Understanding and preventing type 1 diabetes through the unique working model of TrialNet

Abstract

Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches.

Keywords: Autoimmunity; Mechanistic studies; Review; Type 1 diabetes.

Fig. 1

Type 1 diabetes: a disease with three stages of pathology and various opportunities for intervention with disease-modifying therapies and mechanistic analysis. (a) Stage 1 is the start of the disease—there are no symptoms and blood sugar remains normal but the autoimmune process has already begun, manifested by multiple autoantibodies against beta cell targets. In stage 2, like stage 1, autoimmunity is the key feature and there are no symptoms; however, blood sugar control has now become abnormal due to loss of beta cells. From stages 1 and 2, there is an extremely high risk of progression to stage 3, when symptoms of diabetes emerge (thirst, weight loss and fatigue) due to significant beta cell loss, and the clinical diagnosis is made. (b) Each stage of the disease is encompassed within TrialNet and offers an opportunity for interventions or mechanistic analysis. Examples of TrialNet studies (concluded and ongoing) are listed in association with the targeted disease stage. ATG-G-CSF, anti-thymocyte globulin+granulocyte colony stimulating factor; GST, glucagon stimulation test; LIFT, long-term investigative follow-up; MMF, mycophenolate mofetil; MMTT, mixed meal tolerance test; PTP, Pathway to Prevention study. Abatacept is a CTLA-4–immunoglobulin; canakinumab is an anti-IL1β monoclonal antibody (mAb); rituximab is an anti-CD20 mAb; teplizumab is an anti-CD3 mAb

Fig. 2

Archived TrialNet samples distributed over the years. The numbers of TrialNet archived samples allocated to perform ancillary studies are shown according to year of distribution

Fig. 3

Archived TrialNet samples distributed to perform ancillary studies. (a) The number of TrialNet archived samples distributed to perform ancillary studies are shown according to the focus of the ancillary study (immunity [further subdivided into those focused on T cells, B cells and autoantibodies (Aab), and innate immunity and inflammation (innate/inflamm)], ‘omics’ and beta cells). TrialNet studies from which samples were collected are indicated (blue bars, TN01, Pathway to Prevention study; orange bars, all other TrialNet studies). (b) The number of TrialNet archived samples distributed to perform ancillary studies are shown according to the focus of the ancillary study (immunity [further subdivided into those focused on T cells, B cells and Aab, and innate/inflamm], ‘omics’ and beta cells) and by type of sample distributed (serum; peripheral blood mononuclear cells [PBMCs], plasma, DNA and RNA)

Fig. 4

Ancillary studies performed on the same TrialNet donors. Chord diagram of the components (TN ancillary studies, designated AS) and their interactions (connecting lines). Studies that analysed the same TrialNet donors are connected by lines: the wider the line, the higher the number of individuals common to the different ancillary studies. The scale and width of the TrialNet ancillary study component reflects the number of donors shared across other TrialNet ancillary studies