title: A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53076, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.forename: YounJeong
authors.initials: Y
authors.lastname: Choi
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Dawn Belt
authors.initials: DB
authors.lastname: Davis
authors.forename: Mary E
authors.initials: ME
authors.lastname: Rabaglia
authors.forename: Angie T
authors.initials: AT
authors.lastname: Oler
authors.forename: Donald S
authors.initials: DS
authors.lastname: Stapleton
authors.forename: Carmen
authors.initials: C
authors.lastname: Argmann
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Schueler
authors.forename: Steve
authors.initials: S
authors.lastname: Edwards
authors.forename: H Adam
authors.initials: HA
authors.lastname: Steinberg
authors.forename: Elias
authors.initials: E
authors.lastname: Chaibub Neto
authors.forename: Robert
authors.initials: R
authors.lastname: Kleinhanz
authors.forename: Scott
authors.initials: S
authors.lastname: Turner
authors.forename: Marc K
authors.initials: MK
authors.lastname: Hellerstein
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Brian S
authors.initials: BS
authors.lastname: Yandell
authors.forename: Christina
authors.initials: C
authors.lastname: Kendziorski
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000375:Aging; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000473:pathology; D007515:Islets of Langerhans / Q000473:pathology*; D008297:Male; D051379:Mice; D008957:Models, Genetic; D009765:Obesity / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D005947:Glucose