TREATMENT WITH EXENATIDE PRESERVES BETA CELL MASS IN HUMAN ISLETS DURING CULTURE: IMPLICATIONS FOR ISLET TRANSPLANTATION

Islet transplantation has great potential as a cure for type 1 diabetes. At present; the lack of a clinically validated non-invasive imaging method to track islet grafts limits the success of this treatment. Some major clinical imaging modalities and various molecular probes, which have been studied for non-invasive monitoring of transplanted islets, could potentially fulfill the goal of understanding pathophysiology of the functional status and viability of the islet grafts. In this current review, we summarize the recent clinical studies of a variety of imaging modalities and molecular probes for non-invasive imaging of transplanted beta cell mass. This review also includes discussions on in vivo detection of endogenous beta cell mass using clinical imaging modalities and various molecular probes, which will be useful for longitudinally detecting the status of islet transplantation in Type 1 diabetic patients. For the conclusion and perspectives, we highlight the applications of multimodality and novel imaging methods in islet transplantation.

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Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation

Diabetologia ◽

10.1007/s00125-007-0889-4 ◽

2007 ◽

Vol 51 (2) ◽

pp. 298-308 ◽

Cited By ~ 61

Author(s):

A. Fornoni ◽

A. Pileggi ◽

R. D. Molano ◽

N. Y. Sanabria ◽

T. Tejada ◽

...

Keyword(s):

Beta Cell ◽

Glycogen Synthase ◽

Cell Mass ◽

Beta Cell Mass ◽

Human Islets ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3

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miRNA-375 a Sensor of Glucotoxicity Is Altered in the Serum of Children with Newly Diagnosed Type 1 Diabetes

Journal of Diabetes Research ◽

10.1155/2016/1869082 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 31

Author(s):

Lucien Marchand ◽

Audrey Jalabert ◽

Emmanuelle Meugnier ◽

Kathleen Van den Hende ◽

Nicole Fabien ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Human Islets ◽

Rt Pcr ◽

Stem Loop ◽

Cell Alterations ◽

Established Role

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.

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Non-invasive monitoring of glycemia-induced regulation of GLP-1R expression in murine and human islets of langerhans

10.2337/figshare.12840770.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Mijke Buitinga ◽

Christian M.Cohrs ◽

Wael A.Eter ◽

Lieke Claessens-Joosten ◽

...

Keyword(s):

Blood Glucose ◽

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Human Islets ◽

Tracer Uptake ◽

Expression Levels ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Islet Volume

GLP-1R imaging with radiolabelled exendin has proven to be a powerful tool to quantify beta-cell mass (BCM) in vivo. As GLP-1R expression is thought to be influenced by glycemic control, we examined the effect of blood glucose levels on GLP-1R-mediated exendin uptake in both murine and human islets and its implications for BCM quantification. Periods of hyperglycemia significantly reduced exendin uptake in murine and human islets, which was paralleled by a reduction in GLP-1R expression. Detailed mapping of the tracer uptake and insulin and GLP-1R expression conclusively demonstrated that the observed reduction in tracer uptake directly correlates to GLP-1R expression levels. Importantly, the linear correlation between tracer uptake and beta-cell area was maintained in spite of the reduced GLP-1R expression levels. Subsequent normalization of blood glucose levels restored absolute tracer uptake and GLP-1R expression in beta-cells and the observed loss in islet volume was halted. This manuscript emphasizes the potency of nuclear imaging techniques to monitor receptor regulation non-invasively. Our findings have significant implications for clinical practice, indicating that blood glucose levels should be near-normalized for at least three weeks prior to GLP-1R agonist treatment or quantitative radiolabeled exendin imaging for BCM analysis.

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A SELECTIVE DECREASE IN THE BETA CELL MASS OF HUMAN ISLETS TRANSPLANTED INTO DIABETIC NUDE MICE

Transplantation Journal ◽

10.1097/00007890-199503270-00003 ◽

1995 ◽

Vol 59 (6) ◽

pp. 817-820 ◽

Cited By ~ 2

Author(s):

A. M. DAVALLI ◽

Y. OGAWA ◽

C. RICORDI ◽

D. W. SCHARP ◽

S. BONNER-WEIR ◽

...

