Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition characterised by immune-mediated destruction of pancreatic β-cells, leading to absolute insulin deficiency. Its global burden has increased substantially, affecting an estimated 9.15 million people in 2024. 1 Conventional management relies on exogenous insulin and frequent glucose monitoring, which improves glycaemic control but does not address the underlying autoimmune process or prevent long-term complications. 2
Recent research has emphasised β-cell preservation and replacement strategies to reduce insulin dependence and the risk of hypoglycaemia. Immunotherapeutic interventions, particularly the anti-CD3 monoclonal antibody teplizumab, have shown promise in delaying disease onset in high-risk individuals, and a new trial has shown promising results in preserving beta-cell function in newly diagnosed patients. 3 , 4 Other immunomodulatory agents, including CTLA-4 antagonists, IL-1 inhibitors, TNF-α blockers, and IL-6 inhibitors, have been explored but with limited success, underscoring the need for effective therapies to preserve endogenous β-cell function. 5 - 9
Stem cell therapy is being investigated as a possible strategy for re-establishing endogenous insulin production using embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells (MSCs). Although early studies have reported encouraging outcomes, the overall effectiveness remains uncertain. A previous review of randomised and non-randomised studies reported insulin-free status for 1–80 months and insulin dose reductions in two-thirds of patients. 10 Another review showed significant improvements in HbA1c and insulin requirements; however, the results were combined for both T1DM and T2DM. 11 However, several new studies have been published. 12 - 14
Given the expanding evidence base and ongoing clinical development, an updated systematic review and meta-analysis (SRMA) is warranted. This SRMA evaluated the efficacy and safety of stem cell therapy compared with routine care or placebo in patients with T1DM.
Methods
The SRMA protocol was registered in PROSPERO (CRD42023471884). We adhered to the Cochrane Handbook for Systematic Reviews of Interventions and reported findings according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. 15
Eligibility criteria
The randomised controlled trials (RCTs) comparing the efficacy and safety of stem cell therapy in patients with T1DM were included. For inclusion, the RCT was required to meet all the following criteria: Population : T1DM as defined by the American Diabetes Association (ADA) or the International Society for Pediatric and Adolescent Diabetes (ISPAD) criteria; 16 intervention, stem cell therapy (hematopoietic stem cells or mesenchymal stem cells); and comparison, placebo/routine care. Studies involving neonatal diabetes, type 2 diabetes mellitus (T2DM), maturity-onset diabetes of the young (MODY), and nonrandomised study designs were excluded.
Primary and secondary outcomes
The primary outcome was the reduction in HbA1c at 6 or 12 months. The secondary outcomes included C-peptide levels, insulin independence, insulin dose reduction, and episodes of diabetic ketoacidosis (DKA). Safety outcomes included hypoglycaemia and intervention-related adverse effects.
A minimal clinically important difference of 0.5% for HbA1c has been suggested to reduce long-term complications. 17 A fasting C-peptide level >0.6 ng/mL has been associated with a decrease in insulin requirement and fewer complications (risk reduction of 58% for retinopathy and 45% for severe hypoglycaemia). 18 These thresholds were used to inform the GRADE certainty assessments.
Information sources and search strategy
We searched PubMed, Embase, Web of Science, and CENTRAL for RCTs published between January 2005 and January 2025. We used this timeframe because clinically relevant stem cell therapies for T1DM emerged only after 2005. One investigator (JK) developed a database-specific search strategy, which was peer-reviewed and refined by the other co-authors (JY, JM) ( Supplementary Table I ). We also screened the references of the included studies. No language restrictions were imposed.
Supplementary Table I
Study selection, data extraction, and risk of bias assessment
After deduplication, two authors (JY and JK) independently screened title/abstract. The eligible studies were assessed with full-text screening. Any discrepancies between the two were resolved through discussions. Studies including mixed T1DM/T2DM populations were included only if the T1DM data were reported separately. Multiple reports from the same trial were considered as a single study.
