Impact of fetal and neonatal environment on beta cell function and development of diabetes

Abstract

The global epidemic of diabetes is a serious threat against health and healthcare expenses. Although genetics is important it does not explain the dramatic increase in incidence, which must involve environmental factors. Two decades ago the concept of the thrifty phenotype was introduced, stating that the intrauterine environment during pregnancy has an impact on the gene expression that may persist until adulthood and cause metabolic diseases like obesity and type 2 diabetes. As the pancreatic beta cells are crucial in the regulation of metabolism this article will describe the influence of normal pregnancy on the beta cells in both the mother and the fetus and how various conditions like diabetes, obesity, overnutrition and undernutrition during and after pregnancy may influence the ability of the offspring to adapt to changes in insulin demand later in life. The influence of environmental factors including nutrients and gut microbiota on appetite regulation, mitochondrial activity and the immune system that may affect beta cell growth and function directly and indirectly is discussed. The possible role of epigenetic changes in the transgenerational transmission of the adverse programming may be the most threatening aspect with regard to the global diabetes epidemics. Finally, some suggestions for intervention are presented.

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

“…In this regard, maternal food restriction to 50% of the daily intake of control rats decreases birth weight, and the pups show a 25% decrease in β-cell density, a 30% decrease in the absolute β-cell mass and around a 40% decrease in total insulin content relative to the controls (Garofano et al 1997). This phenotype persists into adulthood, and both males and females develop gradual glucose intolerance around 4 months of age, as well as insulin resistance and DM2 at 17 months of age, with a characteristic slower onset and distinct islet morphology in females (Shahkhalili et al 2010, Nielsen et al 2014. In addition, corticosterone levels are elevated by 30% in fetuses from food-restricted dams, while the fetal adrenal weight, the fetal pancreatic insulin content and the β-cell mass decreases.…”

“…Indeed, obese children with small-for-gestational-age birthweights have reduced insulin-secreting capacity (Nielsen et al 2014). The risk of giving birth to a 230:2 macrosomic neonate increases with the body mass index in women with normal glucose tolerance (Sewell et al 2006), and these children have an increased risk of developing DM2 (Nielsen et al 2014).…”

“…Indeed, obese children with small-for-gestational-age birthweights have reduced insulin-secreting capacity (Nielsen et al 2014). The risk of giving birth to a 230:2 macrosomic neonate increases with the body mass index in women with normal glucose tolerance (Sewell et al 2006), and these children have an increased risk of developing DM2 (Nielsen et al 2014). Animal studies confirm that maternal obesity may provoke nonalcoholic fatty pancreas disease in their offspring, which involves fat deposition and inflammation, resulting in pancreatic fibrosis (Cerf et al 2005).…”

Comments on gestational diabetes mellitus: from pathophysiology to clinical practice

“…A series of studies have shown the impact of a high-fat diet on the offspring's mRNA expression, protein concentrations of glucose transporter 2, glucokinase and Pdx-1. 16 Experimental data indicate that epigenetic mechanisms may account for the association between early life nutrition women who would go on to develop complications will be diagnosed as not having GDM. Even the adoption of an intermediate threshold will result in a lower but serious risk for over-and underdiagnosis.…”

Editorial

“…Again, other studies have focused on gestational diabetes mellitus and greater maternal pre-pregnancy body mass index (BMI), both alone or in combination interacting to result in fetal macrosomia [12]. More recent studies both in animals and humans show that maternal nutritional status affects pancreatic beta-cell size and function which causes early changes that predispose to altered glucose and fat metabolism in the next generation [13].…”