Early-life origins of type 2 diabetes: fetal programming of the beta-cell mass

Abstract

A substantial body of evidence suggests that an abnormal intrauterine milieu elicited by maternal metabolic disturbances as diverse as undernutrition, placental insufficiency, diabetes or obesity, may program susceptibility in the fetus to later develop chronic degenerative diseases, such as obesity, hypertension, cardiovascular diseases and diabetes. This paper examines the developmental programming of glucose intolerance/diabetes by disturbed intrauterine metabolic condition experimentally obtained in various rodent models of maternal protein restriction, caloric restriction, overnutrition or diabetes, with a focus on the alteration of the developing beta-cell mass. In most of the cases, whatever the type of initial maternal metabolic stress, the beta-cell adaptive growth which normally occurs during gestation, does not take place in the pregnant offspring and this results in the development of gestational diabetes. Therefore gestational diabetes turns to be the ultimate insult targeting the offspring beta-cell mass and propagates diabetes risk to the next generation again. The aetiology and the transmission of spontaneous diabetes as encountered in the GK/Par rat model of type 2 diabetes, are discussed in such a perspective. This review also discusses the non-genomic mechanisms involved in the installation of the programmed effect as well as in its intergenerational transmission.

Figure 1

From the nondiabetic Wistar rat to the spontaneously diabetic GK (Goto-Kakizaki) rat. The inbred GK rat line (Wistar strain) was produced by Goto et al. at Tohoku University, Sendaï, Japan, by selective breeding of normal Wistar rats over many generations using glucose tolerance value (and not basal glucose value only) as a discriminant phenotype [23]. Only W rats selected at the upper limit of normal distribution for glucose tolerance were used. The diabetic state (basal hyperglycemia) was reported to become stable after the 30 generations of selective crosses in the original Japanese colony. Here is illustrated the distribution of the sum of blood glucose values (∑blood  glucose ) during standardised oral glucose tolerance tests (OGTTs) performed in original parent Wistar rats, in rats from generations F1 to F35 in the original Japanese colony and in rats from generations F35 to F120 bred under our conditions in Paris from 1989 until now (subline GK/Par). In the inbred GK/Par rat line, all rats are nonoverweight, nonketotic, and display moderate fasting hyperglycemia with strong postprandial glucose intolerance. No attenuation, nor aggravation, of the diabetic phenotype overtime (more than 20 years and 80 generations) was registered in the GK/Par line.

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.

Figure 3

Mechanisms for the installation and intergenerational transmission of programmed beta-cell mass (BCM) disruption in the GK/Par rat model of type 2 diabetes. Maternal IGT/diabetes during gestation induces BCM programming in the first (F1) and the subsequent rat generations. Metabolic modifications in the pups during the in utero and suckling periods are followed by the onset of pathological conditions in adulthood (glucose intolerance and type 2 diabetes) and the transmission of programmed endocrine/metabolic capacities to the next generation. W: Wistar strain.