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Two-sample Mendelian randomisation (2SMR) in Europeans was performed for triangulation. Exposures were eight type 2 diabetes-related pathways (\n                      <jats:italic>n<\/jats:italic>\n                      =1,812,017), eight beta cell function indices (\n                      <jats:italic>n<\/jats:italic>\n                      =26,356) and two insulin sensitivity indices (\n                      <jats:italic>n<\/jats:italic>\n                      =53,657). Outcomes were maternal and fetal genetically determined birthweight (\n                      <jats:italic>n<\/jats:italic>\n                      =406,063). Mediation analysis was used to assess the mediation effects of maternal glucose levels and BMI on maternal genetic effects and of cord blood C-peptide on fetal genetic effects. Co-localisation analyses were performed to test for shared causal variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Fetal type 2 diabetes polygenic risk score (PRS) and pPRSs for lipodystrophy-related insulin resistance and impaired fasting glucose (IFG)-related insulin deficiency were associated with lower birthweight and SSF, while maternal type 2 diabetes PRS and pPRSs for IFG-related insulin deficiency and obesity-related insulin resistance were associated with higher offspring birthweight, SSF and LGA. These associations were consistent across five ethnic groups. Maternal post-load hyperglycaemia mediated 44.2% and 34.2% of the effects of type 2 diabetes PRS and IFG pPRS, respectively, while maternal BMI mediated 43.4% of the effect of Obesity pPRS. 2SMR found consistent results in Europeans and further revealed that fetal insulin sensitivity index and corrected insulin response were associated with higher birthweight. Some loci with shared causal variants acted through multiple pathways, including\n                      <jats:italic>CDKAL1<\/jats:italic>\n                      ,\n                      <jats:italic>TCF7L2<\/jats:italic>\n                      ,\n                      <jats:italic>ADCY5<\/jats:italic>\n                      and\n                      <jats:italic>MACF1<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Reduced fetal growth may be driven by lipodystrophy-related insulin resistance and IFG-related insulin deficiency pathways. Targeting pregnant women with high type 2 diabetes PRS\/pPRS and prescribing interventions to reduce their post-load hyperglycaemia and BMI may help reduce offspring risk of LGA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06669-7","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T20:45:57Z","timestamp":1770151557000},"page":"1935-1950","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Maternal and fetal genetic predispositions to insulin deficiency and resistance affect fetal growth through distinct pathways"],"prefix":"10.1007","volume":"69","author":[{"given":"Gechang","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia H. 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We are also grateful to all the study participants for their contribution. Special thanks are extended to all medical and nursing staff at all participating centres for their dedication and professionalism. We thank all team members for their kind assistance, and their efforts on the recruitment of participants and data collection. We acknowledge dbGaP for making the genotype data from the HAPO Study available for analysis.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Genotype and clinical data from HAPO centres other than Hong Kong were obtained from the database of Genotypes and Phenotypes (dbGaP;\n                      \n                      ) with accession number \u2018phs000096.v4.p1\u2019. The GWAS summary statistics can be downloaded from\n                      \n                      (type 2 diabetes),\n                      \n                      (maternal and fetal genetically determined birthweight),\n                      \n                      (insulin secretion) and\n                      \n                      (insulin sensitivity).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The codes for all the analysis in this study are stored in GitHub\n                      \n                      The following software and packages were used for data analysis:R packages: coloc:\n                      \n                      ; meta:\n                      \n                      ; metapower:\n                      \n                      ; LDlinkR:\n                      \n                      ; TwoSampleMR:\n                      \n                      ; MATLAB toolbox: Mediation:","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability"}},{"value":"This work was funded by the RGC Area of Excellence Scheme (AoE\/M-401\/24-R), the RGC Research Impact Fund (R4012\u201318), and the University Grants Committee Research Grants Matching Scheme. RCWM acknowledges support from the International Joint Supervision of PhD Students Scheme from the Office of Academic Links of the Chinese University of Hong Kong. The follow-up of the HAPO Study at the Hong Kong field centre was supported by the General Research Fund of the Research Grants Council of the Hong Kong SAR, China (CUHK 473408, 471713, 14118718, 14102719). The HAPO Study was funded by the National Institute of Child Health and Human Development (grant no. R01-HD34242) and the National Institute of Diabetes and Digestive and Kidney Diseases (grant no. R01-HD34243). HAPO genetics data was generated with the support of National Human Genome Research (grant no. HG-004415). RMF is supported by a Wellcome Senior Research Fellowship (WT220390). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. This research was funded, in part, by the Wellcome Trust (grant no. WT220390). The funding sources do not have any role in the design, interpretation of the study, or the decision to publish the results.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"RCWM is a member of the editorial board of\n                      Diabetologia\n                      . The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"The study was conceived by GY, CHTT, RAO and RCWM. CHTT, CKPL, JCNC, WHT, WL and RCWM were responsible for study infrastructure and logistics. Funding was acquired by WHT, WL Jnr and RCWM. CHTT, WHT and RCWM were responsible for data collection and curation. GY, CHTT, MS, AH, CH, YD, MNW, CKPL, CCW, WHT, RMF, RAO and RCWM performed data analysis and interpretation. The manuscript was drafted by GY, CHTT, AEH, RMF, RAO and RCWM; GY, CHTT, AEH, MS, CH, YD, MNW, CKPL, CCW, JCNC, WHT, WL Jnr, RMF, RAO and RCWM contributed to the writing of the manuscript and critical revisions. All authors approved the final version of the article to be published. RCWM is the guarantor of this work and takes responsibility for the integrity of the data and the accuracy of the data analysis.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}