Current students


PIUBENI LUCIACycle: XL

Advisor: IEVA FRANCESCA
Tutor: CAIANI ENRICO GIANLUCA

Major Research topic:
Exploring the Role of GLP-1 and GLP-2 in Maternal Metabolism Across Pregnancy and Breastfeeding

Abstract:
INTRODUCTION ; Obesity has become the most prevalent chronic metabolic disorder among women of childbearing age. The World Health Organization (WHO) defines obesity as a complex, chronic disease, and estimates that more than one billion individuals will be obese by 2030 if current trends continue (World Health Organization, 2000). As obesity is a major contributor to non-communicable diseases, it’s also closely linked to the rising incidence of type 2 diabetes mellitus (T2DM), including cases that occur during pregnancy (Bashir et al., 2024). ; Over the past thirty years, the number of pregnant individuals diagnosed with T2DM has doubled, bringing a range of severe maternal and fetal complications (Bashir et al., 2024). Women with gestational T2DM are at increased risk of preeclampsia, microvascular damage (e.g., retinopathy, nephropathy), and cardiovascular events across the peripartum period. Their infants face a higher risk of stillbirth, congenital anomalies, macrosomia, respiratory distress and long-term neurological impairments, all of which increase the need for neonatal intensive care admissions and elevate perinatal mortality (Mohamed et al., 2025). ; Traditionally, insulin therapy has been the preferred treatment for glucose control during pregnancy, because it is considered safer for the fetus compared to non-insulin therapies. However, in recent years there had been an emerging of non-insulin agents, particularly glucagon like peptide 1 receptor agonists (GLP-1RAs) and glucagon like peptide 2 (GLP-2) (Varughese et al., 2025). In non-pregnant populations these drugs not only improve hyperglycemia and enhance insulin sensitivity, but have demonstrated efficacy in weight loss, and in enhancing fertility in women affected by obesity and polycystic ovary syndrome (Parker et al., 2025). Yet, despite their clear metabolic benefits, GLP-1RAs and GLP-2 are not currently approved for use during pregnancy. Preclinical animal studies suggest potential teratogenic risks in early gestation exposure, including reduced fetal growth, delayed ossification and visceral abnormalities (Varughese et al., 2025). ; As T2DM and obesity are becoming more prevalent, it is essential to determine whether GLP-1RAs and GLP-2 are causally associated with adverse outcomes during pregnancy and breastfeeding. Focusing on understanding the GLP-1RAs functions could contribute to clearer treatment guidelines, improving the prenatal health of both mothers and infants. ; ; RESEARCH QUESTION ; My research will use advanced statistical techniques and integrative analytical methods combining genetic and other omics data to gain causal insights into these unresolved exposure-outcome associations and their mediation. The study aims to address the following potential research question: “Does the continuation or initiation of GLP-1RAs and/or GLP-2 for T2DM and/or obesity during pregnancy affect pregnancy, breastfeeding and infant outcomes?”. ; This research question has been divided in specific research objectives (RO): ; 1. RO1: Study the omics profiles associated with GLP-1RAs and GLP-2, pregnancy and breastfeeding. ; 2. RO2: Explore the descriptive trends associated to GLP-1RAs and GLP-2 over time ; 3. RO3: Investigate GLP-1RAs-mediated pathways and integrate multi-omics data ; 4. RO4: Evaluate public health implications by assessing potential benefits, risks, and guideline development for GLP-1RAs use in pregnancy ; ; RO1: Omics Profiles of GLP-1RAs, GLP-2, Pregnancy and Breastfeeding ; The primary aim is to identify the genomic, transcriptomic, proteomic, and metabolomics profile linked to GLP-1RAs, pregnancy and breastfeeding. Public genome-wide association (GWAS) studies such as GWAS Catalog, Risteys, UK Biobank, etc. allow researchers worldwide to conduct health research. Using these databases will make it possible to extract SNPs (Single Nucleotide Polymorphisms) associated with GLP-1RAs and GLP-2 and perform annotation enrichment analysis to study the genetic, epigenetic, and proteomic profiles of GLP-1RAs and GLP-2. Similarly, the EGG Consortium will be used to extract SNPs associated with pregnancy and breastfeeding outcomes. ; ; RO2: Descriptive Trends of GLP-1RAs ; Understanding how GLP-1RAs and GLP-2 prescriptions have evolved over time allows to gain an overall picture of external factors that might influence trends and identify potential risk patterns to pregnant women and their offsprings. The Regione Lombardia and similar the FinRegistry database include demographic information of each patient, hospitalization discharge records, outpatient medical visits, vaccinations, drugs prescriptions reimbursed by NHS and certificates of delivery assistance (CeDAP), a certificate drawn up within 10 days after the delivery. Statistical methods like time-series analysis will be used to understand the trends and changes in the use of these treatment and its health consequences over time. ; RO3: T2DM and Obesity Mediating Role ; The main aim is to explore the obesity and T2DM’ mediating role in the indirect effect between GLP1-RAs/GLP-2 and adverse pregnancy, breastfeeding and offsprings outcomes. The study will also analyze the difference between T2DM and obesity groups. ; To establish a potential causal indirect association between GLP1-RAs or GLP-2 and adverse pregnancy, breastfeeding and offsprings outcomes mediated by T2DM and/or obesity, statistical methods such as mediation analysis will be used. ; RO4: Public Health Implications ; Based on the previous results, this phase will assess the risk-benefit profile of GLP-1RAs and GLP-2 use around pregnancy. This will help to formulate potential evidence-based guidelines for GLP-1RAs and GLP-2 management in women who are planning to conceive or are already pregnant. ; ; CONCLUSIONS ; In conclusion, this research aims to explore the impact of GLP1-RAs and GLP-2 on pregnancy, breastfeeding and offsprings through T2DM and obesity. By integrating public resources, EGG consortium, Regione Lombardia, and FinRegistry, it seeks to provide robust epidemiological insights. Using advanced statistical methods, the study ensures reliable results. Ultimately, the findings are expected to significantly improve public health, enhancing the wellbeing of both mothers and their offsprings. ;