Maternal undernutrition increases pancreatic IGF-2 and partially suppresses the physiological wave of β-cell apoptosis during the neonatal period

Abstract

Replication, neogenesis, and apoptosis play a main role in neonatal endocrine pancreas remodeling. IGFs are major contributors to b-cell growth and function and are highly sensitive to nutritional status. We previously showed that maternal malnutrition caused an increase in b-cell mass in fetuses related to the stimulation of b-cell proliferation due to increased pancreatic IGF-1. At 4 days of life, the b-cell mass was decreased in undernourished neonates and persisted until adult age. To clarify whether undernutrition disrupts islet remodeling, we quantified b-cell mass, neogenesis, replication, and apoptosis on days 4, 14, and 23. To determine the impact of food restriction on IGF ontogeny and the consequences for b-cell growth, we measured IGF-1/-2 protein content in pancreas and liver and pancreatic IGF-1 receptor (IGF-1R)-signaling pathway at the same days. Our results indicate that undernutrition alters the timing and intensity of neonatal b-cell ontogeny. However, although malnutrition causes b-cell deficiency in neonates, an active process of b-cell neogenesis and a lower incidence of b-cell apoptosis maintain the regenerative capacity of the endocrine pancreas. Interestingly, our data provide evidence that local production of IGFs seems to be instrumental in these processes. In particular, increased pancreatic IGF-2 in undernourished rats may contribute to the partial suppression of the developmental wave of b-cell apoptosis probably through the inhibition of glycogen synthase kinase-3. In addition, decreased pancreatic levels of IGFBP-1/-2/-3 in undernourished neonates could enhance IGF availability for interacting with IGF-1R/IR.

Role of endogenous IL-6 in the neonatal expansion and functionality of Wistar rat pancreatic alpha cells

“…Decreased beta cell mass correlates with hypoinsulinaemia and hypoglycaemia due to increased insulin sensitivity, as we previously demonstrated in our model [38,39]. In addition, we have observed reduced circulating glucagon levels in suckling pups [22], suggesting that islet adaptations to chronic malnutrition also involve changes in alpha cells. These data prompted us to consider our rat model suitable for further study of the role of IL-6 in pancreatic alpha cell maturation and its contribution to nutritional islet adaptation.…”

“…We and others have previously reported in rodent models that maternal food restriction significantly affects beta cell mass in the offspring neonates [22,37]. Decreased beta cell mass correlates with hypoinsulinaemia and hypoglycaemia due to increased insulin sensitivity, as we previously demonstrated in our model [38,39].…”

“…3f). IUGR disturbs alpha cell growth and function Maternal food restriction jeopardises the development of the endocrine pancreas, and circulating glucagon has been found to be decreased in undernourished (UN) neonates [22]. We therefore questioned whether UN animals showed altered alpha cell expansion capacity.…”

“…Western blot Protein samples from islets were prepared as previously described [22], separated by SDS-PAGE, transferred to polyvinylidene difluoride (PVDF) Immobilon membranes and incubated overnight with the corresponding primary antibodies (phosphorylated signal transducer and activator of transcription 3 [STAT3] [Tyr 705]/STAT3 from Cell Signaling Technology, Barcelona, Spain; and IL-6R from Santa Cruz Biotechnology). SaOS-2 and HeLa cell extracts, known to express Il6r, were used as positive controls.…”

Effects of genetics and in utero diet on murine pancreatic development

“…In contrast, another study demonstrated that maternal under-nutrition increased pancreatic Igf2 expression with no alteration in INS cell mass (de Miguel-Santos, et al 2010). …”