Both investigators independently gathered data using a standardised form. The extracted data comprised author names, year of publication, country, study design and setting, population characteristics, details of the intervention and control groups (dosage, duration, route, and frequency), outcomes as specified above, and funding sources. Any incongruities were addressed through consultation with a third investigator. As all trials were superiority trials, intention-to-treat (ITT) data were used whenever possible. These data were checked for accuracy and completeness by another author (JM). Two investigators (JY and JK) independently assessed the risk of bias within included RCTs using the Cochrane Risk of Bias (RoB2) tool. Disagreements were resolved through discussions.
Statistical analysis
A meta-analysis was conducted using Review Manager ( https://revman.cochrane.org ). A random-effects model was chosen to account for variability in the study populations, intervention doses, and delivery routes. Dichotomous outcomes were summarised using risk ratios (RR) and continuous outcomes using mean differences (MD) or standardised MD with 95% Confidence intervals (Cis). Wherever required, the mean and standard deviation (SD) were calculated from median, interquartile range (IQR), range, and 95% CI using a RevMan calculator or appropriate statistical conversion formulas. We assessed heterogeneity by visually inspecting the forest plots, as well as by considering Cochran’s Q statistics and I 2 statistics. Publication bias (funnel plot, Egger’s test) was planned if ≥10 studies were available for the given outcome. Sensitivity analysis was performed after excluding studies with a high risk of bias. A subgroup analysis was also planned according to the type of stem cells and route of administration.
We also assessed the certainty of the evidence for the studied outcomes using the core GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. 19
Results
We identified 4,985 citations, of which 794 duplicates were removed. The remaining 4,191 records underwent title and abstract screening, and 77 articles were reviewed in their entirety ( Fig. 1 ). Seven RCTs (eight reports) met the inclusion criteria ( Table I ). 12 - 14 , 20 - 24 Six RCTs with seven reports were on T1DM. 12 - 14 , 20 - 23 One RCT included patients with T1DM and T2DM 24 but provided separate T1DM data. The risk of bias was assessed using RoB2 ( Fig. 2 ). Three studies had a low risk of bias. 13 , 14 , 22 One study had a high risk of bias, 21 as it had serious concerns in multiple domains. The remaining three 20 , 23 , 24 had some minor concerns but were not judged to be high risk overall. Common issues included the open-label design, unavailability of study protocols, and insufficient details on allocation concealment. Domain-level assessments are presented in Supplementary Table II .
Table I.
Characteristics of the studies included in the review
BM MSC, bone marrow mesenchymal stem cell; CBC, complete blood count; CGMS, continuous glucose monitoring system; DHA, docosahexaenoic acid; DN, diabetic nephropathy; DPN, diabetic peripheral neuropathy; DRP, diabetic retinopathy; FBG, fasting blood glucose; HbA1c, glycated haemoglobin; HSC, haematopoietic stem cells; IV, intravenous; OGTT, oral glucose tolerance test; RCT, randomised controlled trial; T1DM, type 1 Diabetes mellitus; T2DM, type 2 diabetes mellitus; UCB-MSC, umbilical cord blood mesenchymal stem cell
| Author (yr); country | Study design | Population | Intervention | Comparison | Outcomes | Funding/trial registration |
| Ghodsi et al 24 (2012); Iran | Double-blinded, placebo-controlled RCT | T1DM and T2DM (We included only T1DM data) Age 10-60 yr with T1DM (n=30) b) Disease duration- up to 20 yr c) Blood glucose <270 mg/dL | Foetal liver-derived stem cell, 35-55×10 6 cells (7-11×10 6 CD34+ HSCs) via IV route n= 13 (6 females) Mean age: 21.6±10.5 yr Mean duration: 6.03±2.6 yr | Placebo (normal saline) n= 17 (9 females) Mean age: 21.4±9.80 yr Mean duration: 6±3.3 yr | Primary: FBG, HbA1c, fasting serum c-peptide Secondary: CBC, liver function tests, lipid profile tests | Not mentioned |
