4. Various Early-Life Stressors: One Ultimate Programming Inducer—Perinatal Hyperglycemia
As abundantly illustrated in animal models, early-life stressors such as maternal undernutrition, overnutrition, hypercholesterolemia, corticosteroid therapy, uteroplacental insufficiency, or hypoxia program metabolic adaptations that initially favour survival but are ultimately detrimental to adult health. Interestingly, there exists in fact one crucial commonality between these models with quite different etiologies: in most of the cases, the altered maternal/fetal metabolism appears to be associated with a diabetogenic effect in the adult offspring either male or female, resulting in a permanent deficiency of the endocrine pancreatic function (F1). In females, the combination of a latent diabetogenic tendency (low insulin response) and the metabolic stress of pregnancy promotes gestational diabetes. F1 gestational diabetes per se is an inducing factor for impaired glucose tolerance and gestational diabetes again in the next female generation (F2). 
Finally, the relevant message is that programming of the endocrine pancreas ultimately originates from hyperglycemia experienced during the fetal and/or early postnatal life, whatever the etiology of maternal hyperglycemia, primary (in F0 diabetic mothers) or secondary (in F1 diabetic mothers issued from F0 mothers exposed to undernutrition, UPI, or high glucocorticoid) (Figure 2).