{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n INS‐IGF2 is a complex, imprinted locus that encompasses elements of both the insulin (INS) and insulin‐like growth factor 2 (IGF2) genes, and it functions at the crossroads of metabolic regulation, fetal growth, β‐cell biology, autoimmunity, and neoplasia. Epigenetic modifications at the INS‐IGF2 region are highly sensitive to early environmental influences—such as prenatal nutritional imbalance, maternal smoking, and low socioeconomic status—which can lead to altered DNA methylation profiles and may contribute to later metabolic and developmental outcomes, including changes in growth and type 2 diabetes risk."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Genetic variants and imprinting effects within this region—notably polymorphisms in the 5′ segment and VNTR elements—have been implicated in determining fetal size and modulating susceptibility to diabetes by influencing INS‐IGF2 expression in a parent‐of‐origin–dependent manner."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": " In pancreatic islets, aberrant regulation of INS‐IGF2—including the generation of read‐through transcripts that encode chimeric proteins incorporating the insulin B‐chain and IGF2 sequences—has been observed. Such dysregulation is linked both to reduced β‐cell functionality and to the appearance of autoantibodies in type 1 diabetes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while in neoplastic contexts INS‐IGF2 transcript variants appear to promote cell proliferation and migration in insulinomas and non‐small‐cell lung cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Furthermore, the INS‐IGF2 locus plays a role in reproductive physiology, with associations noted for menstrual cycle length and placental IGF2 content"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and altered methylation within sperm and cord blood further implicates this region in developmental programming."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Early gene-mapping studies have defined the close head-to-tail organization of the TH, INS, and IGF2 genes, providing the structural basis for these complex regulatory and functional interactions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", while additional genome-wide association data further support a contribution of INS‐IGF2 to type 2 diabetes risk."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Collectively, these findings underscore that INS‐IGF2 is not only a key mediator of endocrine and growth-related signals through its finely tuned epigenetic and genetic regulation, but it also represents a nodal point where environmental, developmental, and disease-related processes converge."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elmar W Tobi, L H Lumey, Rudolf P Talens, et al. 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