Low effectiveness of inducing beta cell mass destruction as a model of type 1 diabetes on murine model by Streptozotocin infusion

Background.The use of miRNAs as biomarkers for Type 1 Diabetes (T1D) risk is attractive as T1D is usually diagnosed in front of acute symptoms. As miR-375 is highly expressed in the endocrine pancreas, we postulated that its circulating level might reflect beta cell alterations and might be altered in the blood of T1D patients recently diagnosed.Methods.Sera were obtained from 22 T1D children at onset of the disease, before subcutaneous insulin treatment, and from 10 nondiabetic pediatric controls. MiR-375 seric level was quantified by stem-loop RT-PCR-based assay. MiRNAs regulations in isolated human islets in response to high glucose concentrations were determined by TaqMan Low-Density Array.Results.The abundance of miR-375, among the 410 miRNAs detected in human islets, mirrored its well-established role in rodent islet biology. Upregulated miRNAs targeted genes involved in islet homeostasis and regulation of beta cell mass. Downregulated miRNAs, including miR-375, were involved in pancreas secretion and protein turnover. Seric level of miR-375 was lower in T1D children versus age-matched controls, without any correlations with HbA1c, glycaemia, and number of autoantibodies.Conclusion.Altered circulating level of miR-375 at onset of T1D might be a general biomarker of metabolic alterations and inflammation associated with the disease.

Download Full-text

Age-Corrected Beta Cell Mass Following Onset of Type 1 Diabetes Mellitus Correlates with Plasma C-Peptide in Humans

PLoS ONE ◽

10.1371/journal.pone.0026873 ◽

2011 ◽

Vol 6 (11) ◽

pp. e26873 ◽

Cited By ~ 12

Author(s):

David J. Klinke

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Beta Cell ◽

Type 1 Diabetes Mellitus ◽

Cell Mass ◽

Beta Cell Mass ◽

C Peptide

Download Full-text

Characterization of the endocrine pancreas in Type 1 Diabetes: islet size is maintained but islet number is markedly reduced

10.1101/480509 ◽

2018 ◽

Cited By ~ 2

Author(s):

Peter Seiron ◽

Anna Wiberg ◽

Lars Krogvold ◽

Frode Lars Jahnsen ◽

Knut Dahl-Jørgensen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Beta Cells ◽

Cell Mass ◽

Beta Cell Mass ◽

Cell Loss ◽

Recent Onset ◽

Islet Size ◽

Pancreas Volume

AbstractInsulin deficiency in type 1 diabetes (T1D) is generally considered a consequence of specific beta-cell loss. Since healthy pancreatic islets consist of ~65% beta cells, this would lead to reduced islet size if the beta cells are not replaced by other cells or tissue. The number of islets per pancreas volume (islet density) would not be affected.In this study, we compared the islet density, size, and size distribution in subjects with recent-onset or long-standing T1D, with that in matched non-diabetic subjects. Results show that subjects with T1D, regardless of disease duration, had a dramatically reduced islet number per mm2, while the islet size was similar in all groups. Insulin-negative islets in T1D subjects were dominated by glucagon-positive cells that frequently had lost the alpha-cell transcription factor ARX while instead expressing PDX1, normally expressed in beta cells.Based on our findings, we propose that failure during childhood to establish a sufficient islet number to reach the beta-cell mass needed to cope with episodes of increased insulin demand contributes to T1D susceptibility. Exhaustion induced by relative lack of beta cells could then potentially drive beta-cell dedifferentiation to alpha-cells, explaining the preserved islet size observed in T1D compared to controls.

Download Full-text

100 YEARS OF INSULIN: Arresting or curing type 1 diabetes: an elusive goal, but closing the gap

Journal of Endocrinology ◽

10.1530/joe-20-0552 ◽

2021 ◽

Vol 249 (2) ◽

pp. T1-T11

Author(s):

Pieter-Jan Martens ◽

Conny Gysemans ◽

Chantal Mathieu

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Adaptive Immune System ◽

Future Research ◽

Diabetic Patients ◽

Technological Advances ◽

Current Therapies

Type 1 diabetes is one of the most common chronic diseases in children and adolescents, but remains unpreventable and incurable. The discovery of insulin, already 100 years ago, embodied a lifesaver for people with type 1 diabetes as it allowed the replacement of all functions of the beta cell. Nevertheless, despite all technological advances, the majority of type 1 diabetic patients fail to reach the recommended target HbA1c levels. The disease-associated complications remain the true burden of affected individuals and necessitate the search for disease prevention and reversal. The recognition that type 1 diabetes is a heterogeneous disease with an etiology in which both the innate and adaptive immune system as well as the insulin-producing beta cells intimately interact, has fostered the idea that treatment to specific molecular or cellular characteristics of the patient groups will be needed. Moreover, robust and reliable biomarkers to detect type 1 diabetes in the early (pre-symptomatic) phases are wanted to preserve functional beta cell mass. The pitfalls of past therapeutics along with the perspectives of current therapies can open up the path for future research.

