Diabetes mellitus and cellular replacement therapy: Expected clinical potential and perspectives

Table 1 Summary preclinical data among stem cell transplantation in diabetic animals

Type of cell replaced	Positive effect expected	Negative effect expected
Embryonic stem cells	Direct effect: Differentiation into functional insulin-producing cells Indirect effect: Improving of the fasting blood glucose due to restore the function of islet β cells Decreasing of blood lipid levels Increasing of serum C-peptide level Prevention of free-radical induced oxidative stress injury of beta-cells Improving of pancreatic microcirculation	Ethical problems Rejection High frequency of autoimmune-mediated destruction of the β cells and other autoimmune reactions High immunogenency Malignancy Potential tumor mediated effect
Pluripotent stem cells	Direct and indirect effects: See mentioned above	High frequency of rejection High immunogenency Low frequency of autoimmune-mediated destruction of the β cells and other autoimmune reactions Potential tumor mediated effect
Bone marrow derived mesenchymal stem cells	Direct and indirect effects: See mentioned above	Low frequency of autoimmune-mediated destruction of the β cells Moderate immunogenency Potential tumor mediated effect Low frequency of rejection
Adipose-derived stem cells	Direct and indirect effects: See mentioned above	Extremely low incidences in comparison with bone marrow derived mesenchymal stem cells of rejection, potential tumor mediated effect and autoimmune-mediated destruction of the β cells

Table 2 The basic data among current and completed stem cell-based investigations in diabetic patient population

