More recently, it has become apparent that the onset of type 1 diabetes may not be solely a consequence of irreversible β-cell death. Loss of insulin production more likely results from a combination of β-cell destruction alongside partially reversible loss of β-cell function caused by inflammatory cytokines. In support of this notion, studies of human pancreata suggest that small numbers of insulin-positive β-cells are present in many patients with established type 1 diabetes, suggesting that β-cells can survive but are not able to secrete sufficient insulin to overcome hyperglycemia. In addition, some recent immune intervention trials observed rapid recovery of β-cell function that was too rapid to be explained by β-cell replication or neogenesis. For example, Couri et al. (46
) achieved at least temporary insulin independence and increased C-peptide in most type 1 diabetic patients who were treated with a nonmyeloablative bone marrow transplant after strong immunosuppression. Thus, aborting the inflammatory and autoreactive response in conjunction with relieving metabolic stress might be sufficient to restore function in surviving β-cells. Crucial aspects that need to be studied in the future include determining the frequency of metabolically inactive surviving β-cells and identifying the pathways within β-cells that are affected by inflammatory immune mediators in conjunction with metabolic stress.
This is a significant issue, because mature β-cells have very little ability to proliferate and make up for the loss caused by an autoimmune insult. Specifically, although β-cell proliferation is readily detectable in children, new evidence suggests the proliferative capacity is already markedly reduced during early adolescence (47
). This reduction is partly due to the increased expression of the cyclin-dependent kinase inhibitor p16 in aging β-cells that is partly mediated by components of the polycomb group of histone methyltransferases (48
). Thus, even when the immune insult is blocked, it may be critical to develop approaches to induce the proliferation of remaining β-cells in older patients with long-standing type 1 diabetes to restore normoglycemia.
That said, recent studies have suggested that new β-cells can be generated from progenitor tissue. Indeed, studies in mice that have undergone pancreatic injury have demonstrated that other cell types, including duct or duct-associated cells, can reactivate the endocrine program and generate insulin-producing cells (50
). Recent efforts also suggest that the immune system itself may be important in this regeneration process. Thus, future studies will have to address whether the β-cells found in patients with long-standing type 1 diabetes are derived from the few surviving β-cells that have escaped the immune insult or whether they have formed by neogenesis from a non–β-cell population. Importantly, understanding the origin of the β-cells present in type 1 diabetic patients might influence the choice of immune regulatory drug therapies to maximize islet regeneration and increase β-cell mass, while at the same time halting the immune assault.
Finally, it is likely that physiologic changes of β-cells in response to autoimmunity or unknown environmental factors may be critical to perpetuating islet autoimmunity. Studies of pancreatic sections from patients with both new-onset and a subset of patients with long-term type 1 diabetes reveal β-cell destruction in a lobular pattern, with some regions of the pancreas where all islets contain β-cells, whereas in other regions, all β-cells have been destroyed. As the number of whole pancreata from deceased donors with type 1 diabetes become more readily available, such as those in the Juvenile Diabetes Research Foundation (JDRF) Network for Pancreatic Donors with Diabetes (nPOD) resource (histology available online for research viewing at www.jdrfnpod.org
), it is becoming clear that the degree of insulitis of most patients with type 1 diabetes is not only lobular but is also much less than that present in the NOD mouse or the BB rat animal models. This may relate to the usual very slow progression of β-cell loss in humans, occurring over years.
The nPOD resource also highlights the existence of heterogeneity of pancreatic pathology for patients who were diagnosed with type 1 diabetes. A subset of the pancreata from patients lacking islet autoantibodies or high-risk HLA have no pseudoatrophic islets (islets lacking all β-cells, typically associated with type 1A diabetes) but rather have decreased numbers of β-cells per islet rather than increased islets lacking all β-cells (51
). Both for humans (of pancreata with pseudoatrophic islets) and the NOD mouse, the surviving β-cells are not normal and hyperexpress MHC class I alleles and the survivin molecule. In addition, hyperexpression of MHC class I alleles is seen in a lobular fashion up to 8 years after diagnosis, independently of islet infiltration (51
). Unfortunately, the specific initiators of increased expression of MHC class I molecules on β-cells are not yet clear (see our earlier discussion).