Understanding the Long-Lasting Effects of Fetal Nutrient Restriction versus Exposure to an Obesogenic Diet on Islet-Cell Mass and Function

Abstract

Early life represents a window of phenotypic plasticity. Thus, exposure of the developing fetus to a compromised nutritional environment can have long term consequences for their health. Indeed, undernutrition or maternal intake of an obesogenic diet during pregnancy leads to a heightened risk of type 2 diabetes (T2D) and obesity in her offspring in adult life. Given that abnormalities in beta-cell function are crucial in delineating the risk of T2D, studies have investigated the impact of these exposures on islet morphology and beta-cell function in the offspring in a bid to understand why they are more at risk of T2D. Interestingly, despite the contrasting maternal metabolic phenotype and, therefore, intrauterine environment associated with undernutrition versus high-fat feeding, there are a number of similarities in the genes/biological pathways that are disrupted in offspring islets leading to changes in function. Looking to the future, it will be important to define the exact mechanisms involved in mediating changes in the gene expression landscape in islet cells to determine whether the road to T2D development is the same or different in those exposed to different ends of the nutritional spectrum.

Towards a better understanding of diabetes mellitus using organoid models

“…As a consequence, many organoids still represent a developmental stage rather than a mature organ 10 . As there is genetic evidence that perturbed development of the pancreas can predispose to diabetes mellitus 11 and numerous studies have shown that the environment of the fetus during pregnancy programmes adult metabolic activity 12 , organoids mimicking pancreas development are useful to study these mechanisms. Here we focus on the pancreas, a central organ in diabetes mellitus, and briefly introduce its development.…”

Overnutrition in the early postnatal period influences lifetime metabolic risk: Evidence for impact on pancreatic β‐cell mass and function

“…Data also implicate impaired mitochondrial metabolism, oxidative stress, mammalian target of rapamycin signaling, epigenetic deoxyribonucleic acid modifications, and microRNAs in the impaired b-cell adaptability after gestational nutrition restriction. 79 Taken together, the combination of prenatal undernutrition with postnatal overnutrition and catch-up growth is detrimental for rodent metabolic risk, as it is for human.…”

“…The impact of restricted fetal growth on β‐cell growth and development has been studied in animal models, such as maternal protein deficiency and uterine artery ligation 79 . Offspring with gestational undernutrition are more consistently observed to have increased risk for IGT and type 2 diabetes than offspring exposed to gestational overnutrition 79 .…”

“…78 Like humans, rodent prenatal undernutrition combined with postnatal overnutrition worsens metabolic dysfunction later in life The impact of restricted fetal growth on b-cell growth and development has been studied in animal models, such as maternal protein deficiency and uterine artery ligation. 79 Offspring with gestational undernutrition are more consistently observed to have increased risk for IGT and type 2 diabetes than offspring exposed to gestational overnutrition. 79 b-Cell mass is reported to be lower after fetal undernutrition, even into adult life.…”

Islet Biology and Metabolism

“…In a detailed review, O'Hara et al discussed our current understanding of fetal exposure to either maternal caloric excess or nutrient restriction. Significantly, they discussed the effects of fetal malnutrition with respect to multiple outcomes, from mitochondrial metabolism to islet morphology and beta-cell function and the consequences for Type 2 Diabetes development [10].…”