Title of the study/ClinicalTrials.gov identifier	Phase	n	Gender	Age group	Cell type	Interventions	Results
Tissue distribution of F18-FDG labelled autologous bone marrow derived stem cells in patients with type 2 DM (NCT01694173)	Phase 2/3	28	Both gender	Adult/ senior	Stem cell harvest	Splenic artery transplantation vs placebo	No data, current study
Efficacy of autologous bone marrow derived stem cell transplantation in patients with type 2 diabetes mellitus (NCT00644241)	Phase 2	10	Both gender	Adult/ senior	Stem cell harvest	Angiographic transplantation of stem cells	No data, current study
A pilot study on transplantation therapy using autologous bone marrow mononuclear cells and umbilical cord mesenchymal stem cells in patients with type 1 diabetes mellitus (NCT01143168)	Phase 1	24	Both gender	Adult	Autologous bone marrow mononuclear cells and umbilical cord mesenchymal stem cells	Angiographic transplantation of stem cells	No data, current study
A open labeled and self controlled, safety/efficacy assessed pilot study on transplantation therapy using bone marrow mesenchymal stem cells for insulin resistance of type 2 diabetes mellitus (NCT01142050)	Phase 1	24	Both gender	Adult	Mesenchymal stem cells	Angiographic transplantation of stem cells	No data, current study
Autologous hematopoietic stem cell transplantation in type 1 diabetes mellitus (NCT01121029)	Phase 1/2	15	Both gender	2-35 yr	Autologous hematopoietic stem cell	Transplantation	Beta cell function was increased in all but 1 patient and induced prolonged insulin independence in the majority of the patients
Autologous bone marrow mononuclear cell infusion with hyperbaric oxygen therapy in type 2 diabetes mellitus (NCT00767260)	Phase 1/2	82	Both gender	45-65 yr	Autologous bone marrow mononuclear cell	Autologous bone marrow mononuclear cell Infusion vs standard medical therapy	No data, current study
Phase 1 and 2 study of the use of human adipose derived mesenchymal stem cells as regenerative therapy in diabetic patients with critical limb ischemia (NCT01257776)	Phase 1/2	36	Both gender	18-85 yr	Autologous adipose derived mesenchymal stem cells	Intra-arterial administration through a selective cannulation of target common femoral artery vs no intervention	No data, current study
Efficacy of autologous bone marrow derived stem cell transplantation in patients with type 2 diabetes mellitus (NCT01065298)	Phase 1/2	30	Both gender	30-75 yr	Autologous Bone marrow derived stem cell	Injection into superior pancreatico duodenal artery vs standard combined medical therapy	No data, current study
Study on induced wound healing through application of expanded autologous bone marrow stem cells in diabetic patients with ischemia-induced chronic tissue ulcers affecting the lower limbs (NCT01065337)	Phase 2	30	Both gender	18-80 yr	Bone marrow stem cells	Intraarterial administration vs standard of care wound treatment according guideline of the American Diabetes Association	No data, completed study
Phase 2 study of autologous stem cell and hyperbaric oxygen therapy in type 2 diabetes mellitus (NCT01786707)	Phase 1/2	2	Both gender	45-65 yr	Autologous stem cells	Autologous stem cells and hyperbaric oxygen therapy vs No Intervention	No data, completed study
Reversal of type 1 diabetes in children by stem cell educator therapy (NCT01996228)	Phase 1/2	20	Both gender	6-14 yr	Human Cord Blood-derived multipotent stem cells	Apharesis and stem cell educator therapy	No data, current study
Phase 2 study of stem cell educator therapy in type 1 diabetes (NCT01350219)	Phase 2	100	Both gender	14-60 yr	Human cord blood-derived multipotent stem cells	Apharesis and stem cell educator therapy	No data, current study
A trial of high dose immunosuppression and autologous hematopoietic stem cell support vs intensive insulin therapy in adults with early onset type 1 diabetes mellitus (NCT01285934)	Phase 1/2	30	Both gender	16-35 yr	Autologous hematopoietic stem cell	Autologous hematopoietic stem cell transplantation vs intensive insulin therapy	No data, current study
Stem cell educator therapy in type 2 diabetes (NCT01415726)	Phase 1/2	25	Both gender	14-65 yr	Human cord blood-derived multipotent stem cells	Stem cell educator used for the isolation and purification of cord blood stem cells. No comparator	No data, current study
Safety and efficacy study of umbilical cord/placenta-derived mesenchymal stem cells to treat type 2 diabetes (NCT01413035)	Phase 2	30	Both gender	18-80 yr	Human umbilical cord/placenta-derived mesenchymal stem cells	Human umbilical cord/placenta-derived mesenchymal stem cells iv infusion + oral hypoglycemic drugs, insulins or their combination vs oral hypoglycemic drugs, insulins or their combination	No data, current study
Open study to evaluate the safety and efficacy of autologous mesenchymal stem cells in treatment of recently diagnosed patients with type 1 diabetes mellitus (NCT01068951)	Phase 2	20	Both gender	18-40 yr	Autologous mesenchymal stem cells	Autologous transplantation of the patients own mesenchymal stem cells (approximately 2 × 106 cells/kg body weight) intravenously.	No data, completed study
Umbilical cord mesenchymal stem cells and liraglutide in diabetes mellitus (NCT01954147)	Phase 1/2	100	Both gender	35-65 yr	Umbilical cord mesenchymal stem cell	Umbilical cord mesenchymal stem cell infusion combined with liraglutide vs liraglutide	No data, current study
Umbilical mesenchymal stem cells and mononuclear cells infusion in type 1 diabetes mellitus: a randomized controlled open-label study (NCT01374854)	Phase 1/2	44	Both gender	18-40 yr	UC-MSCs	1 × 106/kg UC-MSCs is infused through pancreatic artery along with mononuclear cells by interventional therapy and another same dose of UC-MSCs is administered one week post-intervention	No data, current study
Autologous transplantation of mesenchymal stem cells for treatment of patients with onset of type 1 diabetes (NCT01157403)	Phase 2	80	Both gender	10-40 yr	Autologous bone marrow mesenchymal stem cells	Autologous transplantation of bone marrow mesenchymal stem cells (approximately 2.5 × 106 cells/kg body weight) intravenously	No data, current study
A phase II, multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of prochymal® (ex vivo cultured adult human mesenchymal stem cells) for the treatment of recently diagnosed T1DM (NCT00690066)	Phase 2	60	Both gender	12-35 yr	Ex vivo cultured adult human mesenchymal stem cells	Intravenous infusion of ex vivo cultured adult human mesenchymal stem cells	No data, current study
A randomized, controlled, parallel design, safety and efficacy study of granulocyte colony stimulating factor mobilized autologous peripheral blood mononuclear cell therapy in subjects with diabetic limb ischemia (NCT00922389)	Phase 1/2	36	Both gender	18-65 yr	Peripheral blood derived mononuclear cells	Implanting stem cells derived from peripheral blood after G-CSF mobilization	No data, current study
Phase 1/2 study: treatment of patients with diabetic foot complications with allogeneic bone marrow derived mesenchymal stromal cells (NCT01686139)	Phase 1/2	10	Both gender	18-81 yr	Cultured Bone Marrow Mesenchymal Stromal Cells (BM-MSCs) from allogeneic donors or autologous BM-MSCs	Multiple injections of ABMD-MSC cells (10-20 × 106 cells)	No data, current study
Autologous hematopoietic stem cell transplantation for the treatment of limb ischemia and diabetic neuropathy in patients with diabetes mellitus type 2: a randomized controlled trial (NCT00730561)	Phase 1/2	20	Both gender	18-74 yr	Hematopoietic stem cell (totipotential, hematopoietic or endothelial lineages)	Intramuscular application of CD34+ hematopoietic stem cells (with a minimum of 2 million CD34+ cells/kg) into the gastrocnemius muscles after stimulation with subcutaneous filgrastim 600 micrograms/kilogram a day for 4 d	No data, completed study