Early undernutrition increases glycogen content and reduces the activated forms of GSK3, AMPK, p38 MAPK, and JNK in the cerebral cortex of suckling rats.

Exposure to maternal undernutrition during development increases the risk for neurological and cognitive defects. However, little is known about the underlying mechanisms involved. Peripheral responses to insulin are increased following food-restriction, thus the possibility arises that brain insulin actions are affected by undernutrition, causing damages to the higher cerebral functions. In this study, we examined the effects of early undernutriton on molecular targets of insulin actions such as glucose transporters, glycogen, glycogen synthase kinase-3 (GSK3) and mitogen-activated protein kinases, as well as proteins involved in apoptosis in the cortex from 10-day-old rats. We show that undernutrition results in an enhanced glycogen content which is confined to astrocytes, according to our histochemical approaches. Cortical phospho-GSK3 is also increased. In addition to glycogen synthesis, GSK3 regulates crucial cellular processes. Therefore, its elevated degree of phosphorylation may have an impact on these processes and, consequently, on the cortical development. Phospho-p38 and both total JNK and phospho-JNK, which regulate apoptosis, are reduced following undernutrition. However, cleaved caspase 3 is not altered, which suggests that this condition does not induce extensive modifications to the cortical apoptosis. Thus, our results indicate that undernutrition gives rise to molecular alterations that may have repercussions on cerebral cortex development and functions.

Undernutrition of the GK rat during gestation improves pancreatic IGF-2 and beta-cell mass in the fetuses.

The Goto-Kakizaki (GK) rat is a type 2 diabetes model with a defective beta-cell mass detectable in late fetal development. Diminished IGF-2 production seems to be involved in this effect. Herein, we analyzed the effect of maternal food-restriction on the beta-cell mass of GK fetuses and the involvement of the IGF system, highly responsive to nutritional status in this process. To this end, in undernourished GK fetuses (U-GK), we measured serum GH/IGF levels, beta-cell mass, replication and differentiation, and IGF-1/-2 protein content in liver and pancreas tissue. Pregnant GK females were food restricted (65% restriction) during the last week of gestation. Our results show that maternal malnutrition ameliorates beta-cell mass in U-GK fetuses and a specific pancreatic IGF-2 increase may be instrumental in this effect. Further studies are needed to determine whether maternal undernutrition is sufficient to delay or decrease the risk of the GK rat for developing diabetes.

Maternal undernutrition increases pancreatic IGF-2 and partially suppresses the physiological wave of {beta}-cell apoptosis during the neonatal period.

Replication, neogenesis, and apoptosis play a main role in neonatal endocrine pancreas remodeling. IGFs are major contributors to beta-cell growth and function and are highly sensitive to nutritional status. We previously showed that maternal malnutrition caused an increase in beta-cell mass in fetuses related to the stimulation of beta-cell proliferation due to increased pancreatic IGF-1. At 4 days of life, the beta-cell mass was decreased in undernourished neonates and persisted until adult age. To clarify whether undernutrition disrupts islet remodeling, we quantified beta-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 beta-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 beta-cell ontogeny. However, although malnutrition causes beta-cell deficiency in neonates, an active process of beta-cell neogenesis and a lower incidence of beta-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 beta-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.