| Haller et al 20 (2013); USA | Open-label RCT | Children with type 1 diabetes who are older than 1 year of age and for whom autologous UCB was stored | Autologous umbilical cord blood 1.1x10 7 cells/kg via IV route n=10 (2 females) Median age: 7.2 yr | Standard care n=5 (2 females) Median age: 6.6 yr | HbA1c, C-peptide, Insulin requirement | Juvenile diabetes research foundation |
| Hu et al 21 (2013); China | Double-blind RCT | T1DM age <25 years Disease duration < 6 months Fasting C-peptide ≥ 0.3 ng/mL | Wharton’s jelly-derived mesenchymal stem cell, IV twice at a 4-wk interval, N=15 (6 females) Mean age: 17.6 ±8.7 yr | Placebo (normal saline) N=14 (6 females) Mean age: 18.2 ±7.9 yr | HbA1c, Fasting C-peptide, Insulin requirement, Diabetes ketoacidosis, Safety | Human Umbilical Cord, Mesenchymal Stem Cell Bank, Shandong Province, China |
| Carlsson et al 22 (2015); Sweden | Open-label RCT | 18-40 yrs old with T1DM diagnosed within three wk C-peptide >0.3 ng/mL | Autologous BM MSC 2.1–3.6x10 6 autologous cells/kg (median 2.75x10 6 cells/kg) via IV route N=9 (4 females) Mean Age: 27±2 yr | Standard care N=9 (1 female) Mean Age: 24±2 yr | Primary: Adverse events such as infections, development of malignancy or other disease, and hypo- or hyperglycaemic events Secondary: HbA1c, Insulin dose, stimulated C-peptide | Swedish Research Council, AFA Insurance, EXODIAB, Swedish Diabetes Association, the Swedish Juvenile Diabetes Foundation. |
| Cai et al 12 , 23 (2016); China | Open-label RCT | 18-40 yr old with T1DM disease duration: 2-16 yr HbA1c: 7.5-10% Insulin requirement: <100 IU/d Mean duration- I-9.2 yr, I-7 yr | 60–80 mL Bone marrow-derived Mononuclear cells (106.8x10 6 /kg) plus 30–50 mL UC-MSCs (1x10 6 /kg) in the dorsal pancreatic artery or its substitute N=21 (9 females) Mean age: 18.3 years Mean duration: 9.2 yr | Standard care N=21(11 females) Mean age: 20.4 yr Mean duration: 7 yr | C-peptide AUC after 3hr of OGTT at 1 year Secondary- HbA1c, exogenous insulin requirement, fasting blood glucose and C-peptide, anxiety, depression, and Quality of life Follow up data on the incidence of chronic complications, DPN, DN, and DRP were published by Wu et al (17). | Fujian Province, The People’s Liberation Army Clinical Innovation Major Project Fund Diabetes Research Institute Foundation, Hollywood, FL, |
| Izzadi et al 13 (2023); Iran | Triple-blind, placebo-controlled RCT | T1DM (8 to 40 yr) within 6 wk of diagnosis C-peptide level ≥0.9 ng/mL and presence of at least one of the three autoantibodies | Autologous BM MSC 1x10 6 /kg, two doses at 0 and 3 wk via IV route N=11(5 females) Mean age: 11.5±2.6 yr | Placebo (Normal Saline) N=10 (5 females) Mean age: 10.3±1.7 yr | Primary: Safety, hypoglycaemia Secondary: FBS, two-hour postprandial glucose test, C-peptide, HbA1c, daily insulin, lability index. | Royan Institute; The Iranian Vice-Presidency for Science and Technology, Council for Development of Stem Cell Sciences and Technologies, NCT04078308 |
| Carlsson et al 14 (2023); Sweden | Double-blind, placebo-controlled RCT | 18-40 yr T1DM Onset < 2 yr fasting plasma C-peptide concentration >0.36 ng/mL | Wharton jelly MSC 200 million cells via IV route N=10(4 females) Mean age: 31±9 yr, | Placebo (Excipients without cells were used in preparation in the intervention arm) N=5 (3 females) Mean age: 31±4 yr | Primary: ∆-change in C-peptide AUC (0–120 min) for a mixed meal tolerance test (MMTT) Secondary: Insulin Independence, insulin needs <0.25 IU/kg, HbA1c glucose variability, hypo/hyperglycaemia duration | Uppsala University NextCell Pharma AB, Stockholm, Sweden. NCT03406585 |
Supplementary Table II
Primary outcome
HbA1c: At 6 months, three studies reported HbA1c, and the pooled estimates showed a statistically significant reduction (MD: -0.57%, 95% CI: -1.13 to -0.02, P = 0.04, I 2 -51 %) in the stem cell arm ( Fig. 3A ) . However, this difference did not meet the MID threshold. At 12 months, six studies reported HbA1c with no significant reduction (MD: -0.49 %, 95% CI: -0.98 to 0.00, P =0.05, I 2 -57%) ( Table II ).
