New Horizons in the Treatment of Type 1 Diabetes: More Intense Immunosuppression and Beta Cell Replacement.

Since the discovery of autoimmunity as the main pathophysiologic process involved in type 1 diabetes, many attempts have tried to delay or stop beta cell destruction. Most research protocols in humans have investigated the effects of therapeutic agents targeting specific steps of the autoimmune response. In spite of safety and some degree of beta cell preservation, the clinical impact of such approaches was similar to placebo. Recently, research groups have analyzed the effects of a more intense and wider immunologic approach in newly diagnosed type 1 diabetic individuals with the "immunologic reset," i.e., high-dose immunosuppression followed by autologous hematopoietic stem cell transplantation. This more aggressive approach has enabled the majority of patients to experience periods of insulin independence in parallel with relevant increments in C-peptide levels during mixed meal tolerance test. However, on long-term follow-up, almost all patients resumed exogenous insulin use, with subsequent decrease in C-peptide levels. This has been at least in part explained by persistence of islet-specific T-cell auto-reactivity. Here, we discuss future steps to induce immune tolerance in individuals with type 1 diabetes, with emphasis on risks and possible benefits of a more intense transplant immunosuppressive regimen, as well as strategies of beta cell replacement not requiring immunomodulation.

The Janus faces of 3-hydroxykynurenine: dual redox modulatory activity and lack of neurotoxicity in the rat striatum.

3-Hydroxykynurenine (3-HK), an intermediate metabolite of the kynurenine pathway, has been largely hypothesized as a neurotoxic molecule contributing to neurodegeneration in several experimental and clinical conditions. Interestingly, the balance in literature points to a dual role of this molecule in the CNS: in vitro studies describe neurotoxic and/or antioxidant properties, whereas in vivo studies suggest a role of this metabolite as a weak neurotoxin. This work was designed to investigate, under different experimental conditions, whether or not 3-HK is toxic to cells, and if the redox activity exerted by this molecule modulates its actions in the rat striatum. In order to evaluate these effects, 3-HK was administered in vitro to isolated striatal slices, and in vivo to the striatum of rats. In striatal slices, 3-HK exerted a concentration- and time-dependent effect on lipid peroxidation, inducing both pro-oxidant actions at low (5-20) micromolar concentrations, and antioxidant activity at a higher concentration (100µM). Interestingly, while 3-HK was unable to induce mitochondrial dysfunction in slices, at the same range of concentrations it prevented the deleterious effects exerted by the neurotoxin and related metabolite quinolinic acid (QUIN), the mitochondrial toxin 3-nitropropionic acid, and the pro-oxidant compound iron sulfate. These protective actions were related to the stimulation of glutathione S-transferase (GST) and superoxide dismutase (SOD) activities. In addition, 3-HK stimulated the protein content of the transcription factor and antioxidant regulator Nrf2, and some of its related proteins. Accordingly, 3-HK, but not QUIN, exhibited reductive properties at high concentrations. The striatal tissue of animals infused with 3-HK exhibited moderate levels of lipid and protein oxidation at short times post-lesion (h), but these endpoints were substantially decreased at longer times (days). These effects were correlated with an early increase in glutathione reductase (GR) and GST activities. However, these changes were likely to be merely compensatory as 3-HK-infused animals did not display behavioral (rotation) alterations or morphological changes in their injected striata. Altogether, these findings suggest that, despite 3-HK might exert pro-oxidant actions under certain conditions, these changes serve to evoke a redox modulatory activity that, in turn, could decrease the risk of cell damage. In light of this evidence, 3-HK seems to be more a redox modulatory molecule than a neurotoxic metabolite.

ß-cell regeneration to treat Type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of the insulin-producing pancreatic ß-cells. The autoimmune response begins years before the presentation of hyperglycemic symptoms. At the time of clinical diagnosis, less than 30% of ß-cell mass still remains. The conventional therapeutic option to T1DM is daily insulin injections, which is shown to promote tight glucose control and reduce the majority of chronic diabetic complications. Subgroup analysis of the Diabetes Control and Complication Trial showed another important aspect related to long-term complications of diabetes, that is, patients with initially higher serum levels of C-peptide with sustained levels over the subsequent years suffered less microvascular complications and less hypoglycemic events than those patients with low or undetected C-peptide levels. In face of this, ß-cell preservation is another important target in the management of T1DM and its related complications. Along the years, many efforts toward the identification of precursors of ß-cells have been made, not only with the aim of understanding the physiology of ß-cell preservation, but also as a potential source of ß-cell replacement. In this review, we summarize the most important studies related to probable precursor cells implied in the process of regeneration, and the results of various immunomodulatory regimens aiming at blocking autoimmunity against pancreatic ß-cells and at promoting ß-cell preservation. Finally, we comment on the future perspective related to stem cell therapy in T1DM.