Islet cells in human type 1 diabetes: from recent advances to novel therapies - a symposium-based roadmap for future research

Abstract

There is a growing understanding that the early phases of type 1 diabetes (T1D) are characterised by a deleterious dialogue between the pancreatic beta cells and the immune system. This, combined with the urgent need to better translate this growing knowledge into novel therapies, provided the background for the JDRF-DiabetesUK-INNODIA-nPOD symposium entitled 'Islet cells in human T1D: from recent advances to novel therapies', which took place in Stockholm, Sweden, in September 2022. We provide in this article an overview of the main themes addressed in the symposium, pointing to both promising conclusions and key unmet needs that remain to be addressed in order to achieve better approaches to prevent or reverse T1D.

Keywords: autoimmune; diabetes; insulin secretion; islet; pancreas.

Figure 1

Progression to type 1 diabetes (T1D). Risk factors for T1D include genetic predisposition and environmental factors, such as viral infections and diet. Although the clinical diagnosis of T1D usually occurs at stage 3 when beta cell mass is depleted and hyperglycaemia is established, several stages precede this. There is increasing recognition of stage 0, in which beta cell dysfunction and impaired glycaemic control may occur in the absence of autoantibodies. Stage 1 represents seroconversion with the engagement of the adaptive immune system and the appearance of autoantibodies. During stage 2 beta cell dysfunction and apoptosis are increased impairing glycaemic control, leading to clinical diagnosis at stage 3. An important concept discussed is the reciprocal interaction between the beta cell and immune system throughout disease progression, along with interperson heterogeneity influenced by factors such as age of onset. Figure created with BioRender.com.

Figure 2

Visualising insulitis in three dimensions. Image of a 3D reconstruction of an nPOD donor (20-year-old T1D subject with 7 months disease duration) stained for glucagon (blue) and CD3 (yellow), revealing the presence of infiltrating immune cells within the islet of Langerhans, interspersed with endocrine cells. 3D reconstruction was performed using Arivis Vision4D.

Figure 3

Summary of pancreas Type 1 diabetes endotypes (T1DE). Images of pancreatic sections from a T1DE1 (left panel) or T1DE2 (right panel) donor. Low magnification images of pancreas sections (left inset panels, 1 cm scale bars) with each islet annotated as being an uninflamed Insulin-containing islet (ICI) – red; inflamed, defined as >15 CD45+ immune cells/ islet, ICI – green; inflamed insulin-deficient islet (IDI) – blue; or uninflamed IDI – pink. T1DE1 donors have evidence of more inflammation (green and blue islet annotations) and fewer residual insulin-containing islets (red/green islet annotations) than individuals with T1DE2. The higher magnification images (right inset panels, 500 µm and 100 µm scale bars) demonstrate the presence of peri-insulitis and invasive insulitis in ICIs of a T1DE1 donor, and an example of low level peri-insulitis observed in a T1DE2 donor. Further immune and beta cell characteristics of the endotypes are described in the boxes.

Figure 4

Human pluripotent stem cell-derived islets (SC islets). Double immunostaining for insulin and glucagon in the immature SC islets (stage 7, week 0) shows many double-positive cells. In the mature stage, the hormone-positive cells are clearly defined as separate populations in an architecture that resembles the human islet. Dynamic insulin secretion was studied with perifusion. The immature SC islets do not respond to high glucose, although they are able to respond to exendin-4 and membrane depolarisation induced by potassium chloride (KCl). In contrast, the mature-stage SC islets show a high response to glucose. (Data from Balboa et al. Nature Biotech 2022. Figure prepared by Väinö Lithovius.)

Figure 5

A suggested roadmap for future type 1 diabetes (T1D) research. Summary of priorities for T1D research as described in detail in the main text. Pathophysiology (upper section). Risk factors for T1D involve a combination of genetic and environmental factors, including gut microbiota and viral infection. There is an urgent need for more research into the early stages of disease onset, including environmental triggers and the interaction between beta cells and the immune system. Progress in recent years has revealed marked heterogeneity in the age of diagnosis, disease progression and residual beta cell function in people with T1D. Further research into the factors underlying this heterogeneity is needed to generate deeper insights into disease aetiology, identify prognostic markers and enable personalised treatment strategies. With increased global obesity, including in childhood, more research into the role of obesity, sedentary lifestyle and insulin sensitivity on T1D progression is warranted. A recurring theme in the meeting was the dysregulation of glucagon secretion from pancreatic alpha cells (in spite of the fact that beta cells but not alpha cells are killed in long-term diabetes) and the imbalance of glucagon and insulin in the T1D pancreas. Finally, alterations in the exocrine and ductal system of the pancreas have been observed in T1D. Lower section, interventions. Summary of established and emerging approaches to treat T1D is provided, with estimated timescales to clinical impact (colour coded: pink, near-term 0–5 years; orange, mid-term 0–8 years; blue, long-term 5–10+ years). Improved pre-diabetes screening will support targeted immunotherapy, beta cell preservation and ultimately T1D prevention. Optimised combination therapies, reduced insulin requirements and smarter insulin delivery have the potential to improve clinical care in the near term. Stem-cell-derived cell transplant therapies are in clinical trials with positive early reports and have the potential to improve regulated insulin release in T1D in the mid-term. Likewise, strategies to improve the success of islet transplant therapy have the potential to reduce insulin dependence in the short term. Strategies to regenerate endogenous beta cells have long-term potential to restore regulated insulin secretion in the pancreas which, if coupled to beta cell protective therapies, may reverse T1D. Improvements in preclinical models and protocols can accelerate many of these therapeutic avenues. Figure created with BioRender.com.