Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia.
Insulin resistance and beta cell toxicity are key features of type 2 diabetes. One leading hypothesis suggests that these abnormalities result from excessive flux of nutrients through the UDP-hexosamine biosynthetic pathway leading to "glucose toxicity." How the products of the hexosamine pathway mediate these effects is not known. Here, we show that transgenic overexpression of an enzyme using UDP-GlcNAc to modify proteins with O-GlcNAc produces the type 2 diabetic phenotype. Even modest overexpression of an isoform of O-GlcNAc transferase, in muscle and fat, leads to insulin resistance and hyperleptinemia. These data support the proposal that O-linked GlcNAc transferase participates in a hexosamine-dependent signaling pathway that is linked to insulin resistance and leptin production.
Department of Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT 84112, USA.
Donald A
DA
McClain
William A
WA
Lubas
Robert C
RC
Cooksey
Mark
M
Hazel
Glendon J
GJ
Parker
Dona C
DC
Love
John A
JA
Hanover
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood* / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011134:Polysaccharides / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism*
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D020738:Leptin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011134:Polysaccharides; D011993:Recombinant Fusion Proteins; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; D014537:Uridine Diphosphate N-Acetylglucosamine; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase