Developmental and environmental epigenetic programming of the endocrine pancreas: consequences for type 2 diabetes

Abstract

The development of the endocrine pancreas is controlled by a hierarchical network of transcriptional regulators. It is increasingly evident that this requires a tightly interconnected epigenetic "programme" to drive endocrine cell differentiation and maintain islet function. Epigenetic regulators such as DNA and histone-modifying enzymes are now known to contribute to determination of pancreatic cell lineage, maintenance of cellular differentiation states, and normal functioning of adult pancreatic endocrine cells. Persistent effects of an early suboptimal environment, known to increase risk of type 2 diabetes in later life, can alter the epigenetic control of transcriptional master regulators, such as Hnf4a and Pdx1. Recent genome-wide analyses also suggest that an altered epigenetic landscape is associated with the β cell failure observed in type 2 diabetes and aging. At the cellular level, epigenetic mechanisms may provide a mechanistic link between energy metabolism and stable patterns of gene expression. Key energy metabolites influence the activity of epigenetic regulators, which in turn alter transcription to maintain cellular homeostasis. The challenge is now to understand the detailed molecular mechanisms that underlie these diverse roles of epigenetics, and the extent to which they contribute to the pathogenesis of type 2 diabetes. In-depth understanding of the developmental and environmental epigenetic programming of the endocrine pancreas has the potential to lead to novel therapeutic approaches in diabetes.

Long-lived crowded-litter mice exhibit lasting effects on insulin sensitivity and energy homeostasis

“…Pancreatic islet mass is reduced and ␤-cell proliferation diminished in CL mice. Similarly, multiple animal models, including maternal protein restriction, caloric restriction, and intrauterine placental ligation models, have identified common metabolic phenotypes in offspring and have identified alterations in insulin sensitivity and the pancreatic ␤-cell (26,30,36,53,56,61). ␤-Cell mass and proliferation were also reduced in GHR-deficient mice (37), and the number of large islets was reduced in Ames dwarf mice (55).…”

Developmental programming of type 2 diabetes

“…Altered pancreatic beta cell function represents a central mechanism associated with developmental programming of T2DM [29,30]. Early life conditions including both under and overnutrition are associated with insulin resistance in key organs controlling glucose homeostasis, including liver, muscle and adipose tissue in adult life placing considerable pressure on the beta cell.…”

Maternal diet–induced microRNAs and mTOR underlie β cell dysfunction in offspring

“…To identify the effects of gain of mTORC1 function during the developmental period on the susceptibility to diabetes induced by maternal protein restriction, we transiently induced mTORC1 signaling from embryonic day 14.5 to birth identified common metabolic phenotypes in offspring and have identified the pancreatic β cell as particularly sensitive to nutrients very early in life (3,29,30). In these experiments, we used engineered animal models with spatial and temporal regulation capabilities to dissect the molecular mechanisms responsible for developmental programming by low protein.…”

“…Genetic studies have demonstrated that known variants account for less than 10% of the estimated overall genetic contribution to T2D predisposition, suggesting that additional unidentified factors contribute to susceptibility of this disease (1, 2). The fetal nutrient environment has been proposed as another component that might modify the risk for developing diabetes later in life (3). There is increasing evidence that alterations in fetal nutrients not only affect fetal/infant growth but also promote a "thrifty phenotype" that increases the subsequent risk of metabolic syndrome, obesity, and T2D (4).…”

“…There is increasing evidence that alterations in fetal nutrients not only affect fetal/infant growth but also promote a "thrifty phenotype" that increases the subsequent risk of metabolic syndrome, obesity, and T2D (4). Indeed, maternal malnutrition during pregnancy is known to predispose offspring to adult-onset metabolic disorders such as T2D (3). Such adverse outcomes point to the importance of optimal nutrition during pregnancy for maintaining the long-term function of key metabolic tissues, such as pancreatic β cells.…”