Maternal malnutrition alters pancreatic islet antioxidant defense and mitochondrial function predisposing the offspring to metabolic disorders

Epidemiological and experimental studies related that maternal malnutrition alters the fetal development predisposing the offspring to glucose intolerance at adult age. The mechanisms underlying this association remain elusive. This study was designed to understand the involvement of enzymatic antioxidant defense and mitochondrial function in the development of islet dysfunction in progeny of malnourished dams. In a first set of experiments, we have found that protein restriction limited to the gestation reduced the enzymatic antioxidant activity in islets isolated from neonates. At 3 months, male offspring of dams fed a low protein diet during early life, gestation or gestation and lactation, presented a higher superoxide-inactivating potential and a lower hydrogen-peroxide inactivating capacity. As a consequence, higher hydrogen peroxide production occurred in -cells of such progeny which downregulated insulin gene expression through, at least in part, an upregulation of the proapoptotic transcription factor c-Myc. A second aspect of the study aimed to determine the programming of mitochondrial function in pancreatic islets of offspring of dams exposed to protein (LP) or calorie restriction (GFR) or to a high fat diet (HF) during gestation. Both consequences for adult female and male progeny were investigated. We showed that each inadequate maternal diet led to similar functional consequences on islets through an absence of normal ATP production and insulin release in response to glucose stimulation. At a molecular level, the programming targeted specific pathway depending of the sex of the progeny and the type of prenatal diet. In conclusion, modification of enzymatic antioxidant status and mitochondrial dysfunction in islets of offspring of malnourished dams provide new insights to define cellular and molecular mechanisms responsible for intrauterine programming of endocrine pancreas.