Dreams for Type 1 Diabetes: Shutting Off Autoimmunity and Stimulating β-Cell Regeneration

Abstract

Although not the first study to show that inhibitors of dipeptidyl peptidase IV (DPP-IV) can reverse newly diagnosed diabetes in nonobese diabetic (NOD) mice (1), a study by Tian et al. (2) in this issue of Endocrinology confirms this finding with a different DPP-IV inhibitor (NVP-DPP728) and provides explanations for the reversal by finding reduced islet inflammation, increases in CD4 CD25 FoxP3 regulatory T cells, and -cell regeneration. Impressively, 6 wk of treatment with this agent reversed diabetes in 73% of the mice. DPP-IV inhibitors are usedclinically to treatdiabetesbecause they slow the breakdown of the incretin hormone glucagon-like peptide 1 (GLP-1), which can stimulate insulin secretion, inhibit -cell apoptosis, and promote -cell replication (3). However, these inhibitors have long been known to have effects on the immune system, which presumably contributed to the marked reduction in islet inflammation. In particular, lymphocytes have a membrane-associated protein with DPP-IV activity, CD26, which has been shown to have important effects upon T-cell development, migration, and cytokine production (4). It has been previously shown that inhibition of DPP-IV can slow the progression of experimental allergic encephalitis and increase the production of TGF, which is known to suppress autoimmunity (5). In the present study, the reversal of diabetes was accompanied by a reduction of insulitis, an increase in CD4 CD25 FoxP3 regulatory T cells, and an increase in circulating TGF. Interestingly, the regulatory T cells were particularly plentiful in the thymus and pancreatic lymph nodes. It is possible that the therapeutic benefit of the present study is not completely due to the effects of DPP-IV inhibition on the immune system but in part a result of increased circulating levels of GLP-1. Inhibition of CD26 is an attractive mechanism, but the actual contribution from this specific mechanism remains to be defined. It is even possible that GLP-1 can somehow ameliorate immune killing of -cells independently of DPP-IV. We certainly have much more to learn about the effects of GLP-1 on the immune system (3). It is noteworthy that the combination of GLP-1 and gastrin has been shown to reverse diabetes in NOD mice, and this reversal was even seen in some mice with just GLP-1 treatment alone (6). The effect of GLP-1 on the target of the immune attack, the -cell, may be very important. GLP-1 is known to have an antiapoptotic effect upon -cells, probably by bolstering the insulin receptor substrate 2 signaling pathway (7, 8). Therefore, it is possible that a reduction of -cell death and less release of antigen could somehow influence the balance of T-cell regulation and slow the rate of immune destruction. Clearly, more work is needed to sort out the relative contributions of DPP-IV inhibition and GLP-1 agonism. Another addition to the equation is gastrin, the circulating levels of which can be increased with either injections of the peptide or the use of proton pump inhibitors. We know that gastrin given in combination with either epidermal growth factor or GLP-1 agonism can stimulate -cell regeneration (6, 9). Now we must ask how gastrin might contribute to reduced autoimmune destruction. The demonstration of -cell regeneration, accompanied by increased -cell replication, is similar to what has been found with some other but not all interventions that reverse diabetes in NOD mice. It seems likely that increases in -cell mass result from replication of residual -cells, although there is a provocative recent report sug-