Advancing Toward a Cure for Diabetes: Insights from iPSC-Derived Islet Cell Transplantation Trial

Daisuke YabeJapan Speaker Advancing toward a Cure for Diabetes: Insights from iPSC-Derived Islet Cell Transplantation TrialType 1 diabetes is characterized by absolute insulin deficiency and marked glycemic variability, creating a constant challenge for individuals who must maintain strict glycemic control to prevent complications and severe hypoglycemia. To address these persistent unmet medical needs, transplantation of pancreatic islet–like cells derived from embryonic stem (ES) or induced pluripotent stem (iPSC) cells has emerged as a promising therapeutic strategy. Encouraging advances have recently been reported from the United States and China. Notably, a world-first autologous transplantation of patient-specific iPSC-derived islet-like cells in China achieved insulin independence with near-normal glycemic control. Despite its promise, concerns remain regarding long-term safety, durability, and broad applicability, underscoring the need for further rigorous clinical evaluation. This lecture will provide an overview of current progress and ongoing challenges in β-cell replacement therapy aimed at curing type 1 diabetes. In addition, I will introduce the study design of our clinical trial at Kyoto University Hospital evaluating allogeneic transplantation of iPSC-derived islet cell sheets (OZTx-410). Through these insights, we aim to highlight both the steady steps already taken and the horizon of possibilities ahead in the pursuit of a functional cure for diabetes.Incretin-Based Therapeutics: Bridging Theory and Practice, and Exploring New HorizonsThe landscape of type 2 diabetes management has been transformed by the advent of incretin-based therapies, including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. In Japan—where more than 70% of individuals with diabetes are aged 65 years or older and commonly present with a non-obese phenotype and reduced insulin secretory capacity—DPP-4 inhibitors continue to serve as a fundamental treatment option, offering effective glycemic control with minimal risk of hypoglycemia. In contrast, among younger adults with obesity, GLP-1 receptor agonists have emerged as essential agents that not only improve glycemic control but also promote weight reduction and confer cardiovascular and renal benefits. A major advance in 2023 was the approval of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist that engages both receptors. Tirzepatide has demonstrated robust glucose-lowering and weight-reducing effects in both clinical trials and real-world practice in Japan, further expanding therapeutic opportunities across the region. However, incretin-based therapies are not without challenges: gastrointestinal adverse events remain common, and potential associations with pancreatic and biliary diseases continue to require caution. In older adults, concerns regarding their impact on frailty and sarcopenia demand careful clinical judgment. Furthermore, inappropriate discontinuation of insulin therapy after initiating incretin treatment has occasionally resulted in severe clinical consequences, highlighting the critical need for decision-making that extends beyond the evidence from controlled trials. In response to these issues, the Japan Diabetes Society (JDS) Committee for the Safe Use of Medications released the Recommendations for the Safe Use of Incretin-Related Agents, Second Edition in 2024. Disseminating these recommendations across East Asia and the broader Asia–Oceania region will be essential to ensure the safe and effective application of incretin-based therapies in diverse clinical settings. In this plenary lecture, I will explore strategies to optimize type 2 diabetes management in Asia by harnessing the therapeutic potential of incretin-based agents while proactively mitigating associated risks. Together, we aim to build a future in which innovation, safety, and patient-centered care advance hand in hand.