Type 1 diabetes (T1D) is an autoimmune disease that destroys the insulin-producing beta-islet cells of the pancreas. Currently, there are no treatment modalities for prevention of T1D, and the mechanisms influencing disease inception and early progression are not well understood. We have used the insulin 2−/− non-obese diabetic (Ins2−/− NOD) model to study stages of T1D and to examine the protective effects of a potent analogue of 1α,25-dihydroxyvitamin D3, 2α-methyl-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2AMD). Pancreatic tissues from control and 2AMD-treated Ins2−/− NOD mice were obtained weekly from 5 to 16 weeks of age. Using immunohistochemical (IHC) analysis, samples were analysed for changes in beta cell survival, islet structure and T cell invasion. Weekly intraperitoneal glucose tolerance tests (IPGTT) were performed to assess comparative beta cell function in control and treated animals. IHC demonstrated progressive beta cell destruction in control mice. In contrast, 2AMD treatment preserved islet cell architecture, arrested intra-islet T cell invasion and prevented the transition from insulitis to diabetes. IPGTT results revealed progressive impairment of beta cell function with increasing age in control mice, while 2AMD treatment resulted in normal beta function throughout the study. These results demonstrate that the Ins2−/− NOD model provides a rapid and effective method for studying T1D and for assessing efficacy of anti-diabetic agents.