Pilot: Targeting GLP-1 Receptor during Pregnancy to Improve Metabolic Health in the Mother and the Offspring

In 2022, 80% of drug-related overdoses were caused by fentanyl. In parallel, an alarming 5-fold increase in opioid use disorder (OUD) diagnoses during pregnancy was observed. In the general population, previous studies have shown chronic use of opioids is associated with increased rates of type 2 diabetes, hepatic steatosis, and hypertension, all risk factors of metabolic disease. Clinical studies have shown that opioid exposure for more than or equal to 90 days results in significant impairment of glucose homeostasis, where glycated hemoglobin was significantly higher in patients with OUD. At the same time, the rates of uncontrolled diabetes were substantially higher in opioid-consuming individuals. However, there is a gap in the field regarding the relationship between opioid consumption and diabetes. We recently developed a unique rat model of in utero fentanyl exposure during preconception and pregnancy using fentanyl self-administration (FEN-SA). After timed pregnancy was confirmed, weight gain was similar between FEN-SA and control groups. In addition, dams that were trained on FEN-SA delivered litters with a similar number of pups, birth weight, and total body length compared to control neonates. However, prenatal fentanyl exposure increased the cephalization index, an indicator of impaired fetal body weight and brain weight gain. After 2 months, FEN-SA increased fasting blood glucose in dams and reduced plasma insulin and oral glucose tolerance in their offspring. Together, these data suggest that our model of prenatal fentanyl exposure induces long-lasting metabolic derangements in the mother and the exposed litter. The effects of opioids on glucose homeostasis are not fully understood and depend on the dose, route, and site of administration, and whether the opioid is natural or synthetic. Fentanyl inhibits glucose-stimulated insulin release from isolated rat pancreatic islets, an effect that is prevented by naloxone, an opioid receptor antagonist. Glucagon peptide like-1 receptor agonist (GLP-1RA) drugs are now widely used for diabetes and weight loss; however, they have also shown potential to suppress drug consumption. Although GLP-1RA drugs are generally not recommended during pregnancy, the use of GLP-1RA as noninsulin antidiabetic medication is emerging as an effective approach to maintaining glycemic control if needed. The benefit of using GLP-1RA, therefore, may outweigh the established deleterious consequences of fentanyl misuse. However, a lack of safety and follow-up studies on mothers using fentanyl during pregnancy limits the development of novel therapies for this vulnerable population. Overall, the goal of this proposal is to investigate the use of GLP1-RA as an effective non-opioid-based therapeutic strategy to prevent OUD during pregnancy while reducing metabolic comorbidities.