Maternal nutrition, nutrient transfer & foetal pancreas development

It is widely accepted that maternal intrauterine environment is associated with foetal growth, development and adult outcomes. In recent past, epidemiological studies have shown that an association exists between impaired intrauterine growth and susceptibility to adult chronic diseases such as type 2 diabetes1. The impaired intrauterine growth retardation/ restriction (IUGR) and low birth weight may occur due to a disagreement in maternal ability to provide nutrients and oxygen to foetus. The foetus responds in predictive and adaptive manner (PAR) to an inadequate amount of nutrients (glucose, amino acids and oxygen) in order to maximize its chances of survival2. It is reported in human studies that reduced supply of oxygen and critical nutrients results in a neonate with low ponderal index and assymetrical IUGR aptly mimicked in a few animal models3. The immediate response to undernutrition is catabolic consumption of substrates to provide energy4. It has been proposed that IUGR and various foetal growth patterns arise due to early stimulus/ insult that occurs during critical period of development affecting development and organization of critical organs/ tissues5. IUGR rat foetuses demonstrated metabolic profile characteristic of IUGR human foetuses such as hypoglycaemia, hypoxia, acidosis, and reduced concentration of insulin and insulin-like growth factor-I (IGF-I)6. It has also been revealed that low birth weight resulting due to maternal undernutrition is associated with insulin resistance, impaired glucose tolerafnce, hyperlipidaemia and type 2 diabetes7. Thus, the proposition that the placenta may act as nutrient sensor with the mammalian target of rapamycin kinase (mTOR) having a major part in nutrient sensing pathway8, along with prolonged undernutrition may influence the foetus to change its metabolic rate, alter hormone production and tissue sensitivity to hormones, for example, decrease in foetal insulin and IGF-I910. During such conditions the blood flow is redistributed to protect key organs such as brain leading to impaired development of muscle, kidneys and endocrine pancreas11. The most extensively studied low-protein animal models of early growth restriction have been correlated to human populations with similar dietary intakes and subsequent outcomes. Studies have shown that animals with 50 per cent restriction of energy intake during last week of pregnancy led to microsomic pups, which had impaired beta cell development with reduced plasma glucose and insulin concentrations1213. It is demonstrated that neonates of protein restricted dams have impaired pancreatic development such as pancreatic islet vascularization, reduced islet size, reduced beta cell mass, and reduced insulin content14 due to reduced beta cell proliferation and increased apoptosis1315. It is also demonstrated that the transcription factor ‘pancreatic duodenal homeobox-1’ (Pdx-1) expression is reduced, which regulates array of genes that contribute to the development of pancreas. Thus disruption of Pdx-1 may lead to absence of insulin producing cells and arresting early pancreatic development1617. Additionally, IGF-II reduced expression was observed in foetal and neonatal islet cells of growth-restricted rats (bilateral uterine ligation model)18 of uteroplacental insufficiency. Such model demonstrated glucose intolerance and insulin resistance at an early age (1 wk) and mild fasting hyperglycaemia and hyperinsulinaemia by 7-10 wk of age, followed by reduction in beta cell mass preceded by impairment in the first phase insulin secretion in response to glucose stimulation19. It was further reported that in this model the arginine stimulated insulin release was similar to control rats, and the loss of glucose stimulated insulin response is caused by intrinsic defect in the β-cell induced by uteroplacental insufficiency. Progressive impairment of glucose tolerance thus led to overt diabetes by 6 months of age as beta cells failed to compensate for secretory defects and insulin resistance19. Although the Dutch Famine Study has been insightful20–22, studies relating maternal nutrition to the development of human pancreas and their potential impact in adult life are lacking. The study by Uday Kumar et al in this issue23 links together data correlating maternal nutrient status and the development of pancreas obtained from mid-gestational age. One of the advantages of the study is that it undertakes the analysis of second trimester human foetal pancreas for identifying morphometric changes to development of insulin producing cells. The limitation however, is the small number of samples assessed in this study and the lack of functional analyses to identify the role of maternal nutrient status on glucose-insulin metabolism. Studies carried out in animal models of intrauterine growth retardation and low-protein diet during gestation have confirmed that the second trimester is an important age for development of insulin producing cells and also for their biochemical maturation141824. The limitation of most human studies has been accessibility to second trimester human pancreas for ethical and other reasons. However, Uday Kumar and colleagues23 have been able to collect a small, yet significant, number of samples from second trimester human foetuses. Although the investigators do not find significant differences in the morphometry of foetal pancreas from different maternal nutrient groups, further studies related to understanding the function of insulin producing cells from such pancreatic islets need to be carried out. These studies would potentially help in understanding the differences, if any, between glucose-insulin metabolism and maternal nutrition in well characterized human pancreatic samples.