Distinct gene expression pathways in islets from individuals with short- and long-duration type 1 diabetes

Teresa L. Mastracci, Jean Valery Turatsinze, Benita K. Book, Ivan A. Restrepo, Michael J. Pugia, Eric A. Wiebke, Mark D. Pescovitz, Decio L. Eizirik, Raghu Mirmira

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Aims: Our current understanding of the pathogenesis of type 1 diabetes (T1D) arose, in large part, from studies using the non-obese diabetic (NOD) mouse model. In the present study, we chose a human-focused method to investigate T1D disease mechanisms and potential targets for therapeutic intervention by directly analysing human donor pancreatic islets from individuals with T1D. Materials and Methods: We obtained islets from a young individual with T1D for 3years and from an older individual with T1D for 27years and performed unbiased functional genomic analysis by high-depth RNA sequencing; the T1D islets were compared with islets isolated from 3 non-diabetic donors. Results: The islets procured from these T1D donors represent a unique opportunity to identify gene expression changes in islets after significantly different disease duration. Data analysis identified several inflammatory pathways up-regulated in short-duration disease, which notably included many components of innate immunity. As proof of concept for translation, one of the pathways, governed by IL-23(p19), was selected for further study in NOD mice because of ongoing human trials of biologics against this target for different indications. A mouse monoclonal antibody directed against IL-23(p19) when administered to NOD mice resulted in a significant reduction in incidence of diabetes. Conclusion: While the sample size for this study is small, our data demonstrate that the direct analysis of human islets provides a greater understanding of human disease. These data, together with the analysis of an expanded cohort to be obtained by future collaborative efforts, might result in the identification of promising novel targets for translation into effective therapeutic interventions for human T1D, with the added benefit of repurposing known biologicals for use in different indications.

Original languageEnglish (US)
JournalDiabetes, Obesity and Metabolism
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Type 1 Diabetes Mellitus
Gene Expression
Inbred NOD Mouse
Interleukin-23 Subunit p19
RNA Sequence Analysis
Biological Products
Islets of Langerhans
Innate Immunity
Sample Size
Cohort Studies
Monoclonal Antibodies
Incidence
Therapeutics

Keywords

  • Functional genomics
  • Human islets
  • IL23
  • IL23/p19
  • Inflammatory pathways
  • RNA-sequencing
  • Short-duration T1D
  • T1D
  • Type 1 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Distinct gene expression pathways in islets from individuals with short- and long-duration type 1 diabetes. / Mastracci, Teresa L.; Turatsinze, Jean Valery; Book, Benita K.; Restrepo, Ivan A.; Pugia, Michael J.; Wiebke, Eric A.; Pescovitz, Mark D.; Eizirik, Decio L.; Mirmira, Raghu.

In: Diabetes, Obesity and Metabolism, 01.01.2018.

Research output: Contribution to journalArticle

Mastracci, Teresa L. ; Turatsinze, Jean Valery ; Book, Benita K. ; Restrepo, Ivan A. ; Pugia, Michael J. ; Wiebke, Eric A. ; Pescovitz, Mark D. ; Eizirik, Decio L. ; Mirmira, Raghu. / Distinct gene expression pathways in islets from individuals with short- and long-duration type 1 diabetes. In: Diabetes, Obesity and Metabolism. 2018.
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abstract = "Aims: Our current understanding of the pathogenesis of type 1 diabetes (T1D) arose, in large part, from studies using the non-obese diabetic (NOD) mouse model. In the present study, we chose a human-focused method to investigate T1D disease mechanisms and potential targets for therapeutic intervention by directly analysing human donor pancreatic islets from individuals with T1D. Materials and Methods: We obtained islets from a young individual with T1D for 3years and from an older individual with T1D for 27years and performed unbiased functional genomic analysis by high-depth RNA sequencing; the T1D islets were compared with islets isolated from 3 non-diabetic donors. Results: The islets procured from these T1D donors represent a unique opportunity to identify gene expression changes in islets after significantly different disease duration. Data analysis identified several inflammatory pathways up-regulated in short-duration disease, which notably included many components of innate immunity. As proof of concept for translation, one of the pathways, governed by IL-23(p19), was selected for further study in NOD mice because of ongoing human trials of biologics against this target for different indications. A mouse monoclonal antibody directed against IL-23(p19) when administered to NOD mice resulted in a significant reduction in incidence of diabetes. Conclusion: While the sample size for this study is small, our data demonstrate that the direct analysis of human islets provides a greater understanding of human disease. These data, together with the analysis of an expanded cohort to be obtained by future collaborative efforts, might result in the identification of promising novel targets for translation into effective therapeutic interventions for human T1D, with the added benefit of repurposing known biologicals for use in different indications.",
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T1 - Distinct gene expression pathways in islets from individuals with short- and long-duration type 1 diabetes

