title: Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects.
abstract: Increased accumulation of fatty acids and their derivatives can impair insulin-stimulated glucose disposal by skeletal muscle. To characterize the nature of the defects in lipid metabolism and to evaluate the effects of thiazolidinedione treatment, we analyzed the levels of triacylglycerol, long-chain fatty acyl-coA, malonyl-CoA, fatty acid oxidation, AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), malonyl-CoA decarboxylase, and fatty acid transport proteins in muscle biopsies from nondiabetic lean, obese, and type 2 subjects before and after an euglycemic-hyperinsulinemic clamp as well as pre-and post-3-month rosiglitazone treatment. We observed that low AMPK and high ACC activities resulted in elevation of malonyl-CoA levels and lower fatty acid oxidation rates. These conditions, along with the basal higher expression levels of fatty acid transporters, led accumulation of long-chain fatty acyl-coA and triacylglycerol in insulin-resistant muscle. During the insulin infusion, muscle fatty acid oxidation was reduced to a greater extent in the lean compared with the insulin-resistant subjects. In contrast, isolated muscle mitochondria from the type 2 subjects exhibited a greater rate of fatty acid oxidation compared with the lean group. All of these abnormalities in the type 2 diabetic group were reversed by rosiglitazone treatment. In conclusion, these studies have shown that elevated malonyl-CoA levels and decreased fatty acid oxidation are key abnormalities in insulin-resistant muscle, and, in type 2 diabetic patients, thiazolidinedione treatment can reverse these abnormalities.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, 9500 Gilman Dr., La Jolla, 92093, USA.
authors.forename: Gautam K
authors.initials: GK
authors.lastname: Bandyopadhyay
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Yu
authors.forename: Jachelle
authors.initials: J
authors.lastname: Ofrecio
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000032:analysis; D000214:Acyl Coenzyme A / Q000032:analysis; D000328:Adult; D002262:Carboxy-Lyases / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D050612:Fatty Acid Transport Proteins / Q000032:analysis; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007333:Insulin Resistance; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D008316:Malonyl Coenzyme A / Q000032:analysis*; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D009097:Multienzyme Complexes / Q000032:analysis / Q000378:metabolism; D018482:Muscle, Skeletal / Q000737:chemistry; D009765:Obesity / Q000378:metabolism*; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014280:Triglycerides / Q000032:analysis
chemical_list: D000214:Acyl Coenzyme A; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D008055:Lipids; D009097:Multienzyme Complexes; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D008316:Malonyl Coenzyme A; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D000103:Acetyl-CoA Carboxylase