Unveiling a novel type 1 diabetes endotype: Opportunities for intervention

Type 1 diabetes (T1D) results from the destruction of insulin-producing pancreatic β-cells by auto-reactive T cells that have escaped central and peripheral immune tolerance.1-6 The disease is characterised by a wide heterogeneity especially in terms of age at onset, insulin secretory capacity (mirrored by the residual β-cell function) and complication/progression rates. Such heterogeneity represents a major barrier for both pathogenesis and especially for translational therapeutic efforts, thus prompting a reflection on different T1D patient endotypes for identifying the specific one that may benefit most from novel therapeutics.7, 8 In this context, Piganelli et al. recently discussed how stress-induced changes, in β-cells in subjects who develop T1D, can alter their function and immunogenicity as well as neo-antigen formation which could contribute to a crosstalk between β-cells and immune cells leading to a breakdown in tissue-specific immune tolerance.4 This commentary highlights the relevance of endotypes in defining immune intervention strategies for T1D. The majority of T1D patients at diagnosis has already undergone a significant loss of functional pancreatic islets as consequence of the autoimmune attack,9 making unlikely to preserve or rescue the β-cell function. However, there is an endotype of T1D patients positive to islet cell related autoantibodies who experience a different natural history, maintaining a residual β-cell function as defined by C-peptide levels ranging between 0.2 and 0.6 nmol/L after diagnosis (Table 1), and whose characteristics have extensively been investigated demonstrating that these patients maintain clinically relevant endogenous insulin secretion for up to 5 years after diagnosis.10-14 Such patients unveil a novel T1D endotype,8 identifying a T1D subpopulation and not just a stage of the disease. Noteworthy, the American Diabetes Association (ADA) now recognises latent autoimmune diabetes of adulthood (LADA) as a distinct T1D endotype15 that is defined by a slow autoimmune β-cell destruction on the basis of C-peptide levels,15-17 whereas T1D staging does not rely on C-peptide measurement.15 Consistently, this novel endotype (C-peptide range, 0.2–0.6 nmol/L) identifies an ideal T1D subpopulation of patients –and not just a stage of the disease– that may benefit most from disease-modifying therapies aiming at protecting endogenous insulin secretion and potentially capable of inducing disease remission. Yet, therapeutic intervention should conceivably be early, as glycaemia dysregulation during the first year after T1D onset is associated with an increased risk of microvascular complications,18 and C-peptide per se might have an active protective factor in reducing this risk (Table 1).10, 11, 13, 14, 19-21 Therefore, prospects for refining innovative treatments should consider the T1D endotype characterised by a clinically relevant C-peptide threshold as a 'target population' for opportunities of intervention aiming at modulating the overreactive autoimmune response while preserving β-cell function. Pathogenesis of T1D is marked by the destruction of the insulin-producing β-cells. Several observations highlight the importance of the programed death (PD)-1/PD-ligand 1 (PD-L1) inhibitory pathway in the maintenance of immune homoeostasis and tolerance.22 In T1D, PD-L1 is up-regulated in pancreatic islets as a response to the inflammatory process and it correlates with CD8+ T cell infiltration, suggesting that PD-L1 up-regulation represents a key mechanism to control T cell activation and promote T cell exhaustion in pancreatic tissues.23, 24 Its key pathogenetic role is also suggested by the observation that blockade of the PD-1/PD-L1 axis in cancer patients treated with anti-PD-1 antibodies results in a 7-fold increase of T1D risk.25 Furthermore, the local delivery of PD-L1 presenting microgels helps the reprogramming of local immune responses to transplanted pancreatic islets26 and PD-L1 overexpression protected human islet-like organoids xenografts such that they were able to transiently restore glucose homoeostasis.27 In this context, Ben Nasr et al.28 demonstrated that genetically engineered murine haematopoietic stem and progenitor cells (HSPCs) overexpressing PD-L1 (PD-L1.Tg) reverse hyperglycaemia abrogating the autoimmune response and preserving endogenous insulin release. Albeit these results demonstrate that the induced expression of PD-L1 in HSPCs may be used as a tool for targeted immunotherapy in T1D,28 this approach failed to induce a clinical benefit in mice with baseline blood glucose levels in the 4–500 mg/dl range, indicating that this immuno-gene therapy approach showed to be effective only in mice that had a partially preserved β-cell function. This preclinical observation provides support for the hypothesis that the novel T1D endotype (defined by C-peptide levels ranging between 0.2 and 0.6 nmol/L after diagnosis) conceivably identifies the subset of patients who can benefit most from immune modulating therapeutic approaches. This endotype may be also the target for strategies aimed at β-cell regeneration29, 30 and at reducing hyperglycaemia-induced cytotoxicity, via the use of insulin pumps to achieve an optimal metabolic control.31, 32 In conclusion, patients with T1D and substantial residual β-cell function identify a specific endotype of T1D, which is a T1D subset and not a stage of the disease. Furthermore, it should also be noted that some patients with this endotype may be overweight and insulin resistant, thus implying that this pathophysiological condition, typical also of LADA, could be tackled. These novel concepts pave the way for new and diverse opportunities for intervention to be offered to well characterised endotypes of T1D patients. None. No potential conflicts of interest relevant to this commentary were reported. Not relevant. Both of the authors contributed substantively to the design, the writing and editing of the commentary, and approved the final version submitted for publication. The peer review history for this article is available at https://publons.com/publon/10.1002/dmrr.3536. Data used in the paper can be found in the bibliography of the paper and are available on PubMed.