Abstract
With the advancement of regenerative medicine and precision medicine, diabetes management is shifting from 'blood glucose control' to a paradigm of 'functional cure + precision intervention.' This paper systematically reviews key breakthroughs in five dimensions—stem cell therapy, precision genotyping, complication management, drug innovation, and future challenges—based on the latest 2025 research. Clinical cures have been achieved through stem cell-derived islet transplantation, while 3D bioprinting technology overcomes limitations in the transplantation microenvironment. Chinese Genetic risk scores (C-GRS) enable early screening for type 1 diabetes, and complication prevention now focuses on organ-specific interventions. The repurposing of established drugs such as DPP-4 inhibitors has uncovered off-target benefits beyond glucose reduction. Future efforts should prioritize universalizing stem cell therapy, precise medication for complications, and establishing comprehensive lifecycle prevention networks.
Stem cells and Regenerative Medicine: from Laboratory to Clinical Cure
Autologous/Allogeneic Regenerated Islet Transplantation
The research team at Shanghai Changzheng Hospital successfully converted patients' peripheral blood mononuclear cells (PBMC) into endodermal stem cells (EnSC) using epigenetic reprogramming technology. These EnSCs were later differentiated into functional regenerated islet tissue (E - islet).
Following minimally invasive portal vein transplantation, the first patient with type 2 diabetes mellitus (T2DM) for 25 years achieved complete insulin independence 33 months post - surgery. The 18% improvement in estimated glomerular filtration rate (eGFR) confirmed concurrent enhancement of renal function[1].
In April 2025, the National Medical Products Administration (NMPA) granted clinical trial approval to the allogeneic universal E - islet 01. Its standardized production system effectively addresses the donor shortage issue[2].
D Bioprinted Islets
The 2025 European Society of Organ Transplantation (ESOT) Annual Meeting presented a groundbreaking advancement: Researchers used alginate-based decellularized pancreatic tissue matrix to develop bio-ink, successfully 3D-printing functional human islets with vascular networks. Subcutaneous transplantation in mice showed graft survival exceeding 21 days and a 3.2-fold increase in glucose-stimulated insulin secretion (GSIS), effectively avoiding the cell loss typical of conventional intrahepatic transplantation[3]. 1.3 Stem Cell-Derived Therapies In Phase I-II clinical trials, Vertex's allogeneic stem cell-derived islet cell product Zimislecel allowed 83% of type 1 diabetes patients (14 out of 17) to achieve complete insulin independence within one year, with a time in range (TIR) exceeding 70% and no severe hypoglycemic events[4].
Regarding the clinical translation characteristics of stem cell technologies, each approach exhibits distinct advantages: Autologous E-islet transplantation achieves complete remission in a type 2 diabetes patient after 33 months, but requires high-cost individualized preparation. Allogeneic E-islet 01, which features standardized shelf-type production, has been approved for clinical use by the National Medical Products Administration (NMPA), although immunosuppressive agents are necessary. 3D bioprinted islets allow for minimally invasive subcutaneous transplantation, with successful trials in animal models, though long-term efficacy has not been confirmed. Zimislecel allogeneic therapy effectively restores islet function, enabling 83% of patients to become insulin-independent; however, two treatment-related deaths have been reported.
Precision Genotyping and Early Intervention: Breaking the Diagnostic Dilemma
Genetic Risk Stratification
Xiangya Second Hospital developed the Type 1 Diabetes China Genetic Risk Score (C-GRS) based on the China Population Genome-Wide Association Study (GWAS). The model improved the diagnostic accuracy of antibody-negative patients to 92.7%, identifying 20-40% more misdiagnoses compared to the international standard (T1D-GRS)[5].
2.2 Preventive Immunization Interventions
The U.S. Food and Drug Administration (FDA) has approved the anti-CD3 monoclonal antibody Teplizumab to delay the onset of type 1 diabetes in high-risk individuals (those with ≥2 types of pancreatic autoantibodies positive). Phase III data showed a 3.4-year median delay in the onset of clinical diabetes[6] .The UK has implemented nationwide screening based on the genetic-environmental interaction model, with prevention and intervention coverage reaching 67% among high-risk populations[7].
Management of Complications: from Passive Treatment to Active Prevention
New Strategies for Heart and Kidney Protection
The combination of vitamin C and metformin significantly improved myocardial fibrosis (collagen volume fraction decreased by 38%) and glomerulosclerosis (KIM-1 decreased by 52%) in diabetic rats by synergistically inhibiting the ROS/NF-κB pathway, showing better efficacy than monotherapy (P<0.01).[8]In the STRIDE trial, semaglutide increased the painless walking distance by 26.4 meters (median) in patients with peripheral arterial disease (PAD), and the improvement in the ankle-brachial index (ABI) confirmed its direct vascular endothelial protective effect[9].
Target Organ Injury Mechanisms
Vagliflozin significantly alleviated pulmonary injury in type 1 diabetic rats by specifically inhibiting the NLRP3-GSDMD-IL-1β pyroptosis pathway, resulting in a 45% reduction in alveolar septum thickness. This effect was statistically significant compared to liraglutide (P=0.003)[10].
Long-term prevention and control of microvascular complications
UKPDS follow-up studies confirmed that continuous treatment with metformin or sulfonylureas for 5-15 years reduced the annual incidence of microvascular complications by 6%-9%, with a 9% reduction in the risk for combination therapy (HR=0.91,95%CI 0.87-0.95).[11]
Drug Therapy Innovation:Beyond Hypoglycemia:Multi-target Interventions
Differences in Organ Protection of DPP-4 Inhibitors
Vigliflozin exhibits significantly superior lung-protective effects compared to ligliflozin, due to its selective inhibition of DPP-8/9 and modulation of the NLRP3 pathway. This finding highlights the need for organ-specific precision in complication management[10].
Immune Metabolic Regulators
DPP-4 inhibitors such as vigratine exhibit anti-inflammatory and anti-apoptotic effects independent of glucose-lowering in type 1 diabetes by modulating the Treg/Th17 balance, offering novel targets for immunometabolic interventions[12].
Future Challenges and Directions
1. Universalization of stem cell therapy: breakthroughs in immune rejection (e.g. CRISPR-Cas9 editing of HLA class I genes), large-scale production, and long-term carcinogenicity validation[13]；
2. Precision medicine for complications: Establish molecular subtypes of organ damage to guide drug selection (e.g., Vagliflozin as the first-line treatment for lung injury)[10]；
3. Advance prevention: Promote C-GRS for early screening of type 1 diabetes, combined with Teplizumab to form a closed-loop 'screening-intervention' system[5-6];
4. Integration of regenerative medicine: 3D-printed vascularized scaffolds improve graft survival, combined with local immune exemption strategy to replace systemic immunosuppression[14].
Summary
The diagnosis and treatment of diabetes has entered a new era characterized by the \"repair-substitution-prevention\" trinity: Therapeutic breakthroughs include stem cell technology achieving β-cell functional reconstruction, progressing from E-islet case cures to exploration of Zimislecel universalization. Precision diagnosis and treatment are advancing with C-GRS resolving classification challenges, and complication management is evolving toward organ-specific differentiation. Enhanced prevention and control strategies involve semaglutide expanding its vascular protective effects, while repurposed combination therapy (Vitamin C + Metformin) has revealed synergistic mechanisms.
Core proposition: Regenerative medicine should be included in the medical insurance payment system within the next decade, and a comprehensive prevention and control network covering 'genetic risk screening, immune prevention, and early warning of complications' should be established.[15]
