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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/E1078    most recent 00337.2007v2 00337.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Weickert, M. O. Articles by Möhlig, M. Search for Related Content PubMed PubMed Citation Articles by Weickert, M. O. Articles by Möhlig, M.

A Thr⁹⁴Ala mutation in human liver fatty acid-binding protein contributes to reduced hepatic glycogenolysis and blunted elevation of plasma glucose levels in lipid-exposed subjects

¹Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal; ²Department of Endocrinology, Diabetes, and Nutrition, Charité-University-Medicine, Campus Benjamin Franklin, Berlin, Germany; ³First Medical Department, Hanusch Hospital, Karl-Landsteiner Institute for Endocrinology and Metabolism, Vienna, Austria; ⁴Department of Medicine, Case Western Reserve University, Cleveland, Ohio; and ⁵Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

Submitted 29 May 2007 ; accepted in final form 1 August 2007

Liver fatty acid-binding protein (L-FABP) is a highly conserved key factor in lipid metabolism. Amino acid replacements in L-FABP might alter its function and thereby affect glucose metabolism in lipid-exposed subjects, as indicated by studies in L-FABP knockout mice. Amino acid replacements in L-FABP were investigated in a cohort of 1,453 Caucasian subjects. Endogenous glucose production (EGP), gluconeogenesis, and glycogenolysis were measured in healthy carriers of the only common Thr⁹⁴-to-Ala amino acid replacement (Ala/Ala⁹⁴) vs. age-, sex-, and BMI-matched wild-type (Thr/Thr⁹⁴) controls at baseline and after 320-min lipid/heparin-somatostatin-insulin-glucagon clamps (n = 18). Whole body glucose disposal was further investigated (subset; n = 13) using euglycemic-hyperinsulinemic clamps without and with lipid/heparin infusion. In the entire cohort, the only common Ala/Ala⁹⁴ mutation was significantly associated with reduced body weight, which is in agreement with a previous report. In lipid-exposed, individually matched subjects there was a genotype vs. lipid-treatment interaction for EGP (P = 0.009) driven mainly by reduced glycogenolysis in Ala/Ala⁹⁴ carriers (0.46 ± 0.05 vs. 0.59 ± 0.05 mg·kg^–1·min^–1, P = 0.013). The lipid-induced elevation of plasma glucose levels was smaller in Ala/Ala⁹⁴ carriers compared with wild types (P < 0.0001). Whole body glucose disposal was not different between lipid-exposed L-FABP genotypes. In summary, the Ala/Ala⁹⁴-mutation contributed significantly to reduced glycogenolysis and less severe hyperglycemia in lipid-exposed humans and was further associated with reduced body weight in a large cohort. Data clearly show that investigation of L-FABP phenotypes in the basal overnight-fasted state yielded incomplete information, and a challenge test was essential to detect phenotypical differences in glucose metabolism between L-FABP genotypes.

endogenous glucose production; gluconeogenesis; insulin resistance; free fatty acids; nutrigenomics; randomized controlled study