Impaired insulin secretion by the pancreatic beta cell and a reduction in beta cell mass are central to the pathogenesis of type 1 and type 2 diabetes. An ideal approach for treating individuals with diabetes is to develop modalities that increase beta cell numbers by inducing their proliferation in situ. Much evidence demonstrates that, in rodents, beta cells exhibit robust proliferative capacity both in vitro and in vivo. Induction of mouse beta cell neogenesis/proliferation has been observed under beta cell stress conditions such as inflammation, obesity, or following continuous glucose infusion1-2. However, given the inherent difficulties of human studies, there are few and often conflicting reports on the proliferative capacity of human beta cells3. Indeed, in vitro conditions that induce rodent beta cell proliferation often fail to induce human beta cell proliferation4, and in vivo human data are often obtained from autopsy specimens3.
To address these limitations, we developed a new strain of immunodeficient hyperglycemic mice based on NOD-Rag1null IL2rγnull (NRG) mice expressing the mutant Ins2Akita (Akita) allele. Mice heterozygous for the Ins2Akita mutation spontaneously develop a non-immune mediated hyperglycemia due to misfolding of insulin-2 protein, induction of endoplasmic reticulum stress, and beta cell apoptosis5. Similar to immunocompetent mice bearing the Ins2Akita allele, NOD-Rag1null IL2rγnull Ins2Akita (NRG-Akita) mice become hyperglycemic at 3-5 weeks6. However, normoglycemia can be restored in these mice by transplantation of optimal numbers (4000 islet equivalents, IEQs) of human islets. In this report, we transplanted sub-optimal numbers (1500 IEQs) of human islets into NRG-Akita mice to investigate the in vivo proliferative capacity of human beta cells in response to hyperglycemia.