Fetal programming and parent-of-origin effects of type 2 diabetes and insulin secretion

Abstract Type 2 diabetes mellitus (T2DM) is a heterogeneous and a complex disease defined by hyperglycemia. The
pancreas and its islets are central for glucose homeostasis and healthy adipose tissue. In turn, lipid levels in the blood
are crucial for glucose level stability. Both genetic and environmental factors and their interaction play a pivotal role in
the risk and development of the disease. In this thesis we aim to better understand the effect of genetic and
environmental factors by investigating parental effects manifesting from early life until adulthood.
In papers I and II we examined gene expression alterations and associated epigenetic changes due to early pregnancy
anemia and gestational diabetes (GDM). Moreover, we investigated associations between these changes and neonatal
anthropometry. We identified several differentially expressed genes between early pregnancy anemia, GDM and
controls. Most of these genes were accompanied by epigenetic changes that correlated with their expression patterns.
Interestingly, we identified several differentially expressed genes associated with neonatal anthropometry indicating
their possible role in fetal programming and risk of T2DM in later life due to maternal exposure to early pregnancy
anemia and GDM.
In paper III we investigated whether genetic variants which were previously reported to be associated with lipid traits
will exert different effects on obesity and blood lipid traits based on their parental origin. We examined These variants
in two European family cohorts, where parental origin of each variant was inferred and parental-specific association
with obesity and blood lipid traits was analyzed. Our results corroborated previous reports and indicated that specific
genetic variants show parent-of-origin specific effects. Moreover, our results indicate possible sex-specific parental
effects on some blood lipid traits.
In paper IV we questioned whether such parental specific effects observed in paper III also manifested in early life. As
a result, we explored parent-of-origin effects on cardiometabolic and anthropometric traits in a birth cohort which was
followed up from delivery until 18 years. Our results indicate that the parental specific effects of cardiometabolic and
anthropometric traits and associated genetic variants manifested in early life. Interestingly, however, not all parental
effects were found to be fixed, and they seemed to transition over time specifically during puberty.
In paper V we have examined the expression of imprinted genes to better understand their role in insulin secretion,
beta-cell development, and function. First, we scrutinized gene expression data from adult pancreas, adult pancreatic
islets, fetal pancreas, and single cell expression data. Next, we analyzed the association of these genes with glycemic
traits. We identified imprinted genes that were specifically expressed in fetal pancreas both on a tissue and single cell
level. Variants in two genes associated with indices of insulin secretion indicating their possible role in beta-cell
development. Additionally, we identified imprinted genes enriched in both fetal and adult pancreas and associated with
glucose and insulin traits in a parent-of-origin manner. This suggests the possible role of these genes in beta-cell
function.
In summary, in this thesis we investigate paternal and maternal effects as a function of fetal programming and parentof-
origin effects to better understand their influence on type 2 diabetes and insulin secretion.