Endocrine Abstracts

Most patients with type 1 diabetes, even children and adolescents, have residual insulin secretion at diagnosis. As long as this can be preserved blood glucose fluctuates less, and the risk of acute and late complications decreases. Gradually the autoimmune process will destroy β-cell function unless immune intervention can stop the destructive process.

Several different interventions have been tried. The very first intervention with plasmapheresis may have had some effect, and lead to, as side effect, the discovery of the 64 kDa, later shown to be GAD. Cyclosporin proved the concept, but had, as several other broad immune suppressive agents, too serious adverse events.

Last decades the immune interventions have followed two different lines:

MABs have been used to block relevant receptors. AntiCD3 seems to be the most effective and certainly can preserve residual β-cell function, but high effective doses unfortunately lead to quite common and disturbing adverse event such as anemia, bleedings, cytokine release syndrome, etc. Phase III trials have failed, but one arm in the Teplizumab study with a moderate dose had significant effect and rather mild and acceptable adverse events, which encourages to further studies. AntiCD20 had also some effect, but short and transient.

Auto-antigen treatment to create tolerance is the other main and attractive approach. GAD-vaccination gave significant preservation of C-peptide in phase II studies in children and adolescents, but phase III did not reach primary endpoint. Efficacy in several pre-specified subgroups, however, support the concept and new studies are ongoing, when vitamin D and anti-inflammatory treatment is combined to improve the vaccination effect. Experimental studies suggest the use of insulin or pro-insulin/proinsulin peptides, and clinical studies are on their way.

In addition to the main stream there are several other trials made to use, e.g. TNF-blocking agents, islet neogenesis associated protein (INGAP), DNA-vaccines, IL1 blocking agents, vitamin D, but further studies are needed.

Conclusion: Preservation of residual insulin secretion is crucial. Clinical intervention studies should be encouraged. Most probably combination therapies will be needed.