One repeated transplantation of allogeneic umbilical cord mesenchymal stromal cells in type 1 diabetes: an open parallel controlled clinical study

Abstract Background The preservation or restoration of β cell function in type 1 diabetes (T1D) remains as an attractive and challengeable therapeutic target. Mesenchymal stromal cells (MSCs) are multipotent cells with high capacity of immunoregulation, which emerged as a promising cell-based therapy for many immune disorders. The objective of this study was to examine the efficacy and safety of one repeated transplantation of allogeneic MSCs in individuals with T1D. Methods This was a nonrandomized, open-label, parallel-armed prospective study. MSCs were isolated from umbilical cord (UC) of healthy donors. Fifty-three participants including 33 adult-onset (≥ 18 years) and 20 juvenile-onset T1D were enrolled. Twenty-seven subjects (MSC-treated group) received an initial systemic infusion of allogeneic UC-MSCs, followed by a repeat course at 3 months, whereas the control group (n = 26) only received standard care based on intensive insulin therapy. Data at 1-year follow-up was reported in this study. The primary endpoint was clinical remission defined as a 10% increase from baseline in the level of fasting and/or postprandial C-peptide. The secondary endpoints included side effects, serum levels of HbA1c, changes in fasting and postprandial C-peptide, and daily insulin doses. Results After 1-year follow-up, 40.7% subjects in MSC-treated group achieved the primary endpoint, significantly higher than that in the control arm. Three subjects in MSC-treated group, in contrast to none in control group, achieved insulin independence and maintained insulin free for 3 to 12 months. Among the adult-onset T1D, the percent change of postprandial C-peptide was significantly increased in MSC-treated group than in the control group. However, changes in fasting or postprandial C-peptide were not significantly different between groups among the juvenile-onset T1D. Multivariable logistic regression assay indicated that lower fasting C-peptide and higher dose of UC-MSC correlated with achievement of clinical remission after transplantation. No severe side effects were observed. Conclusion One repeated intravenous dose of allogeneic UC-MSCs is safe in people with recent-onset T1D and may result in better islet β cell preservation during the first year after diagnosis compared to standard treatment alone. Trial registration ChiCTR2100045434. Registered on April 15, 2021—retrospectively registered, http://www.chictr.org.cn/

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One Repeated Transplantation of Allogeneic Umbilical Cord Mesenchymal Stromal Cells in Type 1 Diabetes: An Open Parallel Controlled Clinical Study

10.21203/rs.3.rs-115774/v1 ◽

2020 ◽

Author(s):

Jing Lu ◽

Shanmei Shen ◽

Qing Ling ◽

Wei Zhang ◽

Duoduo Qu ◽

...

Keyword(s):

Stromal Cells ◽

Cell Function ◽

Treated Group ◽

Control Group ◽

Adult Onset ◽

Juvenile Onset ◽

C Peptide ◽

B Cell Function

Abstract Background: The preservation or restoration of b-cell function in type 1 diabetes (T1D) remains as an attractive and challengeable therapeutic target. Mesenchymal stromal cells (MSCs) are multipotent cells with high capacity of immunoregulation, which emerged as a promising cell-based therapy for many immune disorders. The objective of this study was to examine the efficacy and safety of one repeated transplantation of allogeneic MSCs in individuals with T1D. Methods: This was a nonrandomized, open-label, parallel-armed prospective study. MSCs were isolated from umbilical cord (UC) of healthy donors. 53 participants including 33 adult-onset (³18 years) and 20 juvenile-onset T1D were enrolled. 27 subjects (MSC-treated group) received an initial systemic infusion of allogeneic UC-MSCs, followed by a repeat course at 3 months, whereas the control group (n=26) only received standard care based on intensive insulin therapy. Data at one-year follow-up was reported in this study. The primary endpoint was clinical remission defined as a 10% increase from baseline in the level of fasting and/or postprandial C-peptide. The secondary endpoints included side effects, serum levels of HbA1c, changes in fasting and postprandial C-peptide, and daily insulin doses. Results: After 1-year follow-up, 40.7% subjects in MSC-treated group achieved the primary endpoint, significantly higher than that in the control arm. Three subjects in MSC-treated group, in contrast to none in control group, achieved insulin independence and maintained insulin free for 3 to 12 months. Among the adult-onset T1D, the percent change of postprandial C-peptide was significantly increased in MSC-treated group than in the control group. However, changes in fasting or postprandial C-peptide was not significantly different between groups among the juvenile-onset T1D. Multivariable logistic regression assay indicated that lower fasting C-peptide and higher dose of UC-MSC correlated with achievement of clinical remission after transplantation. No severe side effects were observed. Conclusion: One repeated transplantation of allogeneic UC-MSCs is both safe and beneficial to preserve b-cell function for individuals with T1D. Trial registration: NCT 02763423. Registered on April 19, 2016 - Retrospectively registered, https://clinicaltrials.gov/

