New therapeutic approaches for type 1 diabetes: Disease-modifying therapies

Table 1 Summary of clinical trials using mesenchymal stem cells in type 1 diabetes mellitus

Ref.	Patient characteristics	Treatment	Therapeutic outcomes
Wu et al[105], 20221	n = 14; aged 27-47 yr	Intrapancreatic: Allogeneic UC-MSC + autologous BM-MNC	Insulin independence: No
China, 8 yr	Duration of T1DM: 10-24 yr		Insulin requirement: Improvement at 1 yr but no difference at 8 yr
			FCP and HbA1C: Significant improvement
			Significantly lower occurrence of diabetic complications
Izadi et al[108], 2022	n = 20; aged 8-40 yr	BM-MSC	Insulin independence: No
Iran, 12 mo	Duration of T1DM: < 1 yr (n = 11) and > 1 yr (n = 9)		Insulin requirement, FCP, HbA1C: Significant improvement
	FCP (n = 11): 0.92 ± 0.57 ng/mL		Number of hypoglycemic events decreased
			Patients with early onset of T1DM benefit more
			Adverse effects: Possible mild injection site reactions
Lu et al[106], 2021	n = 27; aged 8-55 yr	IV (2x): Allogeneic UC-MSC	Insulin independence: 3 subjects
China, 12 mo	Median duration of T1DM: 2.3 mo		Insulin requirement, HbA1C: No improvement
	FCP: 100 pmol/L ( 0.3 ng/mL)		SCP: improved in adult-onset T1DM subgroup
			Adverse effects: Mild fever
Dantas et al[103], 20212	N = 7; Aged 16-35 yr	Allogenic AD-MSC + 2000 UI/d cholecalciferol	Insulin independence: 1 subject
Brazil, 6 mo	Duration of T1DM: ≤ 4 mo		Insulin requirement: Stable at 6 mo
	FCP: 0.80 ± 0.38 ng/dL		FCP and HbA1C: Significant improvement
			Adverse effects: Transient headache, mild local reactions, immediate tachycardia, thrombophlebitis + other mild effects
Araujo et al[102], 2020	n = 8; aged 16-28 yr	Allogenic AD-MSC + 2000 UI/d cholecalciferol	Insulin independence: 2 subjects
Brazil, 3 mo	Duration of T1DM: ≤ 4 mo		Insulin requirement, HbA1C: Decreased significantly at 3 mo
			FCP: Only initial improvements, with the same results at the 3-mo visit
			Adverse effects: Transient headache, mild local reactions, immediate tachycardia, thrombophlebitis + other mild effects
Cai et al[104], 2016	n = 21; aged 18-10 yr	Intra-pancreatic: Allogeneic UC-MSC + autologous BM-MNC	Insulin independence: No
China, 12 mo	Duration of T1DM: 2-16 yr		Insulin requirement, HbA1C: Decreased significantly
	FCP: < 0.1 pmol/mL (< 0.3 ng/mL)		FCP: Markedly increased
			Adverse effects: Transient abdominal pain, bleeding
Carlsson et al[107], 2015	n = 9; aged 18-40 yr	IV: Autologous BM-MSC	Insulin independence: No
Sweden, 12 mo	Duration of T1DM: < 3 wk		Insulin requirement, HbA1C, SCP: No significant improvement
	SCP: > 0.1 nmol/L (> 0.3 ng/mL)		Adverse effects: No
Thakkar et al[100], 2015	n = 20; aged 8-45 yr	Into portal + thymic circulation and subcutaneous tissue:	Insulin independence: No
India, 24 mo	Duration of T1DM: > 12 mo		Insulin requirement: Decreased
	2 groups with a mean C-peptide:	Group 1: Autologous IS-AD-MSC+ HSC	HbA1C, C-peptide: Sustained improvement
	Group 1: 0.22 ng/mL	Group 2: Allogeneic IS-AD-MSC+ HSC	Adverse effects: No
	Group 2: 0.028 ng/mL
Dave et al[101], 20153	n = 10; aged 9-29 yr	Into portal + thymic circulation and subcutaneous tissue: autologous IS-AD-MSC+ HSC	Insulin independence: No
India, 27 mo	Duration of T1DM: 2-15 yr		Insulin requirement: Decreased
	Pre-IV C-peptide: 0.22 ng/mL		HbA1C, C-peptide: Sustained improvement + significantly lower GADA levels
			Adverse effects: No
Hu et al[99], 2013	n = 15; aged < 25 yr	IV (2x): Allogeneic WJ-MSC	Insulin independence: 3 subjects
China, 24 mo	Duration of T1DM: < 6 mo	Control group: normal saline	Insulin requirement: 8 patients more than 50% reduction
	C-peptide: ≥ 0.3 ng/mL		HbA1C: Significantly decreased; FCP: Significantly increased
			Adverse effects: No

¹Follow-up trial to Cai et al[104], 2016.

²Extension trial to Araujo et al[102], 2020.

³Preliminary data of Thakkar et al[100], 2015.

AD: Adipose-derived; BM: Bone marrow-derived; FCP: Fasting C-peptide; GADA: Glutamic-acid-decarboxylase antibody; HbA_1C: Glycated hemoglobin; HSC: Hematopoietic stem cell; IS-AD: Adipose-derived insulin-secreting; IV: Intravenous; MNC: Mononuclear cell; MSC: Mesenchymal stem cell; SCP: Stimulated C-peptide; T1DM: Type 1 diabetes mellitus; UC: Umbilical cord-derived; WJ: Wharton’s jelly-derived.