Download Full-text

Potencial role of stem cell therapy in type 1 diabetes mellitus

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302008000200029 ◽

2008 ◽

Vol 52 (2) ◽

pp. 407-415 ◽

Cited By ~ 11

Author(s):

Carlos Eduardo Barra Couri ◽

Júlio César Voltarelli

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Stem Cell ◽

Beta Cell ◽

Type 1 Diabetes Mellitus ◽

Clinical Diagnosis ◽

Cell Mass ◽

Beta Cell Mass ◽

Autoimmune Response

Type 1 diabetes mellitus is the result of the autoimmune response against pancreatic beta-cell(s). At the time of clinical diagnosis near 70% of beta-cell mass is been destroyed as a consequence of the auto-destruction that begins months or even years before the clinical diagnosis. Although marked reduction of chronic complications was seen after development and progression of insulin therapy over the years for type 1 diabetic population, associated risks of chronic end-organ damage and hypoglycemia still remain. Besides tight glucose control, beta-cell mass preservation and/or increase are known to be other important targets in management of type 1 diabetes as long as it reduces chronic microvascular complications in the eyes, kidneys and nerves. Moreover, the larger the beta-cell mass, the lower the incidence of hypoglycemic events. In this article, we discuss some insights about beta-cell regeneration, the importance of regulation of the autoimmune process and what is being employed in human type 1 diabetes in regard to stem cell repertoire to promote regeneration and/or preservation of beta-cell mass.

Download Full-text

PS18 - 2. Quantification of the beta cell mass based on 111In-Exendin imaging in patients with type 1 diabetes and healthy controls

Nederlands Tijdschrift voor Diabetologie ◽

10.1007/s12467-013-0161-0 ◽

2013 ◽

Vol 11 (4) ◽

pp. 200-201

Author(s):

Wietske Woliner-van der Weg ◽

Maarten Brom ◽

Marcel J.R. Janssen ◽

Martin Béhe ◽

Wim J.G. Oyen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Healthy Controls

Download Full-text

Pancreatic islets from cyclin-dependent kinase 4/R24C (Cdk4) knockin mice have significantly increased beta cell mass and are physiologically functional, indicating that Cdk4 is a potential target for pancreatic beta cell mass regeneration in Type 1 diabetes

Diabetologia ◽

10.1007/s00125-004-1372-0 ◽

2004 ◽

Vol 47 (4) ◽

pp. 686-694 ◽

Cited By ~ 50

Author(s):

J. Mart�n ◽

E. F. Usac ◽

C. Franco ◽

M. Barbacid ◽

R. Gomis ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Pancreatic Islets ◽

Pancreatic Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Cyclin Dependent Kinase ◽

Potential Target ◽

Pancreatic Beta Cell Mass

Download Full-text

Gastrin producing syngeneic mesenchymal stem cells protect non-obese diabetic mice from type 1 diabetes

10.1101/2021.05.13.444059 ◽

2021 ◽

Author(s):

Marie-Claude Gaudreau ◽

Radhika R Gudi ◽

Gongbo Li ◽

BENJAMIN JOHNSON ◽

Chenthamarakshan Vasu

Keyword(s):

Stem Cells ◽

Type 1 Diabetes ◽

Beta Cell ◽

Disease Progression ◽

Beta Cells ◽

Cell Mass ◽

Beta Cell Mass ◽

Cell Phenotype ◽

Therapeutic Effects

Progressive destruction of pancreatic islet beta-cells by immune cells is the primary feature of type 1 diabetes (T1D) and therapies that can restore the functional beta-cell mass are needed to alleviate disease progression. Here, we report the use of mesenchymal stromal/stem cells (MSCs) for the production and delivery of Gastrin, a peptide-hormone which is produced by intestinal cells and fetal islets and can increase beta-Cell mass, to promote protection from T1D. A single injection of syngeneic MSCs that were engineered to express Gastrin (Gastrin-MSCs) caused a profound delay in hyperglycemia in non-obese diabetic (NOD) mice compared to engineered control-MSCs. Similar treatment of early-hyperglycemic mice caused restoration of euglycemia for a significant duration, and these therapeutic effects were associated with protection of, and/or increase in, insulin producing islets and less severe insulitis. While the overall immune cell phenotype was not affected profoundly, pancreatic lymph node cells from Gastrin-MSC treated mice, upon ex vivo challenge with self-antigen, showed a Th2 and Th17 bias, and diminished the diabetogenic property in NOD-Rag1 deficient mice suggesting a disease protective immune modulation upon Gastrin-MSC treatment. Overall, this study shows the potential of production and delivery of Gastrin in vivo, by MSCs, in protecting insulin producing beta-cells and ameliorating the disease progression in T1D.

Download Full-text