β Cells that Resist Immunological Attack Develop during Progression of Autoimmune Diabetes in NOD Mice

Abstract

SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disease that involves immune-mediated destruction of β cells. How β cells respond to immune attack is unknown. We identified a population of β cells during the progression of T1D in non-obese diabetic (NOD) mice that survives immune attack. This population develops from normal β cells confronted with islet infiltrates. Pathways involving cell movement, growth and proliferation, immune responses, and cell death and survival are activated in these cells. There is reduced expression of β cell identity genes and diabetes antigens and increased immune inhibitory markers and stemness genes. This new subpopulation is resistant to killing when diabetes is precipitated with cyclophosphamide. Human β cells show similar changes when cultured with immune cells. These changes may account for the chronicity of the disease and the long-term survival of β cells in some patients.

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…Recently, a distinct population of approximately 15% of all beta cells was described to resist immune attack in non-obese diabetic (NOD) mice. These beta cells are characterized by reduced expression of beta cell identity genes including Glut2 and likely reflect the de-differentiation of existing beta cells (Rui et al, 2017). While these cells are distinct from the virgin beta cells that we describe, these observations nevertheless suggest that immature beta cells by virtue of their reduced expression of beta cell identity genes -including the major auto-antigens insulin and G6pc2 -may escape auto-immune diabetes like they resist STZ-mediated beta cell death.…”

Persistence of Pancreatic Insulin mRNA Expression and Proinsulin Protein in Type 1 Diabetes Pancreata

“…The absence of insulin hnRNA and INS-IGF2 mRNA is suggestive of the insulin gene not being actively transcribed (Evans-Molina et al, 2007; Lee and Gorospe, 2010; Welsh et al, 1985), potentially as a means to avoid autoimmune killing (Rui et al, 2017). Therefore, there is a clear need for further studies of the mechanisms underlying long-lasting INS mRNA and proinsulin protein expression despite low to no INS promoter activity.…”

Advances in drug discovery for human beta cell regeneration

“…All were reported in 2015, or shortly thereafter, to drive human beta cell replication by serving as reversible inhibitors of DYRK1A [13,17-20]. In general, the ‘rate’ of human beta cell proliferation with use of these inhibitors has been reported in the 1–3% range [14,22,23], but higher labelling indices of approximately 5% have been observed with multi-day BrdU or EdU labelling protocols [20,21].…”

“…Moreover, harmine treatment improves glucose tolerance in immunodeficient mice transplanted with human islets [14]. For type 1 and type 2 diabetes, in which beta cells are reported to de-differentiate [11-13], this may prove particularly important. Of course, these studies have been performed over days to a week and, so, longer term studies are required to determine whether this enhanced differentiation persists over time.…”