Table II.
Summary of Findings Table for HbA1c, fasting and stimulated C-peptide and insulin requirement at 6 and 12 months
Interpretation: Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimated effect. Explanations: a Includes studies which are at risk of bias or have some concerns, b Moderate heterogeneity, c Clinically meaningful minimal important difference not achieved, d Very high heterogeneity, e 95% CI crosses the threshold of benefit and harm, and the sample size is extremely small CI, confidence interval; MD, mean difference; RCT, randomised controlled trial
| Outcomes | No. of participants (studies) | Anticipated absolute effects (95% CI) with stem cell (compared to control) | Certainty of the evidence (GRADE) |
| HbA1c (%) at 6 months | 87 (3 RCTs) | MD 0.57 lower (1.13 lower to 0.02 lower) | ⨁◯◯◯ Very low a,b,c |
| HbA1c (%) at 12 months | 140 (6 RCTs) | MD 0.49 lower (0.98 lower to 0) | ⨁◯◯◯ Very low a,b,c |
| Fasting C-peptide (ng/mL) levels at 6 months | 72 (2 RCTs) | MD 0.03 higher (0.01 higher to 0.05 higher) | ⨁◯◯◯ Very low a,c |
| Fasting C-peptide (ng/mL) at 12 months | 125 (5 RCTs) | MD 0.09 higher (0.05 higher to 0.13 higher) | ⨁◯◯◯ Very low a,c |
| Insulin requirement (IU/kg/d) at 6 months | 57 (2 RCTs) | MD 0.07 lower (0.35 lower to 0.21 higher) | ⨁◯◯◯ Very low a,c,d,e |
| Insulin requirement (IU/kg/d) at 12 | 110 (5 RCTs) | MD 0.09 lower (0.28 lower to 0.09 higher) | ⨁◯◯◯ Very low a,c,d,e |
| Stimulated C-peptide (ng/mL) (Mixed meal method) at 6 months | 15 (1 RCT) | MD 0.68 lower (1.44 lower to 0.08 higher) | ⨁◯◯◯ Very low a,e |
| Stimulated C-peptide (ng/mL) (Mixed meal method) at 12 months | 15 (1 RCT) | MD 0.13 lower (0.63 lower to 0.37 higher) | ⨁◯◯◯ Very low a,e |
Fasting C-peptide: Two studies reported fasting C-peptide at 6 months, showing significant preservation in the stem cell group (MD: 0.03, 95% CI: 0.03 to 0.03; P < 0.001, I2 = 0%) ( Fig. 3B ). At 12 months, five studies showed a statistically significant benefit (MD: 0.09; 95% CI: 0.05 to 0.13; P < 0.001; I 2 : 0%) in the stem cell arm ( Fig. 3B ). Despite statistical significance, the effects did not meet the MID threshold and were downgraded accordingly ( Table II ).
Four studies reported stimulated C-peptide levels but used heterogeneous methodologies and reporting formats; therefore, pooling was not feasible. All trials individually demonstrated higher stimulated C-peptide levels with stem cell therapy ( Supplementary Table III ).
