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L De Miguel-santos, UCM, DEPARTAMENTO DE BIOQUÍMICA Y BIOLOGÍA MOLECULAR II, FACULTAD DE FARMACIA, MADRID, Spain
E FernÁndez-millÁn, ISCIII, CIBER DE DIABETES Y ENFERMEDADES METABÓLICAS ASOCIADAS (CIBERDEM), MADRID, Spain
M MartÍn, CSIC, DEPARTAMENTO DE METABOLISMO Y NUTRICIÓN, INSTITUTO DEL FRÍO, MADRID, Spain
F EscrivÁ, UCM, DEPARTAMENTO DE BIOQUÍMICA Y BIOLOGÍA MOLECULAR II, FACULTAD DE FARMACIA, MADRID, Spain
C Álvarez, UCM, DEPARTAMENTO DE BIOQUÍMICA Y BIOLOGÍA MOLECULAR II, FACULTAD DE FARMACIA, MADRID, Spain

Correspondence: Carmen Álvarez, Email: calvarez{at}farm.ucm.es

Abstract

Replication, neogenesis and apoptosis play a main role in neonatal endocrine pancreas remodelling. Insulin-like growth factors (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 remodelling 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-1R signalling 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.