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1. Perinatal Risk Factors for Diabetes in Later Life
Type 2 diabetes mellitus (T2D) is a complex polygenic disease that often manifests years before eventual clinical diagnosis [1]. T2D develops as a result of a failure to adequately increase beta-cell function and mass to meet the demands of prevailing insulin resistance [2]. The contribution of beta-cell failure to the pathophysiology of T2D is supported by islet pathology that reveals a beta-cell deficit of approximately 50 and 65% in individuals with impaired fasting glucose and T2D, respectively [3]. Consistent with these observations, most genes linked to T2D by genome-wide association scans have been shown to influence some aspects of beta-cell biology, such as regulation of beta-cell secretory function and development and growth of beta-cell mass [4]. It has long been recognized that nutrient availability during fetal and early postnatal life is an important determinant of adult health [5].
There are strong arguments showing that T2D is more prevalent among subjects that were in utero exposed to maternal diabetes (IUED). The role of maternal inheritance in T2D has been reported in a majority of epidemiological studies [6, 7]. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes was compared in Pima nuclear families in which at least one sibling was born before and one after the mother was diagnosed with T2D. Offspring born after their mother displayed diabetes had a fourfold higher risk of diabetes and a higher body mass index (BMI) than their full siblings born before their mother developed diabetes [8]. These findings indicate that intrauterine exposure to a diabetic environment increases risk of obesity and T2D beyond that attributable to genetic factors, at least in Pima Indians. To circumvent the confounding effect of genes linked to early onset T2D and transmitted by the pregnant T2D mother, the effect of fetal exposure to T1D was evaluated in adult offspring lacking T1D immunological markers. A 33% prevalence of IGT was reported in offspring of T1D mothers compared with none in offspring of T1D fathers (control group) [9]. Altogether, these findings suggest that fetal exposure to maternal diabetes is indeed associated with abnormal glucose homeostasis in offspring and may participate in the excess of maternal transmission in T2D. In adult Pima Indians with normal glucose tolerance and who had been exposed to an intrauterine diabetic environment, acute insulin response to i.v. glucose was found reduced in those offspring whose mother was diabetic before pregnancy while it remained normal in those whose mother developed diabetes after pregnancy, [10]. Body fat and insulin sensitivity (euglycemic hyperinsulinemic clamp) were similar in the two groups of subjects [10]. In the same study, acute insulin response was found reduced in offspring of parents (mother or father) with early onset of T2D [10], suggesting that gene(s) linked to early-onset diabetes is(are) associated with reduced insulin secretory response to glucose [11]. Offspring of T1D mothers had reduced insulin secretion, more pronounced in IGT subjects, but similar fat mass and insulin action compared with offspring of T1D fathers [9]. Also in nondiabetic offspring of mothers with young-onset T2D (diagnosed under age 50), beta-cell function (early insulin release after oral glucose) was found decreased as compared to that of offspring of fathers with young-onset T2D [12]. Therefore, human studies suggest that insulin secretion defect participates in the abnormal glucose tolerance observed in adult offspring exposed to maternal diabetes during fetal life. Importantly, they showed that insulin secretion may be reduced even in normal glucose-tolerant offspring. Nevertheless, in children and adolescent offspring, insulin resistance involvement was suggested and may be related, at least in part, to their higher body weight.
Beside studies in IUED populations, prenatal nutrient insufficiency resulting in low birth weight is also associated with increased risk for development of obesity, cardiovascular disease, and T2D [13–15]. The association between low birth weight and development of T2D was first reported in classic studies by Hales et al. [15] that demonstrated a severalfold increase in the incidence of glucose intolerance and T2D in adult males that were born small compared with those who were born at a normal birth weight. These seminal observations since have been consistently reproduced by numerous investigators worldwide [16]. Although epidemiological evidence linking low birth weight with increased susceptibility to T2DM is strong [16], the molecular and physiological mechanisms underlying this association are still under investigation [17]. It has long been appreciated that low birth weight is associated with adult insulin resistance, which can contribute to the increased risk in development of T2D [18]. However, susceptibility to T2D in low-birth-weight individuals has also been hypothesized to be attributed to inadequate beta-cell mass formation [15]. Because it is not possible to measure beta-cell mass in vivo, this hypothesis cannot yet be tested directly in humans. However, evidence suggests that inadequate beta-cell formation in utero may underlie subsequent susceptibility for T2D. First, the fetal period is critical for endocrine pancreatic development in rodents and humans [19]. Second, clinical data show that children and adults with low birth weight demonstrate impaired beta-cell function compared with their normal birth-weight counterparts [20, 21] and human fetuses with severe growth retardation, have a reduction in pancreatic endocrine cell mass [22].
In this paper, we discuss the evidence for beta-cell dysfunction in IUED (in utero exposed to maternal diabetes), IUEO (in utero exposed to maternal overnutrition) and IUGR (in utero growth restriction) animal models, focusing on the strengths and limits of each, in order to define critical periods and types of alterations that can lead to impaired beta-cell function. We also discuss several potential mechanisms dissected in relevant animal models that begin to explain this outcome.

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