{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:06:05Z","timestamp":1784696765423,"version":"3.55.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The first 1000 days of life, spanning from conception to the end of the second postnatal year, represent a critical developmental window during which environmental and metabolic exposures exert long-lasting effects on offspring health. Among these exposures, maternal and early-life hyperglycemia have emerged as major determinants of metabolic programming and future cardiometabolic disease risk. Increasing evidence suggests that hyperglycemic exposure during this vulnerable period induces complex alterations in placental function, fetal endocrine adaptation, epigenetic regulation, and postnatal metabolic homeostasis, thereby predisposing offspring to obesity, insulin resistance, type 2 diabetes mellitus, and neurodevelopmental disturbances later in life. This review summarizes current evidence regarding the mechanistic pathways linking hyperglycemia during the first 1000 days to adverse metabolic outcomes. We discuss the role of maternal hyperglycemia in placental dysfunction, oxidative stress, inflammation, and altered nutrient transport, as well as its effects on fetal pancreatic development, adipogenesis, and insulin signaling. Particular emphasis is placed on emerging evidence implicating epigenetic modifications, mitochondrial dysfunction, microbiome alterations, and endocrine dysregulation in developmental programming. We further examine the impact of neonatal and early infant metabolic exposures on growth trajectories, adiposity, neurodevelopment, and long-term cardiometabolic health.<\/jats:p>\n                  <jats:p>Finally, we highlight current knowledge gaps and potential opportunities for early intervention, including optimized glycemic control during pregnancy, nutritional modulation, breastfeeding promotion, and precision prevention strategies targeting high-risk mother\u2013infant dyads. A deeper understanding of the biological mechanisms underlying hyperglycemia-induced metabolic programming may facilitate the development of preventive approaches aimed at reducing the intergenerational transmission of metabolic disease.<\/jats:p>","DOI":"10.3389\/fendo.2026.1899593","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:40:31Z","timestamp":1784695231000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hyperglycemia during the first 1000 days as a driver of metabolic programming"],"prefix":"10.3389","volume":"17","author":[{"given":"Marton","family":"Schandl","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical School, University of P\u00e9cs","place":["P\u00e9cs, Hungary"]},{"name":"Clinical Centre, University of P\u00e9cs","place":["P\u00e9cs, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tibor","family":"Ertl","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical School, University of P\u00e9cs","place":["P\u00e9cs, Hungary"]},{"name":"Clinical Centre, University of P\u00e9cs","place":["P\u00e9cs, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reka A.","family":"Vass","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical School, University of P\u00e9cs","place":["P\u00e9cs, Hungary"]},{"name":"Clinical Centre, University of P\u00e9cs","place":["P\u00e9cs, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2017-3716","article-title":"Advocacy for improving nutrition in the first 1000 days to support childhood development and adult health","volume":"141","author":"Schwarzenberg","year":"2018","journal-title":"Pediatrics"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1080\/07315724.2004.10719428","article-title":"The developmental origins of adult disease","volume":"23","author":"Barker","year":"2004","journal-title":"J Am Coll Nutr"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1203\/01.pdr.0000135998.08025.fb","article-title":"Developmental origins of disease paradigm: a mechanistic and evolutionary perspective","volume":"56","author":"Gluckman","year":"2004","journal-title":"Pediatr Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0707943","article-title":"Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045","volume":"157","author":"Saeedi","year":"2019","journal-title":"Diabetes Res Clin Pract"},{"key":"B5","volume-title":"Idf Diabetes Atlas","year":"2021"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1373\/clinchem.2019.303990","article-title":"Hyperglycemia and adverse pregnancy outcomes","volume":"358","author":"Metzger","year":"2008","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1113\/JP284139","article-title":"Obesity and gestational diabetes independently and collectively induce specific effects on placental structure, inflammation and endocrine function in a cohort of South African women","volume":"601","author":"Musa","year":"2023","journal-title":"J Physiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/s0143-4004(03)00183-8","article-title":"Altered placental oxidative stress status in gestational diabetes mellitus","volume":"25","author":"Coughlan","year":"2004","journal-title":"Placenta"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.29.12.1023","article-title":"Banting Lecture 1980. 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