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Pathophysiological characteristics of preproinsulin-specific CD8+ T cells in subjects with juvenile-onset and adult-onset type 1 diabetes: A 1-year follow-up study

Pediatric Diabetes ◽

10.1111/pedi.12536 ◽

2017 ◽

Vol 19 (1) ◽

pp. 68-79 ◽

Cited By ~ 3

Author(s):

Mahinder Paul ◽

Darshan Badal ◽

Neenu Jacob ◽

Devi Dayal ◽

Rakesh Kumar ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Cd8 T Cells ◽

Adult Onset ◽

Juvenile Onset ◽

Onset Type ◽

Follow Up Study

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Clinical and demographic features among patients with type 1 diabetes mellitus in Henan, China

BMC Endocrine Disorders ◽

10.1186/s12902-021-00799-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Liguo Yang ◽

Guangxing Yang ◽

Xialian Li

Keyword(s):

Type 1 Diabetes ◽

Diabetic Retinopathy ◽

Blood Glucose Control ◽

Disease Onset ◽

Overweight And Obesity ◽

Adult Onset ◽

C Peptide ◽

Young Onset ◽

Onset Group

Abstract Background The hallmark of type 1 diabetes (T1D) is an absolute lack of insulin. However, many studies showed a tendency to heterogeneity in TID. We aimed to investigate the demographic and clinical characteristics in T1D and the differences in young-onset and adult-onset patients. Methods This retrospective study was conducted among 1943 patients with clinically diagnosed T1D. Medical records on patients’ demographics, anthropometric measurements, and clinical manifestation were collected. According to the age at onset, the newly diagnosed patients were divided into the young-onset group (< 18 years, 234 patients, mean age 11 years) and adult-onset group (≥ 18 years, 219 patients, mean age 27 years). Pancreatic β-cell function was assessed by fasting C-peptide (FCP) and 2-h C-peptide (2-h CP). Results The median age of patients at disease onset was 22 years. The median duration of patients was 3 years. The overall median glycated hemoglobin (HbA1c) value was 10.3 % [89(mmol/mol)]. The prevalence of diabetic retinopathy was 25.1 %. The overall rate of DKA at onset in the new-onset patients was 59.6 %. The frequency of overall dyslipidemia was 37.8 %. The most frequent dyslipidemia was low high-density lipoprotein-cholesterol (HDL) (29 %). The proportion of patients with anti-glutamic acid decarboxylase (GADA), insulin antibody (IAA) and islet cell antibody (ICA) were 28.1 %, 6.4 % and 21.6 %, respectively. The mean HbA1c showed a downward trend with age. Increasing or decreasing trends of overweight and obesity in this population during the period 2012 to 2018 was not found. Compared with young-onset T1D, adult-onset patients comprised better islet function (FCP: 0.4 vs. 0.3 ng/ml, P < 0.001; 2-h CP: 0.9 vs. 0.7 ng/ml P < 0.001, respectively) and glycemic control [12.9 % (117mmol/mol) vs. 11.7 % (104mmol/mol), P < 0.001], higher prevalence of diabetes condition in the male gender (64.4 % vs. 51.3 %, P = 0.006), higher proportion of obesity or overweight (24.6 % vs. 9.5 %, P = 0.002), higher frequency of GADA (33.7 % vs. 23.3 %, P = 0.025), and lower frequency of diabetic ketoacidosis at disease onset (64.5 % vs. 43.5 %, P < 0.001). Conclusions This population was characterized by poor overall blood glucose control, high prevalence of DKA, dyslipidemia and diabetic retinopathy, and low prevalence of islet-related antibodies, and overweight or obesity. Adult-onset patients with T1D were not uncommon and had better clinical manifestations than young-onset patients. Any findings related to body mass index (BMI) and autoantibodies should be considered strictly exploratory due to excessive missing data.

