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PMID: 15546994 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Distinct pathways of insulin-regulated versus diabetes-regulated gene expression: an in vivo analysis in MIRKO mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 47 ·2004-11-23 ·Pages 16525-30

Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, Kahn CR

Abstract

Diabetes mellitus is a complex metabolic disorder accompanied by alterations in cellular physiology, metabolism, and gene expression. These alterations can be primary (due to loss of direct insulin action) or secondary (due to the metabolic perturbations associated with the disease). To dissect and quantitate these two separate effects, we compared the skeletal muscle gene-expression profiles of muscle insulin receptor knockout (MIRKO) mice and their Lox controls in the basal, streptozotocin-induced diabetic, and insulin-treated diabetic states. Pure deficiency of insulin action as present in the MIRKO mouse results in regulation of 130 genes, with down-regulation of NSF (N-ethylmaleimide-sensitive fusion protein) and VAMP-2 (vesicle-associated membrane protein 2), stearoyl CoA desaturase 1, and cAMP-specific phosphodiesterase 4B, as well as up-regulation of some signaling-related genes, such as Akt2, and the fatty-acid transporter CD36. In diabetes, additional transcriptional mechanisms are activated, resulting in alterations in expression of approximately 500 genes, including a highly coordinated down-regulation of genes of the mitochondrial electron-transport chain and one of the mammalian homologues of the histone deacetylase Sir2, which has been implicated in the link between nutrition and longevity. These distinct pathways of direct and indirect regulation of gene expression provide insights into the complex mechanisms of transcriptional control in diabetes and areas of potential therapeutic targeting.

MeSH Terms
Animals Diabetes Mellitus, Experimental/drug therapy,genetics,metabolism Gene Expression Regulation/drug effects Insulin/metabolism,therapeutic use Male Mice Mice, Knockout Muscle, Skeletal/metabolism Protein Biosynthesis Receptor, Insulin/deficiency,genetics,metabolism Signal Transduction/genetics Transcription, Genetic
Chemicals
Insulin Receptor, Insulin
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Yechoor Vijay K
Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Patti Mary-Elizabeth
Ueki Kohjiro
Laustsen Palle G
Saccone Robert
Rauniyar Ravi
Kahn C Ronald
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0407574101
Published
2004-11-23
Epub
2004-00-16
Pages
16525-30
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC534529
Subset
IM
Grants
NIDDK NIH HHS · DK45935 · United States
NIDDK NIH HHS · DK36836-15 · United States
NIDDK NIH HHS · P30 DK036836 · United States
NIDDK NIH HHS · R01 DK033201 · United States
NIDDK NIH HHS · DK33201 · United States
NIDDK NIH HHS · R01 DK045935 · United States
External Links
PubMed source DOI: 10.1073/pnas.0407574101 PMC Full Text View journal details
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