1656-P: FGF-21 Receptor Variants Demonstrate Severe Insulin Resistance in a Mouse Model of Insulin Mediated Pseudoacromegaly

Abstract

Insulin mediated pseduoacromegaly (IMPA) is a rare insulin resistance syndrome characterized by tall stature, acanthosis nigricans, obesity, and acromegaloid features. Subjects with IMPA have normal growth hormone and IGF-1. However, their insulin levels are markedly elevated. To date, no molecular or genetic etiology has been demonstrated as a definitive cause of IMPA. We previously described an adolescent female diagnosed with IMPA. Exome sequencing identified 2 rare, predicted deleterious, variants in Fibroblast Growth Factor Receptor 1 (FGFR1) and beta-Klotho (KLB) which form the receptor for fibroblast growth factor 21 (FGF-21). Due to FGF-21’s role in insulin signaling, we hypothesized that these mutations may be contributing to our proband’s condition. Our study aimed to knock-in these FGFR1/KLB variants into a mouse model using CRISPR/Cas9 gene editing technology. After embryo microinjection, we were able to generate 4 pups mosaic for the missense mutations in FGFR1 or KLB. The resulting founder mice were backcrossed to wild type mice, and then bred to recapitulate the same digenic geneotype found in our adolescent proband with IMPA. When exposed to a high fat diet, double mutant (FGFR1/KLB) mice demonstrate hyperglycemia (158.0 compared to 125.3 mg/dL, p=<0.0001). At 9 weeks-old, the double mutant mice weighed 40.9 g compared to 25.4 g (p=0.0177). These mice underwent a 2 g/kg intraperitoneal glucose tolerance test. While fasting, both the double mutant and wild type mice had normal glucose (87 and 76 mg/dL). However fasting insulin was elevated in the double mutant mice (1246.1 to 231.5 pg/mL). 30 minutes post glucose, the double mutant mice demonstrated hyperglycemia (414 to 274 mg/dL) and marked hyperinsulinemia (2,358.0 to 884.3 pg/mL). Although further characterization of these mice is required, thus far, these studies suggest that our proband’s digenic variants in FGFR1/KLB are likely to be pathogenic and are a potential cause of IMPA. Disclosure S.I. Stone: Research Support; Self; National Institutes of Health. Speaker’s Bureau; Self; Rhythm Pharmaceuticals. T. Lupu: None. F. Urano: Stock/Shareholder; Self; CytRx Corporation. Other Relationship; Self; AETAS Pharma, Amylyx Pharmaceuticals, Mitochon, National Center for Advancing Translational Sciences, Novus Biologicals?. D.M. Ornitz: None. Funding National Institutes of Health (R21HD098872); Washington University (P30DK020579); National Center for Advancing Translational Sciences (UL1TR002345)