A common Thr94Ala replacement in liver-fatty-acid-binding-protein contributes to improved glucose metabolism upon lipid challenge

• Published in: Experimental and Clinical Endocrinology & Diabetes
• Main Authors: Weickert, MO, Löffelholz, C von, Roden, M, Chandramouli, V, Brehm, A, Nowotny, P, Osterhoff, MA, Isken, F, Spranger, J, Landau, BR, Pfeiffer, AFH, Möhlig, M
• Format: Conference Proceeding
• Language: English
• Published: 29.03.2007
• ISSN: 0947-7349; 1439-3646
• DOI: 10.1055/s-2007-972374

Objectives: Liver-fatty-acid-binding-protein (L-FABP) is abundantly expressed in hepatocytes and influences lipid transport and metabolism. Amino-acid replacements in L-FABP might affect its function and thus glucose metabolism, as indicated by L-FABP knock-out studies. We hypothesized that hepatic glucose metabolism is altered in lipid-exposed homozygous carriers of the only common Thr94Ala amino-acid replacement. Methods: We first investigated all known polymorphisms leading to an amino acid exchange in L-FABP, in a cohort of 1453 Caucasian subjects. Effects of FFA on endogenous glucose production (EGP), gluconeogenesis (GNG), and glycogenolysis (GL) were assessed at baseline and during 320-min lipid/heparin-somatostatin-insulin-glucagon clamps (9 healthy Ala/Ala94-carriers versus 9 gender, age, and BMI matched wild-type (Thr/Thr) controls). On separate study days we investigated whole-body glucose disposal in a subset (n=13), using euglycemic-hyperinsulinemic clamps during 320-min lipid/heparin infusion. Results: Only one coding SNP was found in our cohort, which resulted in an Ala94Thr replacement with a minor allele frequency of 36%. GNG increased in lipid-exposed subjects independent of the L-FABP genotype. However, plasma glucose markedly increased in wild-types vs. Ala/Ala94-carriers (genotype vs. lipid-treatment interaction, P<0.0001). Rates of EGP significantly decreased in Ala/Ala94-carriers from 1.99±0.12 to 1.70±0.15mg·kg-1·min-1 (P=0.003), but not in wild-types (genotype vs. lipid-treatment interaction, P=0.008). GL was significantly reduced in Ala/Ala94-carriers vs. wild-types (0.46±0.05 vs. 0.60±0.05mg·kg-1·min-1, P=0.017). Whole-body glucose-disposal after 320min lipid-exposure was not different between genotypes. Conclusion: The Ala/Ala94-allele significantly contributed to improved glucose metabolism in lipid-exposed subjects. Genetic variation of L-FABP should be considered when assessing lipid regulation of hepatic glucose metabolism; L-FABP function could be a target for treatment of insulin resistant states.