Exploring Adrenomedullin's Actions in Diabetic Pregnancy using Mouse Models

Gestational diabetes mellitus (GDM), defined as glucose intolerance first diagnosed during pregnancy, affects up to 18% of pregnancies in the U.S. and significantly increases risk for both mothers and offspring, including pre-eclampsia and long-term development of type 2 diabetes and metabolic syndromes. Despite its prevalence, GDM lacks treatments targeting its underlying mechanisms. Current therapies focus solely on glucose control while ignoring adipose tissue dysfunction, highlighting the urgent need for novel therapeutic targets addressing both hyperglycemia and adipose dysfunction. Recent studies suggest that adrenomedullin (ADM), a multifunctional peptide, plays a causal role in the development of GDM by suppressing insulin secretion in human β-cells and promoting lipolysis in adipose tissue. Importantly, we and others have found elevated ADM levels in the maternal serum and amniotic fluid of women with GDM, supporting a pathophysiological role during pregnancy. Our preliminary studies demonstrate that ADM infusion in pregnant mice induces GDM-like features, including glucose intolerance, reduced β-cell function, and increased lipolysis. Most significantly, administration of an ADM antagonist, ADM22-52, reverses these abnormalities in our novel GDM mouse model, providing the first evidence for ADM antagonism as a promising therapeutic approach. We hypothesize that increased ADM levels and signaling during pregnancy play a causal role in the manifestation of GDM symptoms through mechanisms involving both β-cell dysfunction and adipose tissue dysregulation. We propose three complementary aims using innovative genetic models and pharmacological approaches. Aim 1 will investigate the role of ADM signaling in β-cell adaptations to pregnancy using newly developed inducible β-cell-specific receptor knockout mice in established GDM models and assessing effects on glucose tolerance, β-cell function and expansion, and underlying signaling pathways. Aim 2 will determine whether elevated placental ADM contributes to GDM pathophysiology using placenta-specific ADM knockdown via targeted lentiviral delivery and assessing the impact on maternal glucose homeostasis, lipid metabolism, and fetal outcomes. Aim 3 will determine if ADM antagonist treatment attenuates GDM symptoms using both prevention and reversal protocols to evaluate therapeutic potential. Building on our published GDM mouse models and preliminary ADM studies, our multidisciplinary team has proven expertise and institutional resources to execute this comprehensive investigation. This work will establish ADM as the first identified molecular target for treating hyperglycemia and adipose dysfunction in GDM, potentially transforming clinical management of this prevalent pregnancy complication. Our findings will provide the mechanistic foundation for developing the first targeted therapy for GDM that addresses its underlying pathophysiology rather than just managing symptoms. The research also has broader implications for understanding metabolic adaptations during pregnancy and may inform treatments for type 2 diabetes, which affects over 37 million Americans. Project Number: 1R01HD119756-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: CHANDRASEKHAR YALLAMPALLI (+1 co-PI) | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $695,659 | Activity Code: R01 | Study Section: Cell Signaling and Molecular Endocrinology Study Section[CSME] View on NIH RePORTER: https://reporter.nih.gov/project-details/11373869