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Continuous subcutaneous insulin infusion alters microRNA expression and glycaemic variability in children with type 1 diabetes

Scientific Reports ◽

10.1038/s41598-021-95824-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Emma S. Scott ◽

Andrzej S. Januszewski ◽

Luke M. Carroll ◽

Gregory R. Fulcher ◽

Mugdha V. Joglekar ◽

...

Keyword(s):

Type 1 Diabetes ◽

Continuous Subcutaneous Insulin Infusion ◽

Insulin Infusion ◽

Diabetes Diagnosis ◽

Subcutaneous Insulin ◽

Glycaemic Variability ◽

Altered Expression ◽

C Peptide

AbstractTo determine whether continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) therapy from near-diagnosis of type 1 diabetes is associated with reduced glycaemic variability (GV) and altered microRNA (miRNAs) expression. Adolescents (74% male) within 3-months of diabetes diagnosis (n = 27) were randomized to CSII (n = 12) or MDI. HbA1c, 1-5-Anhydroglucitol (1,5-AG), high sensitivity C-peptide and a custom TaqMan qPCR panel of 52 miRNAs were measured at baseline and follow-up (median (LQ-UQ); 535 (519–563) days). There were no significant differences between groups in baseline or follow-up HbA1c or C-peptide, nor baseline miRNAs. Mean ± SD 1,5-AG improved with CSII vs. MDI (3.1 ± 4.1 vs. − 2.2 ± − 7.0 mg/ml respectively, P = 0.029). On follow-up 11 miRNAs associated with diabetes vascular complications had altered expression in CSII-users. Early CSII vs. MDI use is associated with lower GV and less adverse vascular-related miRNAs. Relationships with future complications are of interest.

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Insulin micro-secretion in Type 1 diabetes and related microRNA profiles

Scientific Reports ◽

10.1038/s41598-021-90856-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Andrzej S. Januszewski ◽

Yoon Hi Cho ◽

Mugdha V. Joglekar ◽

Ryan J. Farr ◽

Emma S. Scott ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cross Sectional Study ◽

Diabetes Duration ◽

Adult Onset ◽

Sectional Study ◽

Childhood Onset ◽

Cross Sectional ◽

C Peptide ◽

Adult Onset Diabetes

AbstractThe aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood (< 18 y.o.), and diabetes duration was stratified as ≤ 10 years, 10–20 years and > 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p < 0.0001 and in all (n = 253) participants without diabetes (CON). C-peptide levels, when detectable, were lower in the individuals with diabetes than in the CON group [median lower quartile (LQ)–upper quartile (UQ)] 5.0 (2.6–28.7) versus 650.9 (401.2–732.4) pmol/L respectively, p < 0.0001 and lower in childhood versus adult-onset diabetes [median (LQ–UQ) 4.2 (2.6–12.2) pmol/L vs. 8.0 (2.3–80.5) pmol/L, p = 0.02, respectively]. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend < 0.05). Nine miRs significantly correlated with detectable C-peptide levels in people with diabetes and 16 miRs correlated with C-peptide levels in CON. Our cross-sectional study results are supportive of (a) greater beta-cell function loss in younger onset Type 1 diabetes; (b) persistent insulin secretion in adult-onset diabetes and possibly regenerative secretion in childhood-onset long diabetes duration; and (c) relationships of C-peptide levels with circulating miRs. Confirmatory clinical studies and related basic science studies are merited.

