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Increased glucose or fatty acid flux through the hexosamine biosynthesis pathway produces cardiomyocyte insulin resistance and abnormal excitation‐contraction coupling
Author(s) -
Davidoff Amy J,
Carmody Marybeth W,
Dube Nathalie,
Palmer Christopher D,
Wold Loren E
Publication year - 2007
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.21.6.a1398
Subject(s) - medicine , endocrinology , insulin resistance , myocyte , insulin , diabetes mellitus , contraction (grammar) , glucose uptake , type 2 diabetes , chemistry
We have evidence that high glucose (HG) and high fatty acids (HFA) induce myocardial insulin resistance (IR), which mimic the effects of type 1 diabetes, and that IR is associated with abnormal excitation‐contraction coupling (ECC). Although a direct link has yet to be determined, the hexosamine biosynthesis pathway (HBP) may play a central role. We have previously shown that non‐specific PKC inhibition ( in vitro ) prevents HG‐induced impaired ECC and insulin‐stimulated glucose uptake in isolated cardiomyocytes, and reverses these dysfunctions in myocytes isolated from diabetic animals. We now show that inhibiting GFAT (rate limiting enzyme for the HBP), these HG effects are prevented, and the diabetes‐induced abnormal ECC is reversed. For example, glucose uptake is blunted and myocyte relaxation is prolonged in HG cells by ~30% of controls, and both are prevented by co‐culture with azaserine (AZA). HFA also impairs glucose uptake and ECC. Strategies to inhibit HBP (with AZA or DON) or augment insulin sensitivity (with metformin) prevent HFA‐induced abnormal ECC. Culturing cardiomyocytes from type 1 diabetic rats with DON also reverses abnormal ECC (e.g., myocyte relaxation is 2x slower in untreated diabetic myocytes than in normal cells). We suggest that the link between abnormal ECC and IR in each of our models (i.e., HG, HFA and diabetes) involves the HBP. ADA 7‐04‐RA‐23 and NIH R01HL66895 (AJD)