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Insulin, but not lipid availability, regulates calpain‐10 at the transcriptional level in human skeletal muscle
Author(s) -
Norton Luke,
Chokkalingam Kamal,
Jewell Kirsty,
Parr Tim,
Tsintzas Kostas
Publication year - 2006
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.20.5.lb32-c
Subject(s) - medicine , endocrinology , pdk4 , insulin , chemistry , skeletal muscle , lipid metabolism , lipid oxidation , pyruvate dehydrogenase complex , biology , enzyme , biochemistry , antioxidant
We investigated the molecular alterations underlying the reduction in carbohydrate (CHO) utilization with increased lipid availability in human skeletal muscle. On 2 occasions, 10 healthy young men [age 22 ± 1 (mean ± SEM), BMI 24 ± 1] underwent hyperinsulinemic (50 mU/m2/min) euglycemic (4.5 mM) clamps for 6h with (LIPID) and without (CON) intravenous intralipid (20% at a rate of 90 ml/h) plus heparin (200 U prime + 600 U/h) infusion. CHO and fat oxidation rates were determined by indirect calorimetry. Muscle biopsies were obtained before and after 3 and 6h of infusion for the determination of hexokinase II (HKII), pyruvate dehydrogenase kinase 4 (PDK4) and the diabetes linked gene calpain‐10 (CAPN10) mRNA levels by real‐time PCR. Lipid infusion increased fat oxidation after 90 min (P<0.05) and decreased CHO oxidation after 150 min (P<0.05) and glucose disposal after 210 min (P<0.05). At the end of the clamp, CHO disposal was ~50% lower in the LIPID compared to the CON trial (14.5 ± 0.7 vs 6.9 ± 0.8 mg/min/kg lean mass, P<0.001). CAPN10 mRNA levels decreased with insulin in both clamps (P<0.01) and were not affected by lipid infusion. HKII mRNA was upregulated 2‐fold (P<0.01) in the CON trial, but this was impaired in the LIPID trial. PDK4 mRNA content was downregulated by 2‐fold in response to insulin within 3 h in both clamps, and decreased further (6‐fold, P<0.01) at 6 h in the CON but not the LIPID clamp. These results show that lipid‐induced insulin resistance is associated with significant changes in genes regulating CHO utilisation. In contrast, it appears that insulin, and not lipid, regulates CAPN10 at the transcriptional level.