Case Report: Off-Label Liraglutide Use in Children With Wolfram Syndrome Type 1: Extensive Characterization of Four Patients

Aims: Wolfram syndrome type 1 is a rare recessive monogenic form of insulin-dependent diabetes mellitus with progressive neurodegeneration, poor prognosis, and no cure. Based on preclinical evidence we hypothesized that liraglutide, a glucagon-like peptide-1 receptor agonist, may be repurposed for the off-label treatment of Wolfram Syndrome type 1. We initiated an off-label treatment to investigate the safety, tolerability, and efficacy of liraglutide in pediatric patients with Wolfram Syndrome type 1.Methods: Pediatric patients with genetically confirmed Wolfram Syndrome type 1 were offered off-label treatment approved by The Regional Network Coordination Center for Rare Diseases, Pharmacological Research IRCCS Mario Negri, and the internal ethics committee. Four patients were enrolled; none refused nor were excluded or lost during follow-up. Liraglutide was administered as a daily subcutaneous injection. Starting dose was 0.3 mg/day. The dose was progressively increased as tolerated, up to the maximum dose of 1.8 mg/day. The primary outcome was evaluating the safety, tolerability, and efficacy of liraglutide in Wolfram Syndrome type 1 patients. Secondary endpoints were stabilization or improvement of C-peptide secretion as assessed by the mixed meal tolerance test. Exploratory endpoints were stabilization of neurological and neuro-ophthalmological degeneration, assessed by optical coherence tomography, electroretinogram, visual evoked potentials, and magnetic resonance imaging.Results: Four patients aged between 10 and 14 years at baseline were treated with liraglutide for 8–27 months. Liraglutide was well-tolerated: all patients reached and maintained the maximum dose, and none withdrew from the study. Only minor transient gastrointestinal symptoms were reported. No alterations in pancreatic enzymes, calcitonin, or thyroid hormones were observed. At the latest follow-up, the C-peptide area under the curve ranged from 81 to 171% of baseline. Time in range improved in two patients. Neuro-ophthalmological and neurophysiological disease parameters remained stable at the latest follow-up.Conclusions: We report preliminary data on the safety, tolerability, and efficacy of liraglutide in four pediatric patients with Wolfram Syndrome type 1. The apparent benefits both in terms of residual C-peptide secretion and neuro-ophthalmological disease progression warrant further studies on the repurposing of glucagon-like peptide-1 receptor agonists as disease-modifying agents for Wolfram Syndrome type 1.

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Difference in glucagon-like peptide-1 concentrations between C-peptide negative type 1 diabetes mellitus patients and healthy controls

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563214544709 ◽

2015 ◽

Vol 52 (2) ◽

pp. 220-225 ◽

Cited By ~ 3

Author(s):

Karin Zibar ◽

Jadranka Knežević Ćuća ◽

Kristina Blaslov ◽

Tomislav Bulum ◽

Lea Smirčić-Duvnjak

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Healthy Controls ◽

C Peptide ◽

Negative Type ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Clinical Impact of Residual C-Peptide Secretion in Type 1 Diabetes on Glycemia and Microvascular Complications

10.2337/figshare.13225043 ◽

2020 ◽

Author(s):

Anita Jeyam ◽

Helen Colhoun ◽

Stuart McGurnaghan ◽

Luke Blackbourn ◽

Timothy J McDonald ◽

...

Keyword(s):

Type 1 Diabetes ◽

Hospital Admission ◽

Odds Ratio ◽

Regression Models ◽

Microvascular Complications ◽

C Peptide ◽

Peptide Secretion ◽

The Relationship

Objective: To quantify the relationship of residual C-peptide secretion to glycemic outcomes and microvascular complications in type 1 diabetes. Design and Methods: C-peptide was measured in an untimed blood sample in the SDRNT1BIO cohort of 6076 people with type 1 diabetes followed for an average of 5.2 years. Results: In regression models adjusted for age at onset and duration, effect sizes for C-peptide ≥200 versus <5 pmol/l were as follows: insulin dose at baseline 27% lower (p=2×10−39), HbA1c during follow-up 4.9 mmol/mol lower (p=3×10−13), hazard ratio for hospital admission for diabetic ketoacidosis during follow-up 0.44 (p=0.0001), odds ratio for incident retinopathy 0.51 (p=0.0003). Effects on risk of serious hypoglycemic episodes were detectable at lower levels of C-peptide, and the form of the relationship was continuous down to the limit of detection (3 pmol/l). In regression models contrasting C-peptide 30 to <200 with <5 pmol/l, the odds ratio for self-report of at least one serious hypoglycemic episode in the last year was 0.56 (p=6×10−8), and the hazard ratio for hospital admission for hypoglycemia during follow-up was 0.52 (p=0.03). Conclusion: These results in a large representative cohort suggest that even minimal residual C-peptide secretion could have clinical benefit in type 1 diabetes, in contrast to a follow-up study of the DCCT intensively-treated cohort where an effect on hypoglycemia was seen only at C-peptide levels ≥130 pmol/l. This has obvious implications for design and evaluation of trials of interventions to preserve or restore pancreatic islet function in type 1 diabetes.

