SAT415 Development Of A Novel, Preclinical Swine Model Of Transgender Men To Assess Testosterone Impact On Insulin Sensitivity And Whole-Body Metabolism
Authors: Mahabir Nirvana , Ahmad Irshad , Wright Traver , Ten Have Gabrie , Deutz Nicolaas , Newell-Fugate Annie Elizabeth 
Published: October 2023

Disclosure: N. Mahabir: None. I. Ahmad: None. T. Wright: None. G. Ten Have: None. N. Deutz: None. A.E. Newell-Fugate: None.

The effects oftestosterone therapy on peripheral insulin sensitivity in transgender men areequivocal due to heterogeneity of the population, short term patientfollow-up, and small cohort sizes. Most research has found testosterone therapyto decrease or have no effect on insulin sensitivity, but in one studytransgender men had increased insulin sensitivity. We have found thatshort-term, virilizing doses of testosterone in female pigs suppress circulatinginsulin levels. The objective of the current study was to develop a long-term,preclinical model of transgender men to assess insulin sensitivity and whole-bodymetabolism. A swine model of transgender men is superior to other models,because pigs closely mimic human cardiometabolic physiology and their largebody size permits longitudinal sampling and interventional procedures. Togenerate stable, long-term serum testosterone (TEST) concentrations in femalepigs, we fabricated testosterone silastic implants at the following doses:placebo (30 mm, n=1) or 15 mm (n=2), 30 mm (n=2), 60 mm (n=2), or 120 mm (n=1)TEST. Eight sexually mature female pigs were administered 14 days of progestin(Altrenogest) which was withdrawn on day 15. On day 16, 400 I.U. of pregnantmare serum gonadotropin and 200 I.U of human chorionic gonadotropin (PG600®,Merck Animal Health) were administered intramuscularly to stimulatefolliculogenesis and ovulation. Pigs had estrus detection performed dailythroughout the study and came into estrus 3-7 days post PG600® injection.Twenty-four hours post-estrus, implants were surgically placed subcutaneously,blood was taken, and biopsies of subcutaneous white adipose tissue werecollected from the incision site for baseline assessment of mitochondrialoxygen flux (Oroboros) and proteomic measurement of mitochondrial and insulinpathway abundance. After implant placement, fasted blood was collected at 24,48, 72 hours and every three days thereafter for six weeks. During weeks 2-6post-implantation, continuous glucose monitoring was performed (Freestyle Libre3). Twenty-four hours prior to study completion, a catheter was placed in thecranial vena cava and an intravenous glucose tolerance test was performed (0,5, 10, 20, 30, 40, 50, 60 min). The next morning fasted blood was collected (time0) and a stable isotopic tracer bolus was administered to measure whole bodyproduction of glycerol, branched chain amino acids, branched chain keto acids, and β-hydroxyβ-methylbutyric acid. After tracer bolus, blood was collected at 10, 20, 40, 60and 120 minutes. At 120 minutes post-bolus, tissues were collected for isotopiccompound measurement, mitochondrial function assays, and insulin signalingpathway assessment. This translational swine model will help uncover themechanistic effects of testosterone therapy on insulin sensitivity and whole-bodymetabolism in female to male transitioning patients.

Presentation: Saturday, June 17, 2023