2. Compromised Intrauterine Environment and Risk for Diabetes in Later Life
Thanks to abundant studies mostly in rodents in which the foetal environment can be manipulated, a substantial body of data now addresses the mechanisms involved in the developmental programming of glucose intolerance and T2D.
IUED Models
In rat, maternal diabetes may be induced experimentally by streptozotocin (STZ) injection that selectively destroys beta-cells. Mild or severe diabetes ensue depending on the dose used. At birth, the progeny of mild diabetic mothers had normal weight or slight macrosomia and an enhanced percentage of pancreatic endocrine tissue due to hyperplasia and hypertrophy of the islet cells [24, 25], leading to a higher beta-cell mass that was hyper-vascularized [26]. The pancreatic insulin content and insulin secretion were raised in these fetuses [27]. On the other hand, fetuses from severe diabetic dams were small at birth and had decreased pancreatic weight [28]. Their beta-cells were almost degranulated, leading to low pancreatic insulin content and low plasma insulin [27]. Similar endocrine pancreas/beta-cell alterations with low beta-cell mass have been reported in fetuses from spontaneous diabetic BB rats [29] or spontaneous diabetic GK rats [30, 31]. The long-term consequences have been evaluated in the progeny of these models. Impaired glucose tolerance was observed in the offspring of mild STZ diabetic rats due to lower insulin secretion in response to glucose, while insulin resistance was reported in the offspring of the severe STZ diabetic mothers [32–34]. Glucose tolerance was also impaired in offspring of normal mothers receiving glucose infusion during late gestation, and it was associated with decreased glucose-induced insulin secretion [24, 35–37].
The greatest difficulty in most animal models of diabetic pregnancy has been the attainment of a stable degree of mild hyperglycemia during gestation. Though useful, most techniques used to achieve models of diabetes in pregnancy have some drawbacks. Maternal glucose infusions limited to the last trimester of pregnancy result in hyperglycemia and hyperinsulinemia and do not mimic the relative insulin deficiency of gestational diabetes [38]. The multiple lipid and protein abnormalities associated with diabetes may be as important in the induction of fetal abnormalities as hyperglycemia, but they are not replicated by the maternal glucose infusion model. A concern of studies using STZ during pregnancy is the possibility that the toxin might cross the placenta and be directly harmful to the fetal pancreas and other fetal tissues, and thus make any analysis of the long-term effects of hyperglycemia in utero difficult [39]. The problem may be circumvented by giving STZ to female neonates who will later become pregnant: this will result in moderate gestational hyperglycemia [40]. Finally it must be recognized that none of the previously mentioned models will serve directly as a model of human gestational diabetes.
An ideal animal model to test the isolated impact of diabetic pregnancy would enter the pregnancy in a euglycemic state, become exposed to hyperglycaemic during whole pregnancy, and return postpartum to normoglycemic environment. Such a model also would allow study of the long-term effects of diabetes independent of any genetic influence. It was recently proposed that the pregnant GK rat being transferred normal Wistar (W) rat embryo represents a more relevant paradigm in such a perspective [41]. Using the GK/Par rat (Figure 1) we have transferred W rat oocytes to diabetic GK/Par females, and at their birth the W neonates were suckled by nondiabetic W foster mothers. Under these unique conditions, we have found that maternal diabetes negatively imprints the growth of a genetically normal (Wistar) beta-cell mass in a way as the insult is still present later at adult age as a decreased beta-cell population [42, 43].Not only maternal diabetes but also intrauterine undernutrition induced by several means such as protein (IUPR) or calorie (IUCR) restriction, or alteration in the availability of the nutrients by uterine/placental insufficiency (UPI) induced by uterine artery ligation, alter early islet development and provoke lasting consequences in rodents. 
IUCR Models
Global restrictions (to 40–50% of normal intake) (IUCR) in the last week of rat pregnancy results in low birth weight offspring with decreased beta-cell mass. Although these animals can regain their body and pancreatic weights upon normal postnatal feeding, they still demonstrate a reduced beta-cell mass and insulin content in adulthood [44, 45]. Extending this level of nutrient restriction during suckling results in a permanent reduction of beta-cell mass [46, 47] and subsequent age-dependent loss of glucose tolerance in the offspring [48]. Underfeeding the rat mothers during the first two weeks of gestation exerts no adverse effect upon insulin secretion and insulin action in the adult male offspring [49]. 
