A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility
Open accessAbstract
Insulin resistance is necessary but not sufficient for the development of type 2 diabetes. Diabetes results when pancreatic beta-cells fail to compensate for insulin resistance by increasing insulin production through an expansion of beta-cell mass or increased insulin secretion. Communication between insulin target tissues and beta-cells may initiate this compensatory response. Correlated changes in gene expression between tissues can provide evidence for such intercellular communication. We profiled gene expression in six tissues of mice from an obesity-induced diabetes-resistant and a diabetes-susceptible strain before and after the onset of diabetes. We studied the correlation structure of mRNA abundance and identified 105 co-expression gene modules. We provide an interactive gene network model showing the correlation structure between the expression modules within and among the six tissues. This resource also provides a searchable database of gene expression profiles for all genes in six tissues in lean and obese diabetes-resistant and diabetes-susceptible mice, at 4 and 10 wk of age. A cell cycle regulatory module in islets predicts diabetes susceptibility. The module predicts islet replication; we found a strong correlation between 2 H 2 O incorporation into islet DNA in vivo and the expression pattern of the cell cycle module. This pattern is highly correlated with that of several individual genes in insulin target tissues, including Igf2, which has been shown to promote beta-cell proliferation, suggesting that these genes may provide a link between insulin resistance and beta-cell proliferation.
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A cell cycle regulatory module in islets distinguishes diabetes-resistant from diabetes-susceptible leptin-deficient Ob/Ob mouse strains and predicts their predisposition to diabetes.
“Furthermore, gene expression studies uncovered a cell cycle regulatory module in islets that distinguishes between diabetes-resistant and diabetes-susceptible strains of leptin-deficient Ob/Ob mice, and successfully predicts their predisposition to diabetes [33].”
From Expansion of β-cell mass in response to pregnancy (2010) · cites this paper as [33]
In skeletal muscle, Ngf expression correlates strongly with the islet cell cycle regulatory module that is activated during obesity.
“Ngf expression in skeletal muscle is strongly correlated with the islet cell cycle regulatory module activated during obesity, again suggesting a link to β-cell proliferation [33].”
From Expansion of β-cell mass in response to pregnancy (2010) · cites this paper as [33]
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- Authors
- Keller, M. P., Choi, Y., Wang, P., Belt Davis, D., Rabaglia, M. E., Oler, A. T., Stapleton, D. S., Argmann, C., Schueler, K. L., Edwards, S., Steinberg, H. A., Chaibub Neto, E., Kleinhanz, R., Turner, S., Hellerstein, M. K., Schadt, E. E., Yandell, B. S., Kendziorski, C., & Attie, A. D.
- Affiliations
- University of Wisconsin–Madison (US)
- KineMed (United States) (US)
- University of California, San Francisco (US)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-03-17
- Volume
- 18
- Issue
- 5
- Pages
- 706-716
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC2336811
- OpenAlex
- W1968055555
- Cited by
- 377
- References
- 48
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 11 · 2023: 29 · 2022: 11 · 2021: 32 · 2020: 10 · 2019: 25 · 2018: 17 · 2017: 16 · 2016: 28 · 2015: 31 · 2014: 23 · 2013: 32 · 2012: 22
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- KineMed
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- U.S. Public Health Service (69430, 58037, 76274, 66369)
- National Institute of General Medical Sciences
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- type 2 diabetes, gene co-expression network, cell cycle regulation, pancreatic islets, beta-cell proliferation, insulin resistance, diabetes susceptibility, obesity, insulin-like growth factor II, gene modules, tissue-specific gene expression
- MeSH terms
- Adipose Tissue, Aging, Animals, Cell Cycle, Diabetes Mellitus, Type 2, Gene Expression Regulation, Glucose, Insulin, Islets of Langerhans, Male, Models, Genetic, Obesity, RNA, Messenger, Transcription, Genetic, Genetic Predisposition to Disease, Cell Proliferation, Insulin-Secreting Cells, Mice
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