AU - Mastracci, Teresa L.

AU - Turatsinze, Jean Valery

AU - Book, Benita K.

AU - Restrepo, Ivan A.

AU - Pugia, Michael J.

AU - Wiebke, Eric A.

AU - Pescovitz, Mark D.

AU - Eizirik, Decio L.

AU - Mirmira, Raghu

PY - 2018/1/1

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N2 - Aims: Our current understanding of the pathogenesis of type 1 diabetes (T1D) arose, in large part, from studies using the non-obese diabetic (NOD) mouse model. In the present study, we chose a human-focused method to investigate T1D disease mechanisms and potential targets for therapeutic intervention by directly analysing human donor pancreatic islets from individuals with T1D. Materials and Methods: We obtained islets from a young individual with T1D for 3years and from an older individual with T1D for 27years and performed unbiased functional genomic analysis by high-depth RNA sequencing; the T1D islets were compared with islets isolated from 3 non-diabetic donors. Results: The islets procured from these T1D donors represent a unique opportunity to identify gene expression changes in islets after significantly different disease duration. Data analysis identified several inflammatory pathways up-regulated in short-duration disease, which notably included many components of innate immunity. As proof of concept for translation, one of the pathways, governed by IL-23(p19), was selected for further study in NOD mice because of ongoing human trials of biologics against this target for different indications. A mouse monoclonal antibody directed against IL-23(p19) when administered to NOD mice resulted in a significant reduction in incidence of diabetes. Conclusion: While the sample size for this study is small, our data demonstrate that the direct analysis of human islets provides a greater understanding of human disease. These data, together with the analysis of an expanded cohort to be obtained by future collaborative efforts, might result in the identification of promising novel targets for translation into effective therapeutic interventions for human T1D, with the added benefit of repurposing known biologicals for use in different indications.

AB - Aims: Our current understanding of the pathogenesis of type 1 diabetes (T1D) arose, in large part, from studies using the non-obese diabetic (NOD) mouse model. In the present study, we chose a human-focused method to investigate T1D disease mechanisms and potential targets for therapeutic intervention by directly analysing human donor pancreatic islets from individuals with T1D. Materials and Methods: We obtained islets from a young individual with T1D for 3years and from an older individual with T1D for 27years and performed unbiased functional genomic analysis by high-depth RNA sequencing; the T1D islets were compared with islets isolated from 3 non-diabetic donors. Results: The islets procured from these T1D donors represent a unique opportunity to identify gene expression changes in islets after significantly different disease duration. Data analysis identified several inflammatory pathways up-regulated in short-duration disease, which notably included many components of innate immunity. As proof of concept for translation, one of the pathways, governed by IL-23(p19), was selected for further study in NOD mice because of ongoing human trials of biologics against this target for different indications. A mouse monoclonal antibody directed against IL-23(p19) when administered to NOD mice resulted in a significant reduction in incidence of diabetes. Conclusion: While the sample size for this study is small, our data demonstrate that the direct analysis of human islets provides a greater understanding of human disease. These data, together with the analysis of an expanded cohort to be obtained by future collaborative efforts, might result in the identification of promising novel targets for translation into effective therapeutic interventions for human T1D, with the added benefit of repurposing known biologicals for use in different indications.

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KW - Type 1 diabetes

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