(7) Metformin paradoxically increases insulin resistance during pregnancy in a Rhesus macaque model

Thursday, January 30, 2025

9:30 AM – 9:45 AM

Location: Aurora Ballroom, Lobby Level

Submitting Author and Presenting Author(s)

Enrico R. Barrozo, PhD

Assistant Professor
Baylor College of Medicine and Texas Children’s Hospital
Houston, Texas, United States

Coauthor(s)

TD

Tyler Dean, BS

Oregon National Primate Research Center
Beaverton, Oregon, United States
Claire E. Jensen, MD, MSCR (she/her/hers)

Fellow
University of North Carolina
Chapel Hill, North Carolina, United States
Melissa A. Suter, PhD

Baylor College of Medicine and Texas Children’s Hospital
Houston, Texas, United States
MS

Maxim D. Seferovic, PhD

Baylor College of Medicine and Texas Children’s Hospital
Houston, Texas, United States
KS

Kristin Sauter, BS

Oregon National Primate Research Center
Beaverton, Oregon, United States
JF

Jacob E. Friedman, PhD

Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
MG

Maureen Gannon, PhD

Vanderbilt University Medical Center
Nashville, Tennessee, United States
SW

Stephanie R. Wesoloski, PhD

University of Colorado, Anschutz Medical Campus
Aurora, Colorado, United States
CM

Carrie E. McCurdy, PhD

University of Oregon
Eugene, Oregon, United States
PK

Paul Kievit, PhD

Oregon National Primate Research Center
Beaverton, Oregon, United States
Kjersti M. Aagaard, MD, PhD

Medical Director, HCA Healthcare and HCA Research Institute
Boston Children’s Hospital, Division of Fetal Medicine and Surgery, Boston, MA; HCA Healthcare and HCA Healthcare Research Institute, Nashville, TN; HCA Texas Maternal Fetal Medicine, Houston, TX; Baylor College of Medicine and Texas Children's Hospital, Houston, TX
Tomball, Texas, United States

Objective: Normal human and non-human primate pregnancy physiology includes mild insulin resistance, which enables appropriate fetal growth & species-specific accumulation of fetal adiposity. With rising diabetes in pregnancy, metformin use has become common despite its inferiority to insulin in managing maternal hyperglycemia. We hypothesized metformin inferiority during pregnancy may be due to differing pathophysiology of insulin resistance in pregnancy and tested this hypothesis in our recent Rhesus macaque model.

Study Design: Dams (n=75) were randomized to vehicle control (VEH) or metformin (MET, 10 mg/kg twice daily) at pregnancy confirmation by GD30 and allocated to control (CHOW) or an isocaloric 35% fat Western-style diet (WSD). Glucose tolerance tests were conducted pre-pregnancy (Baseline), 3rd trimester, and 3 months postpartum. AUC for glucose and insulin, HOMA-IR, QUICKI, and Matsuda Index were calculated as insulin resistance (IR) and sensitivity (IS) measures, respectively. Data were analyzed using two-way ANOVA or mixed-effects models and Tukey’s test for multiple comparisons (p< 0.05).

Results: Consistent with pregnancy physiology, dams were insulin resistant during pregnancy (insulin AUC p< 0.0001) but not hyperglycemic (p=0.3; Fig 1). Relative to VEH, initiation of metformin by GD30 resulted in increased IR (HOMA-IR, p=0.03) and decreased IS (QUICKI & Matsuda, p=0.001 & p< 0.001), both of which appropriately varied during gestation. Metformin was ineffective at treating IR during pregnancy and postpartum, with a paradoxical effect of significantly increased IR with metformin use compared to VEH (baseline vs 3rd trimester q< 0.05, Fig 2). Results were consistent when stratified by fetal sex and lactation status.

Conclusion: In our non-diabetic rhesus macaque model, we found that the pathophysiology and metformin-responsiveness of maternal pregnancy-related IR differ from non-pregnancy IR. These data are consistent with the lack of efficacy in human trials and underscore the need for longitudinal studies on the mechanisms and long-term health risks of metformin exposure during pregnancy.