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Epigallocatechin gallate delays the onset of type 1 diabetes in spontaneous non-obese diabetic mice

British Journal Of Nutrition ◽

10.1017/s0007114510004824 ◽

2010 ◽

Vol 105 (8) ◽

pp. 1218-1225 ◽

Cited By ~ 63

Author(s):

Zhuo Fu ◽

Wei Zhen ◽

Julia Yuskavage ◽

Dongmin Liu

Keyword(s):

Type 1 Diabetes ◽

Cell Mass ◽

Epigallocatechin Gallate ◽

Nod Mice ◽

Cost Effective ◽

Treated Group ◽

Control Group ◽

Plasma Insulin Levels ◽

Glucose Lowering Effect

Type 1 diabetes (T1D) results from the autoimmune-mediated destruction of pancreatic β-cells, leading to deficiency of insulin production. Successful islet transplantation can normalise hyperglycaemia in T1D patients; however, the limited availability of the islets, loss of islet cell mass through apoptosis after islet isolation and potential autoimmune destruction of the transplanted islets prevent the widespread use of this procedure. Therefore, the search for novel and cost-effective agents that can prevent or treat T1D is extremely important to decrease the burden of morbidity from this disease. In the present study, we discovered that ( − )-epigallocatechin gallate (EGCG, 0·05 % in drinking-water), the primary polyphenolic component in green tea, effectively delayed the onset of T1D in non-obese diabetic (NOD) mice. At 32 weeks of age, eight (66·7 %) out of twelve mice in the control group developed diabetes, whereas only three (25 %) out of twelve mice in the EGCG-treated group became diabetic (P < 0·05). Consistently, mice supplemented with EGCG had significantly higher plasma insulin levels and survival rate but lower glycosylated Hb concentrations compared with the control animals. EGCG had no significant effects on food or water intake and body weight in mice, suggesting that the glucose-lowering effect was not due to an alteration in these parameters. While EGCG did not modulate insulitis, it elevated the circulating anti-inflammatory cytokine IL-10 level in NOD mice. These findings demonstrate that EGCG may be a novel, plant-derived compound capable of reducing the risk of T1D.

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Systemic TNFα correlates with residual β-cell function in children and adolescents newly diagnosed with type 1 diabetes

BMC Pediatrics ◽

10.1186/s12887-020-02339-8 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Anne Julie Overgaard ◽

Jens Otto Broby Madsen ◽

Flemming Pociot ◽

Jesper Johannesen ◽

Joachim Størling

Keyword(s):

Type 1 Diabetes ◽

Cell Function ◽

Disease Onset ◽

Newly Diagnosed ◽

Β Cell ◽

Entire Study ◽

C Peptide ◽

Disease Remission ◽

Β Cell Function

Abstract Background Type 1 diabetes (T1D) is caused by immune-mediated destruction of the β-cells. After initiation of insulin therapy many patients experience a period of improved residual β-cell function leading to partial disease remission. Cytokines are important immune-modulatory molecules and contribute to β-cell damage in T1D. The patterns of systemic circulating cytokines during T1D remission are not clear but may constitute biomarkers of disease status and progression. In this study, we investigated if the plasma levels of various pro- and anti-inflammatory cytokines around time of diagnosis were predictors of remission and residual β-cell function in children with T1D followed for one year after disease onset. Methods In a cohort of 63 newly diagnosed children (33% females) with T1D with a mean age of 11.3 years (3.3–17.7), ten cytokines were measured of which eight were detectable in plasma samples by Mesoscale Discovery multiplex technology at study start and after 6 and 12 months. Linear regression models were used to evaluate association of cytokines with stimulated C-peptide. Results Systemic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2 and IL-6 inversely correlated with stimulated C-peptide levels over the entire study (P < 0.05). The concentrations of TNFα and IL-10 at study start predicted stimulated C-peptide level at 6 months (P = 0.011 and P = 0.043, respectively, adjusted for sex, age, HbA1c and stage of puberty). Conclusions In recent-onset T1D, systemic cytokine levels, and in particular that of TNFα, correlate with residual β-cell function and may serve as prognostic biomarkers of disease remission and progression to optimize treatment strategies. Trial Registration The study was performed according to the criteria of the Helsinki II Declaration and was approved by the Danish Capital Region Ethics Committee on Biomedical Research Ethics (journal number H-3-2014-052). The parents of all participants gave written consent.