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Addition of glucagon‐like peptide‐1 receptor agonist therapy to insulin in C‐peptide‐positive patients with type 1 diabetes

Diabetes Obesity and Metabolism ◽

10.1111/dom.13609 ◽

2019 ◽

Vol 21 (4) ◽

pp. 1054-1057

Author(s):

Nitesh D. Kuhadiya ◽

Ben Prohaska ◽

Husam Ghanim ◽

Paresh Dandona

Keyword(s):

Type 1 Diabetes ◽

Receptor Agonist ◽

Agonist Therapy ◽

C Peptide ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Effect of Glucagon-Like Peptide-1 on α- and β-Cell Function in C-Peptide-Negative Type 1 Diabetic Patients

Endocrine Reviews ◽

10.1210/edrv.31.2.9986 ◽

2010 ◽

Vol 31 (2) ◽

pp. 258-258

Author(s):

Urd Kielgast ◽

Meena Asmar ◽

Sten Madsbad ◽

Jens J. Holst

Keyword(s):

Cell Function ◽

Diabetic Patients ◽

Β Cell ◽

C Peptide ◽

Negative Type ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Type 1 Diabetic Patients

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Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype–Phenotype Correlations

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18094796 ◽

2021 ◽

Vol 18 (9) ◽

pp. 4796

Author(s):

Maurizio Delvecchio ◽

Matteo Iacoviello ◽

Antonino Pantaleo ◽

Nicoletta Resta

Keyword(s):

Clinical Presentation ◽

Neurodegenerative Disorder ◽

Transmembrane Protein ◽

Wolfram Syndrome ◽

Disease Genes ◽

Syndrome Type ◽

Phenotype Correlation

Wolfram syndrome is a rare neurodegenerative disorder that is typically characterized by diabetes mellitus and optic atrophy. Other common features are diabetes insipidus and hearing loss, but additional less-frequent findings may also be present. The phenotype spectrum is quite wide, and penetrance may be incomplete. The syndrome is progressive, and thus, the clinical picture may change during follow-up. Currently, two different subtypes of this syndrome have been described, and they are associated with two different disease-genes, wolframin (WFS1) and CISD2. These genes encode a transmembrane protein and an endoplasmic reticulum intermembrane protein, respectively. These genes are detected in different organs and account for the pleiotropic features of this syndrome. In this review, we describe the phenotypes of both syndromes and discuss the most pertinent literature about the genotype–phenotype correlation. The clinical presentation of Wolfram syndrome type 1 suggests that the pathogenic variant does not predict the phenotype. There are few papers on Wolfram syndrome type 2 and, thus, predicting the phenotype on the basis of genotype is not yet supported. We also discuss the most pertinent approach to gene analysis.

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Clinical Impact of Residual C-Peptide Secretion in Type 1 Diabetes on Glycemia and Microvascular Complications

10.2337/figshare.13225043.v1 ◽

2020 ◽

Author(s):

Anita Jeyam ◽

Helen Colhoun ◽

Stuart McGurnaghan ◽

Luke Blackbourn ◽

Timothy J McDonald ◽

...

Keyword(s):

Type 1 Diabetes ◽

Hospital Admission ◽

Odds Ratio ◽

Regression Models ◽

Microvascular Complications ◽

C Peptide ◽

Peptide Secretion ◽

The Relationship

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Faculty Opinions recommendation of Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8727957.11798054 ◽

2011 ◽

Author(s):

Kyong Soo Park ◽

Soo Heon Kwak

Keyword(s):

Type 1 Diabetes ◽

Blood Glucose ◽

Blood Glucose Level ◽

Rat Model ◽

Renal Injury ◽

Receptor Agonist ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Inflammatory Action

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

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02417-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jing Lu ◽

Shan-mei Shen ◽

Qing Ling ◽

Bin Wang ◽

Li-rong Li ◽

...

Keyword(s):

Type 1 Diabetes ◽

Stromal Cells ◽

Treated Group ◽

Control Group ◽

Adult Onset ◽

Β Cell ◽

Juvenile Onset ◽

C Peptide

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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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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