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A lipid mediated mechanism increases protein O‐glycosylation in hearts of Type 2 diabetic mice
Author(s) -
Fricovsky Eduardo Santiago,
Suarez Jorge,
Hu Yong,
Belke Darrell,
Scott Brian,
Wang Hong,
Dillmann Wolfgang H.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1226.52
Subject(s) - medicine , endocrinology , insulin resistance , streptozotocin , glycosylation , type 2 diabetes , chemistry , diabetes mellitus , insulin , biology , biochemistry
Increased nuclear protein O‐linked β‐N‐acetylglucosamine glycosylation (O‐GlcNAcylation) mediated by severe hyperglycemia of diabetes mellitus Type 1 contributes to cardiac myocyte dysfunction. However, it is unknown if increased O‐GlcNAcylation also occurs in the hearts of Type 2 diabetic (T2D) mice with mild hyperglycemia and insulin resistance. Type 2 diabetes was induced in mice by feeding a high fat diet (60% fat) and administering a single low dose of streptozotocin (50mg/Kg). Animals were studied after 10 weeks. Our results show that T2D mice have slightly increased fasting blood glucose levels compared with normal (N) mice (T2D; 5.25±1.43 vs. N; 4.01±0.4 mM). Insulin serum levels were 3 fold increased in T2D mice suggesting insulin resistance. Surprisingly, we found increased protein O‐GlcNAcylation in T2D mouse hearts. Cardiac UDP‐GlcNAc level was also increased. To investigate the basis for the increased protein O‐GlcNAcylation neonatal cardiomyocytes were cultured in 400 μM oleic acid (OA) and normal glucose (5mM) for 48 h. OA dramatically increased protein O‐GlcNAcylation which was reduced after expression of O‐GlcNAcase, which is the enzyme that removes O‐GlcNAc residues from protein. In conclusion, these data suggest that increased lipid utilization results in augmented hexosamine biosynthetic pathway as indicated by increase in protein UDP‐GlcNAcylation levels.