This critical "β" may be the "star of hope" for conquering diabetes!

It is estimated that the number of people living with diabetes will reach 783 million by 2045. Managing diabetes places a significant burden on both individual patients and the healthcare system as a whole.

Diabetes and its treatment

Insulin is the most important hormone regulating glucose metabolism and is synthesized in the β cells of the islets of Langerhans in the pancreas. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are the two main types of diabetes, of which T1DM involves autoimmune β cell destruction (about 5% of diabetes cases) and T2DM has insulin resistance with varying degrees of β cell dysfunction (90-95% of diabetes cases).

For patients with T1DM, immediate insulin replacement therapy is essential, while patients with T2DM are mainly treated with oral hypoglycemic drugs (OADs). Although various treatments for diabetes have made progress in recent years, achieving optimal blood sugar control remains challenging. Fundamentally, there is still no cure for diabetes, and truly curing diabetes and achieving real-time control of physiological blood sugar requires the restoration of functional β-cell populations. Allogeneic islet transplantation is currently the main treatment strategy for restoring β-cell function, but it faces limiting factors such as donor scarcity, implantation failure, and the need for lifelong immunosuppression. However, the functional integration of stem cell-derived β cells/islets at the transplant site is still not ideal, which is more obvious in intraportal allogeneic transplant recipients. Subcutaneous transplantation of stem cell-derived β cells may be safer and more practical, but it still faces challenges such as impaired graft revascularization, and its clinical efficacy still has differences and limitations.

β-cell regeneration for diabetes

Harnessing the regenerative capacity of the pancreas to reconstitute functional β cells in situ is an attractive alternative. Research into adult β cell regeneration has primarily relied on rodent models, with a focus on stimulating replication, inducing redifferentiation, and generating new β cells from non-β cells. Although the field is primarily preclinical, recent advances in rodent and human studies are moving β cell regenerative therapies closer to clinical application.

Replication is the primary mechanism by which β-cell number is maintained in mice and adult humans. Several molecules have been identified that regulate β-cell regeneration by stimulating their own replication, including local and circulating factors. Translation of β-cell replication to clinical applications has been extensively studied but remains unclear, and achieving clinical translation may depend on the development of a drug that synergistically combines the actions of multiple molecules.

Figure: Local and circulating factors that promote β-cell replication. Source: References

Metabolic or inflammatory stress can induce β-cell dedifferentiation, causing it to lose its characteristics and exhibit a more progenitor-like state. This process reduces glucose sensitivity, impairs insulin secretion, and exacerbates the disruption of glucose homeostasis, thereby promoting the onset of diabetes. Counteracting β-cell dedifferentiation and redifferentiating undifferentiated β-cells is also a strategy for β-cell regeneration. Research directions include using anti-inflammatory treatments to offset β-cell dedifferentiation caused by proinflammatory cytokines, strengthening insulin therapy to "reduce the burden" on β-cells, and targeted interventions on dedifferentiated β-cells.

Recently, targeted β-cell redifferentiation has made significant progress in the treatment of diabetes. Another β-cell regeneration strategy is to reprogram differentiated non-β cells into functional β cells. Cell reprogramming refers to the conversion of one somatic cell type into another without going through the pluripotency stage. Several methods have been explored to reprogram non-β cells into β cells in mice. Mainly, ectopic expression of key regulators of pancreatic/endocrine/β cell development, reprogramming pancreatic α, δ and exocrine cells, as well as non-pancreatic cells such as hepatocytes, gallbladder and gastrointestinal cells into β-like cells. Although studies have demonstrated the feasibility of converting non-β cells into β cells, questions remain. For example, to what extent are the newly formed β cells similar to true β cells, are the new β cells generated in vitro and need to be transplanted, how to identify target cell-specific surface markers, and safety issues associated with transgenesis. Solving these key issues is crucial for clinical translation.

Advancing regenerative therapies to cure diabetes

Diabetes is a highly heterogeneous disease, and personalized medicine has become a new template for diabetes research and treatment, aiming to adjust interventions according to individual needs and characteristics to achieve the best treatment effect.

Currently, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) guidelines recommend insulin as the first-line treatment for T1DM, and OAD/GLP-1R agonists are preferred for T2DM. In T2DM, treatment selection is based on body mass index (BMI), risk of hypoglycemia, comorbidities, and cost/accessibility. Advancing personalized treatment requires early diagnosis and a comprehensive understanding of individual pathophysiological mechanisms. Some studies suggest that therapeutic strategies can be used to increase β-cell regeneration based on residual β-cell function.

Figure: Beyond current guidelines: Flowchart for integrating emerging regenerative strategies into contemporary diabetes management guidelines. Source: References.

Summary and Future Outlook

The rapid increase in the number of people with diabetes has highlighted the urgent clinical need for β-cell replacement and regeneration strategies. Unlike current treatments and islet transplantation, in situ β-cell regeneration has the advantage of direct regeneration in an optimal environment, ensuring precise blood sugar control.

Despite promising results in rodents, β-cell regeneration has not yet achieved clinical translation. A deeper understanding of the complex mechanisms and signaling pathways that control β-cell loss and regeneration is still needed. In addition, comprehensive characterization of β-cells and non-β-cells is essential for identifying molecular targets for targeted therapy and cell-specific delivery of regenerative cells. Advancing personalized medicine for diabetic patients requires focusing on early screening and diagnosis, accurate prediction of disease progression, quantification of residual β-cell function using non-invasive techniques, and prediction of drug response. In addition, in T1DM, strategies need to be found to prevent, stop or reverse autoimmunity.

In summary, through iterative cycles of basic, translational, and clinical research, transformative solutions will emerge, driven by a passion for studying beta-cell biology, understanding diabetes pathophysiology, and delivering tangible treatments for people with diabetes.

References:

[1] Bourgeois S, Coenen S, Degroote L, Willems L, Van Mulders A, Pierreux J, Heremans Y, De Leu N, Staels W. Harnessing beta cell regeneration biology for diabetes therapy. Trends Endocrinol Metab. 2024 Apr 20:S1043-2760(24)00082-1. doi: 10.1016/j.tem.2024.03.006. Epub ahead of print. PMID: 38644094.