Keyword(s):

Beta Cell ◽

Nude Mice ◽

Cell Mass ◽

Beta Cell Mass ◽

Human Islets

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JNK3 Is Required for the Cytoprotective Effect of Exendin 4

Journal of Diabetes Research ◽

10.1155/2014/814854 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 9

Author(s):

Hélène Ezanno ◽

Valérie Pawlowski ◽

Saida Abdelli ◽

Raphael Boutry ◽

Valery Gmyr ◽

...

Keyword(s):

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Human Islets ◽

Protective Role ◽

Mitogen Activated Protein Kinase ◽

Cytoprotective Effect ◽

Amino Terminal ◽

Therapeutic Benefits ◽

Glucagon Like Peptide 1

Preservation of beta cell against apoptosis is one of the therapeutic benefits of the glucagon-like peptide-1 (GLP1) antidiabetic mimetics for preserving the functional beta cell mass exposed to diabetogenic condition including proinflammatory cytokines. The mitogen activated protein kinase 10 also called c-jun amino-terminal kinase 3 (JNK3) plays a protective role in insulin-secreting cells against death caused by cytokines. In this study, we investigated whether the JNK3 expression is associated with the protective effect elicited by the GLP1 mimetic exendin 4. We found an increase in the abundance of JNK3 in isolated human islets and INS-1E cells cultured with exendin 4. Induction of JNK3 by exendin 4 was associated with an increased survival of INS-1E cells. Silencing of JNK3 prevented the cytoprotective effect of exendin 4 against apoptosis elicited by culture condition and cytokines. These results emphasize the requirement of JNK3 in the antiapoptotic effects of exendin 4.

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Improved outcome of islet transplantation in insulin-treated diabetic mice: effects on beta-cell mass and function

Diabetologia ◽

10.1007/s001250050781 ◽

1997 ◽

Vol 40 (9) ◽

pp. 1004-1010 ◽

Cited By ~ 31

Author(s):

J. F. Merino ◽

V. Nacher ◽

M. Raurell ◽

O. Aranda ◽

J. Soler ◽

...

Keyword(s):

Beta Cell ◽

Islet Transplantation ◽

Cell Mass ◽

Beta Cell Mass ◽

Diabetic Mice ◽

And Function ◽

Improved Outcome

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Non-invasive monitoring of glycemia-induced regulation of GLP-1R expression in murine and human islets of langerhans

10.2337/figshare.12840770 ◽

2020 ◽

Author(s):

Ada Admin ◽

Mijke Buitinga ◽

Christian M.Cohrs ◽

Wael A.Eter ◽

Lieke Claessens-Joosten ◽

...

Keyword(s):

Blood Glucose ◽

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Human Islets ◽

Tracer Uptake ◽

Expression Levels ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Islet Volume

GLP-1R imaging with radiolabelled exendin has proven to be a powerful tool to quantify beta-cell mass (BCM) in vivo. As GLP-1R expression is thought to be influenced by glycemic control, we examined the effect of blood glucose levels on GLP-1R-mediated exendin uptake in both murine and human islets and its implications for BCM quantification. Periods of hyperglycemia significantly reduced exendin uptake in murine and human islets, which was paralleled by a reduction in GLP-1R expression. Detailed mapping of the tracer uptake and insulin and GLP-1R expression conclusively demonstrated that the observed reduction in tracer uptake directly correlates to GLP-1R expression levels. Importantly, the linear correlation between tracer uptake and beta-cell area was maintained in spite of the reduced GLP-1R expression levels. Subsequent normalization of blood glucose levels restored absolute tracer uptake and GLP-1R expression in beta-cells and the observed loss in islet volume was halted. This manuscript emphasizes the potency of nuclear imaging techniques to monitor receptor regulation non-invasively. Our findings have significant implications for clinical practice, indicating that blood glucose levels should be near-normalized for at least three weeks prior to GLP-1R agonist treatment or quantitative radiolabeled exendin imaging for BCM analysis.

Download Full-text