Accelerated glucose intolerance, nephropathy, and atherosclerosis in prostaglandin D2 synthase knock-out mice.
Type 2 diabetics have an increased risk of developing atherosclerosis, suggesting the mechanisms that cause this disease are enhanced by insulin resistance. In this study we examined the effects of gene knock-out (KO) of lipocalin-type prostaglandin D(2) synthase (L-PGDS), a protein found at elevated levels in type 2 diabetics, on diet-induced glucose tolerance and atherosclerosis. Our results show that L-PGDS KO mice become glucose-in-tolerant and insulin-resistant at an accelerated rate when compared with the C57BL/6 control strain. Adipocytes were significantly larger in the L-PGDS KO mice compared with controls on the same diets. Cell culture data revealed significant differences between insulin-stimulated mitogen-activated protein kinase phosphatase-2, protein-tyrosine phosphatase-1D, and phosphorylated focal adhesion kinase expression levels in L-PGDS KO vascular smooth muscle cells and controls. In addition, only the L-PGDS KO mice developed nephropathy and an aortic thickening reminiscent to the early stages of atherosclerosis when fed a "diabetogenic" high fat diet. We conclude that L-PGDS plays an important role regulating insulin sensitivity and atherosclerosis in type 2 diabetes and may represent a novel model of insulin resistance, atherosclerosis, and diabetic nephropathy.
Ragolia
Louis
L
Vascular Biology Laboratory, Winthrop-University Hospital, Mineola, New York 11501, USA. lragolia@winthrop.org
Palaia
Thomas
T
Hall
Christopher E
CE
Maesaka
John K
JK
Eguchi
Naomi
N
Urade
Yoshihiro
Y
D017667:Adipocytes / Q000473:pathology; D052242:Adiponectin; D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology*; D001786:Blood Glucose / Q000032:analysis; D003928:Diabetic Nephropathies / Q000209:etiology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D018149:Glucose Intolerance / Q000209:etiology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000502:physiology*; D054834:Lipocalins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics
D052242:Adiponectin; D001786:Blood Glucose; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D054834:Lipocalins; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase