The Clinical Efficacy and Safety of Stem Cell Therapy for Diabetes Mellitus: A Systematic Review and Meta-Analysis

Abstract

Diabetes mellitus (DM) is a chronic metabolic disease with high morbidity and mortality. Recently, stem cell-based therapy for DM has shown considerable promise. Here, we undertook a systematic review and meta-analysis of published clinical studies to evaluate the efficacy and safety of stem cell therapy for both type 1 DM (T1DM) and type 2 DM (T2DM). The PubMed, Cochrane Central Register of Controlled Trials, EMBASE, and ClinicalTrials.gov databases were searched up to November 2018. We employed a fixed-effect model using 95% confidence intervals (CIs) when no statistically significant heterogeneity existed. Otherwise, a random-effects statistical model was used. Twenty-one studies met our inclusion criteria: ten T1DM studies including 226 patients and eleven T2DM studies including 386 patients. Stem cell therapy improved C-peptide levels (mean difference (MD), 0.41; 95% CI, 0.06 to 0.76) and glycosylated hemoglobin (HbA1c; MD, -3.46; 95% CI, -6.01 to -0.91) for T1DM patients. For T2DM patients, stem cell therapy improved C-peptide levels (MD, 0.33; 95% CI, 0.07 to 0.59), HbA1c (MD, -0.87; 95% CI, -1.37 to -0.37) and insulin requirements (MD, -35.76; 95% CI, -40.47 to -31.04). However, there was no significant change in fasting plasma glucose levels (MD, -0.52; 95% CI, -1.38 to 0.34). Subgroup analyses showed significant HbA1c and C-peptide improvements in patients with T1DM treated with bone marrow hematopoietic stem cells (BM-HSCs), while there was no significant change in the mesenchymal stem cell (MSC) group. In T2DM, HbA1c and insulin requirements decreased significantly after MSC transplantation, and insulin requirements and C-peptide levels were significantly improved after bone marrow mononuclear cell (BM-MNC) treatment. Stem cell therapy is a relatively safe and effective method for selected individuals with DM. The data showed that BM-HSCs are superior to MSCs in the treatment of T1DM. In T2DM, MSC and BM-MNC transplantation showed favorable therapeutic effects.

Keywords: cell therapy; diabetes mellitus; meta-analysis; regenerative medicine; stem cells; systematic review.

Figure 1.

Flow chart of the selection process for this meta-analysis.

Figure 2.

Forest plot of C-peptide levels in type 1 diabetes mellitus (T1DM). Comparison of C-peptide levels in T1DM individuals between baseline and 12 months after stem cell therapy. A random-effects meta-analysis model (Mantel-Haenszel method) was used in this analysis. Each trial is represented by a square, the center of which denotes the mean difference (MD) for that trial. The size of the square is proportional to the information in that trial. The ends of the horizontal bars denote a 95% confidence interval. The black diamond gives the overall MD for all trials combined.

Figure 3.

Forest plot for glycosylated hemoglobin (HbA1c) in T1DM. Comparison of HbA1c levels in T1DM individuals between baseline and 12 months after stem cell therapy. A random-effects meta-analysis model (Mantel-Haenszel method) was used in this analysis.

Figure 4.

Forest plot of C-peptide levels in type 2 diabetes mellitus (T2DM). Comparison of C-peptide levels in T2DM individuals between baseline and 12 months after stem cell therapy. A random-effects meta-analysis model (Mantel-Haenszel method) was used in this analysis.

Figure 5.

Forest plot of HbA1c in T2DM. Comparison of HbA1c levels in T2DM individuals between baseline and 12 months after stem cell therapy. A random-effects meta-analysis model (Mantel-Haenszel method) was used in this analysis.

Figure 6.

Forest plot of insulin requirement in T2DM. Comparison of insulin requirement in T2DM individuals between baseline and 12 months after stem cell therapy. A fixed-effects meta-analysis model (Mantel-Haenszel method) was used in this analysis.

Figure 7.

Forest plot of fasting plasma glucose (FPG) in T2DM. Comparison of FPG levels in T2DM individuals between baseline and 12 months after stem cell therapy. A random-effects meta-analysis model (Mantel-Haenszel method) was used in this analysis.