Supplementary Table III
Secondary outcomes
Insulin dose: At 6 months, two studies reported insulin requirements (IU/kg/d). The pooled effect did not show a significant difference (MD: -0.07, 95%CI: -0.35 to 0.21, P=0.61, I 2 =86%; very low certainty evidence) ( Fig. 4 ). At 12 months, five studies reported insulin requirements. There was no significant difference at 12 months (MD: -0.09, 95%CI: -0.28, 0.09, P =0.32, I 2 =89%, very low certainty evidence) ( Table II ).
No patient in either group achieved insulin-free status during the study period. Two studies assessed quality of life (QoL). Cai et al 23 reported significantly improvement in anxiety, depression, and overall QoL; whereas Izadi et al 13 found no significant differences ( Supplementary Table IV ).
Supplementary Table IV
Safety outcomes:
Hypoglycaemia: Cai et al 23 reported fewer severe hypoglycaemic episodes in the stem cell therapy group than control [0.43 (0–2) vs . −0.048 (−1 to 1), P = 0.02]. Izadi et al 13 also observed significantly fewer grade I ( P =0.046), grade II ( P <0.001), and overall hypoglycaemic events ( P =0.016) in the stem cell group. Hu et al 21 reported a non-significant trend towards fewer diabetes ketoacidosis episodes with stem cell therapy (0/15 vs . 3/14) than control group.
Other adverse events: Stem cell therapy was generally well tolerated across all trials. None of the patients developed severe adverse events. Most adverse effects were mild and self-limiting, including cough, transient headache, abdominal discomfort, flu-like symptoms, injection site reactions, and minor laboratory abnormalities ( Supplementary Table V ). These minor events were self-limiting and comparable between the groups.
Supplementary Table V
Sensitivity and subgroup analysis: Sensitivity analysis excluding a single high-risk-of-bias study (Hu et al 21 ) did not affect the results, as this trial did not contribute to the quantitative synthesis. Planned subgroup analyses by stem cell type and route of administration were not feasible because of substantial variability in stem cell sources, doses, and protocols. We also intended to provide subgroup analysis based on the route of administration. However, only one study used the pancreatic artery route (the rest used the intravenous route), and formal subgroup analysis is not desirable (unlikely to provide a meaningful inference and at risk of false interpretation). A narrative summary is provided in Supplementary Table VI .
Supplementary Table VI
Publication bias: We planned to evaluate publication bias using funnel plots complemented with Egger’s regression test. However, due to fewer studies (a maximum of six studies were available for a given outcome), these tests were not performed because they are not recommended for detecting significant biases with a small number of studies (<10).
Discussion
In this systematic review, stem cell therapy for T1DM showed only marginal short-term improvements in glycaemic and β-cell–related outcomes, with no evidence of durable clinical benefit. There is very low-certainty evidence that stem cell therapy may reduce HbA1c levels at 6 months post-therapy; however, this effect was not sustained at 12 months. This reduction was marginal and unlikely to be clinically significant. Although fasting C-peptide levels were modestly higher in the stem cell group at both time points, the improvements were small, transient, and unlikely to have any meaningful impact. The low certainty of evidence across all outcomes reflects limited confidence in the estimated effects. Therefore, the actual effect may differ substantially from the reported estimates.
Restoration of endogenous insulin secretion remains the central objective of T1DM therapeutics. Ideally, such interventions should provide durable improvements in HbA1c, increase time in range, reduce glycaemic variability, and lower exogenous insulin requirements. HbA1c levels have a well-established relationship with microvascular and macrovascular complications. With exogenous insulin therapy, the aim is to maintain HbA1c levels below 7%. In clinical practice, a reduction of 0.5% or more in HbA1c is considered clinically meaningful. 25 , 26 Despite this benchmark, current stem cell trials rarely demonstrate improvements approaching this threshold, and reported C-peptide gains, although statistically significant in some studies, do not translate into clinically relevant β-cell preservation.
