Gestational Programming of β-Cell Mass and Pancreatic Function in the Next Generation

The gestational environment can have profound effects on the future health of the offspring, including a greater risk of type 2 diabetes and of cardiovascular diseases. Whilst the function of numerous tissues that can impact on future metabolism are altered by an adverse fetal environment, including the hypothalamic control of appetite and the release of glucocorticoids, hepatic function, and the insulin sensitive tissues such as skeletal muscle and adipose, some of the most definitive data concerns changes in the phenotype and function of the pancreatic β-cells. A number of animal models of intrauterine growth restriction (IUGR) have been utilized to study the longterm effects on the offspring, such as a reduced maternal calorie intake, a reduced protein content of the diet, uterine vessel occlusion, and nicotine administration. Changes to the pancreatic β-cells are remarkably similar and include a reduced tissue mass, lower rate of proliferation, increased developmental apoptosis, less plasticity following damage postnatally, higher sensitivity to cytotoxic cytokines, and reduced glucose-stimulated insulin release. These changes persist into adulthood and result in impaired glucose tolerance, Similar changes are also seen in offspring from pregnancies complicated by maternal diabetes. The mechanisms responsible for the altered β-cells function include changes to the mTOR signaling pathway, epigenetic changes altering the expression of key genes involved with β-cell growth and insulin synthesis, and changes in the rate of telomere shortening resulting in premature cellular aging. These pathways may also be influenced by environmental toxins during pregnancy. Nutritional intervention by micronutrient supplementation of the mother, or treatment of the newborn with peptide hormones trophic for the β-cells can reverse the pancreatic phenotype and reduce the risk of adult metabolic disease.

Keywords: β-cell mass, Epigenetics, Fetal programming, Gestational diabetes, Intra-uterine growth restriction, MTOR, Pregnancy, Type 2 diabetes.