Early-Life Origins of Type 2 Diabetes: Fetal Programming of the Beta-Cell Mass
Figure 2
Mechanisms for the installation and intergenerational transmission of programmed beta cell mass (BCM) disruption in response to compromised intrauterine environment. The initial insults in F0 mother (mF0) impact the developing BCM of the fetuses (fF1). Diverse initial insults (IUED, IUCR, IUPR, UPI, IUEO), alone or in combination, give rise to the same programmed BCM outcome. Altered BCM phenotype in F1 females does not allow normal BCM adaptation during pregnancy and IGT/diabetes ensues (gestational diabetes). Gestational diabetes in the F1 pregnant mother (mF1) acting as an ultimate insult impacts the developing BCM of the F2 fetuses (fF2). Altered BCM phenotype in F2 females does not allow normal BCM adaptation during pregnancy and IGT/diabetes ensues (gestational diabetes). Gestational diabetes in the F2 pregnant mother (mF2) acting as an ultimate insult impacts the developing BCM of the F3 fetuses (fF3), therefore perpetuating similar BCM programming across generations. There are at least two potential scenarii for the transmission of BCM programming to subsequent generations: (1) the insult as seen in the F1 mother (IGT/diabetes insult during pregnancy) directly impairs BCM development, but BCM malprogramming is not necessarily irreversible. However, as the environmental insult (gestational diabetes) persists across generations, it recreates the same gestational phenotype in each subsequent generation (panel 1 in Figure 2); (2) the insult as seen in the F1 mother permanently affects BCM and results in the perpetuation of BCM malprogramming in the subsequent generations, in the absence of a further gestational insult (panel 2 in Figure 2). M: mother; f: fetus; F1: first-generation animals procreated by parent (F0) females submitted to experimentally disturbed metabolism during their pregnancy; F2: second-generation animals procreated by F1 females exposed to intrauterine-disturbed metabolism; IUED: in utero exposed to maternal diabetes; IUCR: in utero exposed to maternal calorie restriction; IUPR: in utero exposed to maternal protein restriction; UPI: uteroplacental insufficiency; IUEO: in utero exposed to maternal overnutrition or obesity.