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Preserved β-Cell Function in Type 1 Diabetes by Mesenchymal Stromal Cells

Diabetes ◽

10.2337/db14-0656 ◽

2014 ◽

Vol 64 (2) ◽

pp. 587-592 ◽

Cited By ~ 116

Author(s):

Per-Ola Carlsson ◽

Erik Schwarcz ◽

Olle Korsgren ◽

Katarina Le Blanc

Keyword(s):

Type 1 Diabetes ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Cell Function ◽

Β Cell ◽

Β Cell Function

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Evaluation of Children with Type 1 Diabetes Mellitus in terms of Overweight / Obesity in Tertiary Care Hospital

10.22541/au.161536137.71801232/v1 ◽

2021 ◽

Author(s):

Eda Çelebi Bitkin ◽

Cengiz Kara ◽

Gülay Can Yılmaz ◽

Jamala Mammadova ◽

Hasan Murat Aydın

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Tertiary Care ◽

Normal Weight ◽

Obese Group ◽

Care Hospital ◽

C Peptide

Abstract Objective: Obesity was once a rare problem in Type 1 diabetes mellitus, but is a growing problem today. The aim of our study is to determine the frequency of overweight / obesity at the time of diagnosis and during follow-up in children with type 1 diabetes mellitus as well as review the conditions that may accompany. Methods: 315 patients with type 1 diabetes mellitus were retrospectively analyzed. The patients were divided into two groups according to the last examination as normal weight and overweight / obese. The two groups were compared in terms of age at diagnosis, gender, birth weight, family history, anthropometric measurements, insulin dose used and blood pressure measurements, and insulin, c-peptide, hemoglobin A1c, triglyceride, and high-density lipoprotein levels at the time of diagnosis and follow-up. Results: The prevalence of overweight / obese in all patients was 4.8% at the time of diagnosis, while it was 9.8% at the last examination. The height, weight and BMI SD scores and c-peptide levels at the time of diagnosis of the overweight / obese group were higher than those with normal weight (p <0.001 and p = 0.008, respectively). The frequency of dyslipidemia and hypertension was higher in the overweight / obese group than in the normal weight group [18.2% versus 5% (p = 0.015) and 10% versus 1.5% (p = 0.003), respectively]. Conclusion: In our study, the fact that the overweight / obese group had higher BMI and c-peptide and lower HDL values at the time of diagnosis can be evaluated as indicators that insulin resistance syndrome can accompany T1DM from the beginning (double diabetes). When determining the treatment and follow-up strategies of patients with type 1 diabetes mellitus, considering the risk of obesity and taking the necessary precautions is very important in terms of morbidity.

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Children with type 1 diabetes have elevated high sensitivity C-reactive protein compared to a control group

10.21203/rs.3.rs-19068/v1 ◽

2020 ◽

Author(s):

Pilar Pérez-Segura ◽

Olaya de Dios ◽

Leticia Herrero ◽

Claudia Vales-Villamarín ◽

Isabel González-Aragón ◽

...

Keyword(s):

Type 1 Diabetes ◽

Waist Circumference ◽

High Sensitivity ◽

Control Group ◽

Z Score ◽

C Reactive Protein ◽

Anthropometric Parameters ◽

Reactive Protein

Abstract Objectives To compare high sensitivity C-reactive protein (hsCRP) levels in children with type 1 diabetes, healthy controls, and children with obesity. Additionally, we aimed to analyze the association between hsCRP levels and glycemic control measured by glycohemoglobin A (HbA1c) and anthropometric and biochemical variables. Methods We conducted a non-randomized descriptive study of children with type 1 diabetes matched for sex and age with a control group and group with obesity. We recorded anthropometric parameters and studied variables related to diabetes, blood pressure, lipid profile, and HbA1c. HsCRP was measured by ELISA.Results We included 49 children with type 1 diabetes, 46 controls, and 40 children with obesity. hsCRP levels were significantly higher in the group with type 1 diabetes compared to controls and nearly significantly lower than in the group comprising children with obesity. We found no correlation between hsCRP and HbA1C and characteristics of type 1 diabetes with the exception of albuminin creatinine ratio (ACR). Statistically significant association was found between hsCRP and BMI and waist circumference Z-score. Conclusions Children with type 1 diabetes have a higher hsCRP than healthy subjects; this difference is not associated with HbA1c, but is related to waist circumference, BMI, and ACR. Obesity prevention should be a priority when performing follow-up in children with type 1 diabetes.

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