Type 1 diabetes research: poised for progress

Since type 1 diabetes was first proposed to be an autoimmune disease in the 1970s, the search has been on to identify the key pathogenic determinants and immune cell types involved. The Immunology of Diabetes Society Congress in October, 2018 (London, UK) featured a debate questioning the Achilles’ heel of type 1 diabetes: is it regulatory T-cell dysfunction, misdirected cytotoxic T cells, autoimmune B cells, type 1 interferon, or a viral infection? The audience—comprising many of the world’s leading experts on the disease—could not agree. After years of intensive research, including dozens of carefully designed clinical trials, how is it possible that the mystery underlying type 1 diabetes pathogenesis remains unsolved?
It turns out that the immunopathology of type 1 diabetes is extremely complicated and might even differ from patient to patient. Most major recent discoveries have revealed even more questions and additional layers of pathogenic complexity, prompting the field to repeatedly revise conceptual frameworks and the design of clinical trials testing new therapies. However, since we last wrote on this topic 5 years ago, many landmark studies have been reported, including those of several international collaborative efforts, leading to an important consolidation of ideas on many fronts, portending that the field is now poised to progress in a meaningful way.
It is therefore timely to highlight our new two-paper Series that takes stock of the field of immune-based therapies for type 1 diabetes. In the first paper, Mark Atkinson and colleagues provide an overview of how hypotheses about disease pathogenesis have evolved with the findings of recent research, and in turn how new thinking can inform the design of new clinical trials. In the second paper, Bart Roep and colleagues zero in on antigen-specific therapies, a goal that will be increasingly realistic with accumulating information regarding type 1 diabetes antigens, disease heterogeneity, and general principles of balancing inflammatory and regulatory immune mechanisms.

If the past 5 years of type 1 diabetes immunological research have been rewarding, the next 5 and beyond hold even more promise. Among the keys to recent resurgence in progress has been increased access to human pancreas samples from patients with type 1 diabetes. When combined with new technologies enabling high-content single-cell analysis such as multiplex ion beam imaging, CO-Detection by indEXing, and RNA sequencing, it is certain that even deeper insights into disease pathogenesis and heterogeneity are on the horizon. Longer follow-up of well characterised high-risk cohorts will continue to advance what we know about environmental determinants and disease endotypes. Through omics methods, knowledge of the number and nature of disease-relevant antigens will illuminate more about the natural history of the disease and inform personalised therapies, including antigen-specific approaches. Ongoing research efforts will also give rise to improved biomarkers that better quantify risk for type 1 diabetes, disease stage, and treatment response in trials and later in practice. Beyond the realms of immunological research in type 1 diabetes, we can anticipate that insulin delivery systems will become increasingly sophisticated through accumulating evidence and improved algorithms, hopefully leading to new device approvals and ultimately delivering better glycaemic control, less hypoglycaemia, and reduced risk of complications. Opportunities for non-insulin adjunct therapies—such as SGLT inhibitors—will be broadened, and the use of continuous glucose monitoring increased. Clinical trials will prove whether stem-cell therapies are a realistic solution for islet-replacement.

The incidence of type 1 diabetes is still increasing in some high-income countries, and many of these patients can look forward to benefiting from all of this progress in the near future. But let us not forget the global majority who will not—those whose main concern is simply to obtain insulin to stay alive. Moving towards the necessary ideal of universal insulin affordability and access in the coming years will have substantial effects on prevalence of type 1 diabetes in low-income and middle-income countries (LMICs). A key aim for the next era is therefore to continue to improve quality of life for existing patients with type 1 diabetes worldwide through optimum glycaemic control—which includes ensuring a steady supply of essential glucose monitoring supplies in LMICs—and reduction of morbidity and mortality, while ongoing research continues to strive for the ultimate goal of type 1 diabetes cure.
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