A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility.
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.
Keller
Mark P
MP
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53076, USA.
Choi
YounJeong
Y
Wang
Ping
P
Davis
Dawn Belt
DB
Rabaglia
Mary E
ME
Oler
Angie T
AT
Stapleton
Donald S
DS
Argmann
Carmen
C
Schueler
Kathy L
KL
Edwards
Steve
S
Steinberg
H Adam
HA
Chaibub Neto
Elias
E
Kleinhanz
Robert
R
Turner
Scott
S
Hellerstein
Marc K
MK
Schadt
Eric E
EE
Yandell
Brian S
BS
Kendziorski
Christina
C
Attie
Alan D
AD
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
D007328:Insulin; D012333:RNA, Messenger; D005947:Glucose