Effects of Autoimmunity and Immune Therapy on β-Cell Turnover in Type 1 Diabetes

Abstract

␤-Cell mass can expand in response to demand: during pregnancy, in the setting of insulin resistance, or after pancreatectomy. It is not known whether similar ␤-cell hyperplasia occurs following immune therapy of autoimmune diabetes, but the clinical remission soon after diagnosis and the results of recent immune therapy studies suggest that ␤-cell recovery is possible. We studied changes in ␤-cell replication, mass, and apoptosis in NOD mice during progression to overt diabetes and following immune therapy with anti-CD3 monoclonal antibodies (mAbs) or immune regulatory T-cells (Tregs). ␤-Cell replication increases in pre-diabetic mice, after adoptive transfer of diabetes with increasing islet inflammation but before an increase in blood glucose concentration or a significant decrease in ␤-cell mass. The pathogenic cells are responsible for increasing ␤-cell replication because replication was reduced during diabetes remission induced by anti-CD3 mAb or Tregs. ␤-Cell replication stimulated by the initial inflammatory infiltrate results in increased production of new ␤-cells after immune therapy and increased ␤-cell area, but the majority of this increased ␤-cell area represents regranulated ␤-cells rather than newly produced cells. We conclude that ␤-cell replication is closely linked to the islet inflammatory process. A significant proportion of degranulated ␤-cells remain, at the time of diagnosis of diabetes, that can recover after metabolic correction of hyperglycemia. Correction of the ␤-cell loss in type 1 diabetes will, therefore, require strategies that target both the immunologic and cellular mechanisms that destroy and maintain ␤-cell mass. Diabetes 55:3238 -3245, 2006

Detection of β cell death in diabetes using differentially methylated circulating DNA

“…The fasting glucose levels remained normal at all time points (Fig. 5 A and B) (24). The demethylation index increased significantly before the decline in insulin levels and before the increase in fasting glucose levels (P = 0.0002) (Fig.…”

“…Moreover, β cell function might be affected by ambient glucose level, certain drugs, and other factors (31). With the caveat that stressed β cells may methylate insulin DNA and die without release of demethylated insulin, we do not expect our measurements to be affected by changes in β cell function, in contrast to measurements of circulating insulin mRNA in the serum of recipients of islet allografts (24,31,32). Thus, our approach to analysis may be useful in distinguishing β cell death from impaired function.…”

“…As shown by our analysis of prediabetic NOD mice, this was clearly the case, with the greatest increase in the demethylation index seen before hyperglycemia was identified. We have previously shown that β cells may fail to express insulin (i.e., are degranulated) at the time of onset of diabetes in NOD mice but are still viable and may recover with immunotherapy, such as anti-CD3 mAb (24). Moreover, β cell function might be affected by ambient glucose level, certain drugs, and other factors (31).…”

“…The decline in β cell-derived DNA after the onset of hyperglycemia suggests that the relative abundance of demethylated insulin DNA in the circulation may be reduced because of a total loss of β cell mass. For example, a higher percentage of β cells may be destroyed after diagnosis with hyperglycemia than before diagnosis, but fewer β cells actually may be destroyed (24,31,32).…”

Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

“…The insulin-producing  cells can regenerate through various mechanisms, which is another topic of debate. Notably, an association between microenvironment inflammation and increased  cell proliferation was recognized during insulitis and pancreatitis (Sherry et al, 2006;Cano et al, 2008;Faleo et al, 2012). A mode of  cell regeneration through replication was demonstrated in animal models, but it was evident only after months of follow up (Dor et al, 2004).…”