Gestational Programming of β-Cell Mass and Pancreatic Function in the Next Generation
Pp. 58-83 (26)
David J. Hill
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.
β-cell mass, Epigenetics, Fetal programming, Gestational diabetes,
Intra-uterine growth restriction, MTOR, Pregnancy, Type 2 diabetes.
Lawson Health Research Institute, St. Joseph’s Health Care, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada.