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A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
Identification of Four Mouse Diabetes Candidate Genes Altering β-Cell Proliferation
Oliver Kluth1, Daniela Matzke1, Anne Kamitz1
1Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
Abstract:
Beta-cell apoptosis and failure to induce beta-cell regeneration are hallmarks of type 2-like diabetes in mouse models. Here we show that islets from obese, diabetes-susceptible New Zealand Obese (NZO) mice, in contrast to diabetes-resistant C57BL/6J (B6)-ob/ob mice, do not proliferate in response to an in-vivo glucose challenge but lose their beta-cells. Genome-wide RNAseq based transcriptomics indicated an induction of 22 cell cycle-associated genes in B6-ob/ob islets that did not respond in NZO islets. Of all genes differentially expressed in islets of the two strains, seven mapped to the diabesity QTL Nob3, and were hypomorphic in either NZO (Lefty1, Apoa2, Pcp4l1, Mndal, Slamf7, Pydc3) or B6 (Ifi202b). Adenoviral overexpression of Lefty1, Apoa2, and Pcp4l1 in primary islet cells increased proliferation, whereas overexpression of Ifi202b suppressed it. We conclude that the identified genes in synergy with obesity and insulin resistance participate in adaptive islet hyperplasia and prevention from severe diabetes in B6-ob/ob mice.
Insights
New Zealand Obese mice exhibit beta-cell loss in diabetes, unlike resistant mice that show beta-cell regeneration. Specific genes identified in resistant mice promote islet cell proliferation, preventing severe diabetes.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- Type 2 diabetes is characterized by beta-cell apoptosis and impaired regeneration.
- Mouse models display distinct responses to diabetes, with some strains resisting disease progression.
Purpose of the Study:
- To investigate the genetic mechanisms underlying differential beta-cell responses to diabetes in obese mouse models.
- To identify genes involved in beta-cell proliferation and survival in diabetes-resistant strains.
Main Methods:
- Comparative genome-wide RNA sequencing (RNAseq) of islets from obese, diabetes-susceptible (NZO) and diabetes-resistant (C57BL/6J-ob/ob) mice.
- Analysis of differentially expressed genes, focusing on those within the diabesity QTL Nob3.
- Adenoviral overexpression of candidate genes in primary islet cells to assess their impact on proliferation.
Main Results:
- NZO mouse islets failed to proliferate and underwent beta-cell loss upon glucose challenge, unlike B6-ob/ob islets.
- RNAseq revealed 22 cell cycle-associated genes upregulated in B6-ob/ob islets but not in NZO islets.
- Seven differentially expressed genes mapped to the Nob3 QTL; Lefty1, Apoa2, and Pcp4l1 promoted proliferation, while Ifi202b suppressed it.
Conclusions:
- Adaptive islet hyperplasia, driven by specific genes like Lefty1, Apoa2, and Pcp4l1, prevents severe diabetes in B6-ob/ob mice.
- These genes, in conjunction with obesity and insulin resistance, play a crucial role in maintaining beta-cell function.
- Understanding these genetic factors offers potential therapeutic targets for type 2 diabetes.
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