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Impaired Fat Oxidation After a Single High-Fat Meal in Insulin-Sensitive Nondiabetic Individuals With a Family History of Type 2 Diabetes

¹ Diabetes and Obesity Program, Garvan Institute of Medical Research, New South Wales, Australia
² Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus, Denmark

Address correspondence and reprint requests to Dr. Leonie Heilbronn, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW, 2010, Australia. E-mail: l.heilbronn{at}garvan.org.au

Abbreviations: ACC, acetyl CoA-carboxylase; adipoR, adiponectin receptor; CPT, carnitine palmitoyltransferase; FAT, fatty acid translocase; FFA, free fatty acid; FFM, fat-free mass; PDK, pyruvate dehydrogenase kinase; PGC, peroxisome proliferator–activated receptor coactivator; REE, resting energy expenditure; RQ, respiratory quotient

Individuals with insulin resistance and type 2 diabetes have an impaired ability to switch appropriately between carbohydrate and fatty acid oxidation. However, whether this is a cause or consequence of insulin resistance is unclear, and the mechanism(s) involved in this response is not completely elucidated. Whole-body fat oxidation and transcriptional regulation of genes involved in lipid metabolism in skeletal muscle were measured after a prolonged fast and after consumption of either high-fat (76%) or high-carbohydrate (76%) meals in individuals with no family history of type 2 diabetes (control, n = 8) and in age- and fatness-matched individuals with a strong family history of type 2 diabetes (n = 9). Vastus lateralis muscle biopsies were performed before and 3 h after each meal. Insulin sensitivity and fasting measures of fat oxidation were not different between groups. However, subjects with a family history of type 2 diabetes had an impaired ability to increase fatty acid oxidation in response to the high-fat meal (P < 0.05). This was related to impaired activation of genes involved in lipid metabolism, including those for peroxisome proliferator–activated receptor coactivator-1 (PGC1) and fatty acid translocase (FAT)/CD36 (P < 0.05). Of interest, adiponectin receptor-1 expression decreased 23% after the high-fat meal in both groups, but it was not changed after the high-carbohydrate meal. In conclusion, an impaired ability to increase fatty acid oxidation precedes the development of insulin resistance in genetically susceptible individuals. PGC1 and FAT/CD36 are likely candidates in mediating this response.

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