IUPR Models
The maternal protein restriction (5–8% as compared to 20% in normal diet) (IUPR) model has been one of the most extensively studied models. The low-protein-fed mothers give birth to growth-restricted offspring [50–54], and when suckled by their mothers maintained on the same low-protein fed, they remain permanently growth restricted, despite being weaned on a normal diet [53]. Reduced placental weight and endocrine and metabolic abnormalities are also observed [50, 55, 56]. Despite young offspring of low-protein-fed dams demonstrating improved glucose tolerance [56, 57], the male offspring undergo an age-dependent loss in glucose tolerance, such that by 17 months of age they develop T2D and insulin resistance [58]. Female offspring only develop hyperinsulinemia and impaired glucose tolerance at a much later age (21 months) [54]. Studies in this model have also demonstrated reductions in beta-cell mass [51], skeletal muscle mass [53], central adipose deposit weights [57, 59], and insulin signalling defects in muscle, adipocytes, and liver [59–61]. This IUPR model has also been associated with the development of hypertension with the kidney and the rennin-angiotensin system as playing a role [62]. 
UPI Models
Fetal growth retardation may also result from experimental uteroplacental insufficiency (UPI). Fetal UPI rats have decreased levels of glucose, insulin, IGF1, amino acids, and oxygen [63–65]. UPI offspring develop diabetes in later life [66, 67] with a phenotype that is similar to that observed in T2D humans with alterations in insulin secretion and action and a failure of beta-cell function and growth [68, 69]. 
IUEO Models
There are several reports on the consequences of a high-fat diet (during gestation only or both gestation and lactation) on the adult progeny. High-fat diet consumption by female rats malprograms the male offspring for glucose intolerance and increased body weight in adulthood [70]. Some of the observed consequences include reduced whole-body insulin sensitivity, impaired or normal insulin secretion and changes in the structure of pancreas [71–74], defective mesenteric artery endothelial function [75], hypertension [76, 77], alterations in renal functions [78], increased body adiposity [72, 76], deranged blood lipid profile [71, 76, 78], hyperleptinemia [72], and proatherogenic lesions [79]. There are not many reports on fetal islet adaptations due to a high-fat dietary modification in the dam. Cerf et al. [80] demonstrated that feeding rat female with a high-fat diet throughout gestation resulted in significant decreases in beta-cell volume and number resulting in hyperglycemia in 1-day-old newborn rat pups without changes in serum insulin concentrations. However, the report of fetal hyperinsulinemia in the high-fat term rat fetus [70] is not consistent with this finding.
Maternal obesity in mice, in the absence of diabetes, can also impair glucose tolerance in genetically normal offspring. This was shown using mothers carrying the Agouti (Ay) mutation on a C57BL/6 background. On this background, the Ay mutation produces marked obesity without diabetes. At adult age while maintained on normal diet, genetically normal, adult female offspring of Ay-positive mothers exhibited reduced glucose-induced insulin secretion in vivo [81].
Also male mice whose mothers consumed a high-fat diet were heavier, glucose intolerant, and insulin resistant and produced second-generation offspring who were insulin resistant, although not obese [82]. Whether this is a consequence of paternal in utero exposure or their adult sequelae of obesity and diabetes is unclear. It was recently reported that chronic high-fat diet consumption in father rats induced increased body weight, adiposity, impaired glucose tolerance, and insulin sensitivity in their offspring [83]. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time and normal adiposity. Among the differentially expressed islet genes, hypomethylation of the Il13ra2 gene was demonstrated. This is a proof of concept that paternal high-fat-diet exposure programs beta-cell dysfunction in rat F1 female offspring. This is the first report in mammals of nongenetic, intergenerational transmission of metabolic sequelae of a high-fat diet from father to offspring [83].
Among the many types of maternal metabolic stress used to produce IUGR, hypercholesterolemia combined to high fat diet was recently added since feeding LDL receptor null (LDLR−/−) mice with a high-fat resulted in litters with significant growth retardation. The LDLR−/− high-fat diet offspring developed significantly larger atherosclerotic lesions by 90 days compared with chow diet offspring [84]. Importantly, maternal hypoaminoacidemia proved to be an important antecedent in this hypercholesterolemic IUGR mouse [84] as in a protein-deficient IUGR mouse model [84] and an IUED rat model [85]. It may be an important link in the mechanisms that contribute to adult-onset glucose intolerance, obesity, and atherosclerosis. In this study beta-cell mass was not investigated.
To sum up, it turns to be manifest that, despite differences in the type, timing, and duration of intrauterine insult, most animal models of IUED, IUCR, IUPR, or IUEO have outcomes of impaired glucose tolerance or T2D (Figure 2).