Sweet beginnings with lasting consequences : mechanisms linking maternal diabetes with adverse cardiometabolic outcomes in offspring

Therefore, the work included in this thesis aimed to study how mild maternal diabetes affects the germline and uterine environment, and how this subsequently can alter offspring disease susceptibility.</p><p dir="ltr">In Paper I, we optimized a well-used model of type 1 diabetes, the streptozotocin (STZ) model, to reflect the improved glycemic levels seen in current clinical context. Using this model, we demonstrated that the oocyte transcriptome was unaltered when glycemic control was improved, in contrast to the large alterations seen in worse glycemic conditions.

However, we also found that the placenta and embryonic development was still negatively affected, highlighting how improved glycemic management in maternal diabetes is still associated with an impaired uterine environment.</p><p dir="ltr">In Paper II, we used our optimized model of maternal diabetes to study the effects of maternal diabetes on offspring endothelial function. Specifically, we aimed to understand if concurrent metabolic dysfunction in offspring is a prerequisite for cardiovascular disease to be present.

Using animal models, we found that male, but not female, offspring of dams with mild diabetes developed early-onset endothelial dysfunction independently of any metabolic comorbidity. Mechanistically, this was found to be driven by increased oxidative stress and Arginase 1 activity. Moreover, we used Swedish and Danish nationwide registry-based cohorts and a clinical case-control study to translate our experimental findings into a clinically relevant human context.</p><p dir="ltr">Finally, in Paper III, we once again used our optimized model of maternal diabetes to study the effects of maternal diabetes on offspring metabolic function, with a particular focus on offspring fatty liver disease.

Once again, we found a sex-dimorphic offspring phenotype, with females being more prone to develop liver-specific metabolic disease, both on chow diet and after a diet challenge with a high-fat diet or a western diet.</p><p dir="ltr">Taken all together, our work highlights that whereas improved glycemic levels in maternal diabetes can protect the oocyte transcriptome from alterations, the uterine environment and placenta is still impaired.

Moreover, we found that this gestational impairment is directly connected with an elevated sex-specific cardiometabolic disease susceptibility in offspring exposed to maternal diabetes, highlighting how offspring born to women with diabetes are an important risk group for cardiometabolic disease in early adulthood even when maternal glycemic conditions are improved.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. Appropriate glycemic management protects the germline but not the uterine environment in hyperglycemia<b>. </b><b>Allan Zhao</b>, Hong Jiang, Arturo Reyes Palomares, Alice Larsson, Wenteng He, Jacob Grünler, Xiaowei Zheng, Kenny A Rodriguez Wallberg, Sergiu-Bogdan Catrina & Qiaolin Deng.

EMBO Rep. 2024 Jul;11(28):e2401772. <a href="doi.org/10.1038/s44319-024-00097-7" target="_blank" rel="noreferrer">doi.org/10.1038/s44319-024-00097-7</a></p><p dir="ltr">II. Maternal diabetes programs sexually dimorphic early-onset cardiovascular dysfunction in metabolically healthy offspring.<b> </b><b>Allan Zhao</b>, Yuxia Wei, Eftychia Kontidou, Ali Mahdi, Paulo R Jannig, Sara Torstensson, Hong Jiang, Alice Larsson, Aida Collado, Rawan Humoud, Jacob Grünler, David Ersgård, Buket Öztürk Esen, Xiaowei Zheng, Haojiang Lu, Eva Lindgren, Sanjiv Risal, Jian Zhao, Elisabet Stener-Victorin, Henrik Toft Sørensen, Lars Pedersen, John Pernow, Zhichao Zhou, Sofia Carlsson, Sergiu-Bogdan Catrina & Qiaolin Deng.

Cell Rep Med. 2025 Nov 18;6(11):102454. <a href="doi.org/10.1016/j.xcrm.2025.102454" target="_blank" rel="noreferrer">doi.org/10.1016/j.xcrm.2025.102454</a></p><p dir="ltr">III. Female-specific vulnerability to hepatic disease programmed by maternal diabetes<b>. </b><b>Allan Zhao</b>, Paulo R Jannig, Christine Kallenberg, Xuelei Wang, Bufan Jin, Lena König, Yuxia Wei, Fahim Ebrahimi, Denise Parreira, Hong Jiang, Annika Blaufuss, Valentina Clio ZIngerle, Sara Torstensson, Haojiang Lu, Elisabet Stener-Victorin, Jonas F. Ludvigsson, Sofia Carlsson & Qiaolin Deng.

[Manuscript]</p>