ESPEYB21 12. Type 2 Diabetes, Metabolic Syndrome and Lipids Pregnancy and Youth Onset T2D (2 abstracts)
12.9. DNA methylation signatures of youth-onset type 2 diabetes and exposure to maternal diabetes
Salama OE , Hizon N , Del Vecchio M , Kolsun K , Fonseca MA , Lin DTS , Urtatiz O , MacIsaac JL , Kobor MS , Sellers EAC , Dolinsky VW , Dart AB , Jones MJ & Wicklow BA
Clin Epigenetics. 2024 May 13;16(1):65. doi:10.1186/s13148-024-01675-1.
Brief Summary: This cross-sectional analysis showed that DNA methylation (DNAm) patterns differ between youth-onset and adult-onset T2D. In utero exposure to maternal diabetes was linked to these distinct changes. These findings highlight unique molecular pathways disrupted by youth-onset T2D, and suggest potential intervention targets to prevent its health impacts.
Comment: Growing evidence suggests that T2D in children and adolescents is essentially different from that in adults. While adult-onset T2D is characterized by the gradual progression of insulin resistance and β-cell dysfunction, youth-onset T2D involves rapid deterioration in β-cell function and early onset of complications. An established risk factor for youth-onset T2D is exposure to diabetes during pregnancy. However, the mechanism linking in utero exposure to diabetes and risk of youth-onset T2D remains unclear. These authors hypothesized that DNA methylation may explain this difference.
DNA methylation is an epigenetic phenomenon, in which the C5 carbon of the cytosine residue attaches to a methyl group, predominantly at cytosine-phosphate-guanine (CpG) sites. This epigenetic alteration influences gene expression, and thereby, gene function. This study compared DNAm in youth-onset T2D (n=218) and adolescents with normoglycemia (n=77). They then investigated differences in youths exposed in utero to maternal diabetes (including gestational and pre-gestational diabetes) and youths who had a normoglycemic intrauterine environment.
This study identified 3,830 differentially methylated sites and 516 differentially methylated regions in peripheral blood with?> 1% difference in DNAm between youth with vs. without T2D, of which 36 sites and 17 DMRs displayed?more than 5% difference. Of these, 3 sites in PFKFB3 were also associated with exposure to intrauterine maternal diabetes. These sites showed decreased DNAm in youth of mothers with T2D which was even lower in youth who had T2D themselves. PFKFB3 protein, predominantly expressed in endothelial cells, plays an important role in glycolysis. It is suggested that in utero exposure to maternal diabetes could affect the expression of PFKFB3, either in β -cells themselves or in other tissues, which in turn affects responsiveness to glucose.
Finally, comparing data with epigenome-wide association data on adult-onset T2D revealed that the majority of youth-onset T2D sites was not associated with adult-onset T2D, obesity, or youth obesity. This further supports the concept that youth-onset T2D is distinct from adult-onset T2D.
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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