabetes, namely stem-cell derived cell replacement therapy and senolytics. In chapter 2 I describe the IsletTester mouse, a novel immunodeficient, moderately hyperglycemic mouse model for the study of primary and stem-cell derived islets. IsletTester mice are heterozygous for a nonsense mutation in glucokinase, the β-cell glucose sensor, resulting in stable, moderate hyperglycemia and glucose intolerance resulting from blunted glucose-stimulated insulin secretion. I demonstrated the suitability of this mouse model for the engraftment and study of both human primary islets and stem-cell derived islets. In chapter 3, I describe the derivation and characterization of a cell-type specific senescence cell ablation (senolytic) mouse model, the SenKiller mouse. This mouse employs a fragment of the p16Ink4a promoter, a key senescence mediator and marker gene, to drive the expression of a diphtheria toxin-green fluorescent protein fusion after activation by Cre-mediated recombination. This mouse was derived by site-specific integration into the Col1a1 safe-harbor locus, and its efficacy was demonstrated in a chemically induced model of liver fibrosis. Together, these new mouse models will help to advance the therapeutic development of both stem-cell derived islet products and senolytics for the treatment of diabetes.