Evidence That Insulin is Imprinted in the Human Yolk Sac

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From: Diabetes(Vol. 50, Issue 1)
Publisher: American Diabetes Association
Document Type: Article
Length: 3,296 words

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Allelic variation in the size of the insulin (INS) variable number tandem repeat (VNTR) correlates with the expression of both INS in the pancreas and thymus and IGF2 (the gene downstream of INS) in the placenta. In addition, the shorter, class I alleles are associated with type 1 diabetes, whereas the longer, class III alleles are associated with type 2 diabetes, polycystic ovary syndrome (PCOS), and size at birth. Parent-of-origin effects have been reported for type 2 diabetes and PCOS, thus implicating a role for genomic imprinting in these phenotypes. In mice, Ins2 is imprinted and paternally expressed in the yolk sac. In humans, evidence for the imprinting of INS is circumstantial, with occasional monoallelic expression in the thymus. In the present study, we found evidence for the imprinted paternal expression of INS in the human yolk sac. Two other imprinted genes from the same cluster are also expressed monoallelically in the human yolk sac. IGF2 was expressed solely from the paternal allele, and H19 was expressed solely from the maternal allele. These data suggest not only further functional roles for the human yolk sac in early fetal growth, but also evidence for a potential causal link between the control of insulin expression during development and insulin/growth-related diseases in later life. Diabetes 50:199-203, 2001

Allelic variation at the insulin (INS) variable number tandem repeat (VNTR) is known to regulate the level of expression of both INS in the pancreas and thymus and IGF2 in the placenta (1-5). The shorter, class I alleles correlate with levels of gene expression that are higher for INS in the pancreas, lower for INS in the thymus, and higher for IGF2 in the placenta. Higher levels of INS expression associated with the longer, class III VNTR alleles in the thymus offer an explanation for the protective role of these alleles in type 1 diabetes susceptibility by inducing self-tolerance to preproinsulin peptides (1,2). The class I alleles are associated with type 1 diabetes, and the class III alleles are associated with type 2 diabetes, polycystic ovary syndrome (PCOS), and size at birth (5-10). In PCOS and type 2 diabetes, disease susceptibility is conferred in a parental sex-specific fashion (6,9), such that in nuclear families, the susceptible allele is transmitted preferentially from fathers. This suggests that the etiological effect is occurring when only the paternal allele is active, implicative of parental imprinting. Although the imprinting of IGF2 is well established (11), evidence for monoallelic expression of insulin comes only from mice, in which Ins2 (the mouse ortholog of INS) is imprinted in the yolk sac after 14.5 days (12,13). In mammals, the secondary yolk sac is regarded as being the primitive liver, involved in protein synthesis and nutrient transfer and acting as a stem-cell reservoir (14,15). The secondary yolk sac may also play a role as a primitive pancreas, because in the fourth week of development, the yolk sac forms the primitive gut, the endoderm of which gives rise to the epithelium and glands of the digestive...

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Gale Document Number: GALE|A70385299