Our findings align with those of the broader literature, which highlights inconsistent and uncertain benefits. Madani et al 10 reported improvements in HbA1c and fasting C-peptide, but these conclusions were largely drawn from non-randomised studies (3 RCTs and 24 non-RCTs). He et al 27 assessed the efficacy of stem cells in T1DM and T2DM and reported similar results as of index meta-analysis. In their meta-analysis, there was no significant effect on fasting plasma glucose (FPG) and fasting C-peptide levels. Kassem et al 28 evaluated umbilical-cord-derived mesenchymal stem cells (MSCs) and Wharton’s jelly MSCs in T1 DM and T2 DM. In their meta-analysis, umbilical cord blood (UCB)-derived MSCs did not significantly improve HbA1c%, C-peptide levels, or insulin requirements. In contrast, Wharton’s jelly MSCs showed a statistically significant improvement in all three parameters. However, that review included a mixed population of T1DM and T2DM, and combined randomised and non-randomised studies (the majority). Hence, the findings should not be directly compared with the index review, which is limited to RCTs on T1DM. Studies showing long-term HbA1c reductions had too few patients to be generalised. Taken together, the wide confidence intervals across available studies highlight the substantial uncertainty regarding the durability of treatment effects. Stem cell therapies may offer short-term improvements in glycaemic control; however, their impact on β-cell function and long-term clinical outcomes remains inconclusive.
In the index meta-analysis, all patients continued to require exogenous insulin to maintain HbA1c levels, and the reduction in the daily insulin dose was not significant. This contrasts with the findings of Madnai et al 10 , who reported an insulin-free period in 26.4% of patients and insulin dose reduction in 68.5%. However, as mentioned above, the study population and type of studies are not comparable to the index review. In T2DM, several studies have demonstrated reductions in insulin requirements following SCT, suggesting potentially different mechanisms and responses between diabetes subtypes. 29 - 31
The intervention was generally well tolerated. However, considering the limited data and open-label study design, these findings should be interpreted cautiously. Stem cell interventions in T2DM patients have been reported to cause serious adverse events, including malignancy (meningioma and multiple myeloma) and mortality. 31 - 33
This meta-analysis is one of the few meta-analyses exclusively conducted on T1DM, focusing solely on RCTs, and evaluating MID and certainty of evidence using a rigorous GRADE approach. However, there are several limitations. It included a small number of studies with very few participants, most of which were open-label and underpowered for efficacy and safety. The follow up durations were short, limiting the assessment of long-term outcomes. Considerable heterogeneity in patient selection, stem cell sources, protocols, and outcome measures further reduces the robustness of these findings. While ITT was used where available, reporting inconsistencies across trials (and occasional lack of clearly specified ITT analyses) represent a limitation and may affect outcome estimates.
Based on the current evidence, stem cell therapy for T1DM remains investigational and has not demonstrated consistent or durable efficacy. Key challenges persist, including immunogenicity and immune rejection, limited proliferative and differentiation capacities, the requirement for immunosuppression, potential for tumerogenesis, especially from pluripotent cells and ethical concerns related to certain stem cell sources.
Acknowledgment
Authors acknowledge the role of the technical resource centre Neonatal Unit, PGIMER, Chandigarh, for their intellectual input.
Footnotes
How to cite this article: Yadav J, Kumar J, Kumar R, Dawman L, Meena J, Saini L et al. Efficacy and safety of stem cell therapy in type 1 diabetes: A systematic review and meta-analysis of randomised controlled trials. Indian J Med Res . 2026;164:81-90. doi: 10.25259/IJMR_2655_2025
Author contributions
JY, JK, JM: Literature search, screening, study selection, data extraction and analysis, manuscript writing; LD, LS BKP: Literature search and screening of studies, data analysis; RK, DD, RP: Critical inputs, manuscript writing. All authors have read and approve the final printed version of the manuscript.
Financial support and sponsorship
The study received a financial grant from Indian Council of Medical Research (grant no EOI/syst.review/RMRU/2023/BMS).
Conflicts of Interest
None.
Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation
The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.
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Associated Data
Supplementary Materials
Supplementary Table I
Supplementary Table II
Supplementary Table III
Supplementary Table IV
Supplementary Table V
Supplementary Table VI