Fibroblast growth factor 21 (FGF-21) is a hepatokine with multiple important metabolic functions. However, the role of FGF-21 in human insulin sensitivity remains unclear. We report an adolescent female with severe acanthosis nigricans and extremely elevated insulin levels (2446 uIU/mL). Due to her severe insulin resistance, we looked into the possibility that she might have a genetic syndrome of insulin resistance. Whole exome sequencing revealed that she carries 2 variants of unknown significance in genes critical for FGF-21 signaling, Fibroblast Growth Factor Receptor 1 (FGFR1) and beta-Klotho (KLB). FGFR1 and KLB are transmembrane co-factors that bind FGF-21 leading to downstream signaling. A bicistronic expression plasmid was created recapitulating the above variants found in our subject. These plasmids were transfected into L6 myoblasts, a cell line known to express low levels of endogenous FGF receptor. ERK phosphorylation (pERK), a major downstream signal of FGF-21, was measured after treatment with FGF-21. pERK was strongly upregulated in cells transfected with wild type FGFR1 and KLB (500,710 AU). However, variant FGFR1 and KLB greatly attenuated pERK (107,068 AU). Canonical FGF-2 treatment led to robust upregulation of pERK in both wild type and variant cell lines (374,968 AU and 441,654 AU respectively). Expression of Slc2a1 (Glut1) and Slc2a4 (Glut4) was also measured in response to FGF-21. Cells transfected with wild type FGFR1 and KLB led to a 1.7-fold increase in both Glut1 and Glut4 expression, whereas Glut1 and Glut4 expression was attenuated in cells transfected with the FGFR1 and KLB variants (1.2 and 0.7-fold respectively). These results suggest that the digenic FGFR1 and KLB variants found in our subject lead to an endocrine specific FGF-21 resistance with decreased GLUT1- and GLUT4-mediated glucose uptake. This helps explain our subject’s severe insulin resistance, and may represent a novel disorder related to FGF-21.
S.I. Stone: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Self; AbbVie Inc. D.J. Wegner: None. J.A. Wambach: None. F.S. Cole: None. D.M. Ornitz: None. F. Urano: Board Member; Self; Healthbeat. Research Support; Self; Aetas, Amylyx, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Stock/Shareholder; Self; CytRx. Other Relationship; Self; Novus Biologicals.
National Institutes of Health (HL120002); Institute of Clinical and Translational Sciences/Children's Discovery Institute (UL1TR00448)