Review
Modeling intrauterine growth retardation in rodents: Impact on pancreas development and glucose homeostasis

https://doi.org/10.1016/j.mce.2009.02.019Get rights and content

Abstract

Fetal adverse environment, such as insufficient maternal nutrition, placental insufficiency and stress, alters organ development and leads to poor fetal growth, also called intrauterine growth retardation (IUGR). IUGR is associated with an increased risk of perinatal mortality and morbidity as well as late-onset metabolic diseases, such as obesity, diabetes and hypertension in adulthood. In the rodent model, IUGR can be induced by fetal caloric restriction, fetal protein restriction, by exposure to high levels of glucocorticoids or by restricted placental blood supply. Such experimental IUGR models show a decreased beta cell mass and lower pancreatic insulin content. Recent research has provided an insight into the mechanisms responsible for the loss of beta cells. Here we review models that give further details about the molecular determinants of fetal and postnatal pancreatic islet development that are required to understand the consequences of fetal insults.

Introduction

Newborns with intrauterine growth retardation (IUGR), defined as a birth weight below the 10th percentile of birth weight for gestational age reference curve, carry a six to 10 times higher perinatal mortality compared to newborns with a normal birth weight (de Onis, 2000). IUGR, also referred to as fetal growth restriction, remains a major determinant for morbidity and disability throughout infancy and childhood and has a long-term impact on health outcomes in adult life. For example, low birth weight is associated with an increased risk of metabolic diseases in adults, such as diabetes, obesity and hypertension (Barker, 1990). The World Health Organization (WHO) estimates the worldwide annual incidence for IUGR at 30 millions newborns. Maternal malnutrition is the leading cause of IUGR; other main factors include stress and smoking during pregnancy. In a recent policy paper (http://www.who.int/nutrition/topics/lbw_strategy_background.pdf), the WHO has reiterated the importance of the problem and has proposed a global strategy for improving birth weight and maternal nutrition.

Section snippets

Pancreatic developmental program

Insulin and insulin-like growth factors are the major drive of fetal growth. Not surprisingly, perturbation of pancreas development with decreased insulin secretion leads to IUGR. Lack of fetal insulin secretion reduces the birth weight by 20–33% in mice and humans (Jonsson et al., 1994, Duvillie et al., 1997, Hattersley and Tooke, 1999, Schwitzgebel et al., 2003).

The pancreas arises from a multipotent endodermal cell population that will give rise to ductal, exocrine and endocrine cells (

Caloric restriction model

As discussed above, metabolic insults during fetal life lead to IUGR and reduced beta cell mass. Several animal models of IUGR have been developed to study the underlying molecular mechanisms. When feeding of pregnant rats is restricted by 50% in the last week before birth, IUGR develops. The offspring show a decreased beta cell mass at birth (Fig. 2). At 21 days of age, beta cell mass is still reduced by 40% (Garofano et al., 1997). The effect is even more profound, when caloric restriction is

IUGR by glucocorticoid exposure

In addition to malnutrition, glucocorticoids can lead to IUGR. This can occur by pharmacological exposure to glucocorticoids or inhibition of the placental 11-beta-hydroxysteroid dehydrogenase type 2, the enzyme protecting the fetus from maternal glucocorticoids (Lindsay et al., 1996). Glucocorticoids are commonly used to accelerate lung maturation in pregnant mothers at risk for premature labor. Such treatments, when administered on long-term have been reported to induce IUGR (Reinisch et al.,

Protein restriction model

In developing countries maternal nutritional protein deficiency represents the leading cause of IUGR. In rats, selective protein restriction (40–50% of normal), while maintaining caloric intake constant during pregnancy leads to IUGR and reduction in beta cell mass and size of islets (Dahri et al., 1991). The alpha cell as well as the delta cell mass remains unchanged in IUGR animals compared to controls (Petrik et al., 1999). When the pancreas is examined at e15 and e21, the beta cell mass is

Ischemic model/uterine artery ligation

In industrialized countries, utero-placental deficiency is the most common cause of impaired fetal growth, resulting in IUGR, particularly in women who smoke during pregnancy. A model of restricted blood flow to the fetus has been developed that consists of the ligation of both uterine arteries in rats at embryonic days 18–19 (Ogata et al., 1986, Simmons et al., 1992). This manipulation results in lower birth weight, as compared to sham-operated animals (Simmons et al., 2001). Although the

Relevance of rodent models of IUGR to human disease

Many differences exist between humans and rodents, in terms of duration of gestation, size of the litter, beta cell function and organization. Epidemiologically it has been demonstrated repetitively in humans, that small birth weight and size is associated with increased rates of type 2 diabetes, obesity, coronary heart disease and stroke in adult life (Barker and Osmond, 1986, Osmond et al., 1993). This indicates that permanent modifications arise prenatally or in the early postnatal period

Regulation of the beta cell mass

An observation common to all the rodent models presented above is the decrease in beta cell mass, suggesting that the underlying mechanism may converge on this parameter. Beta cell mass is tightly regulated by multiple factors, both during prenatal development of the pancreas and postnatal life during which beta cells have to adapt to changing needs of the body (Fig. 2).

The largest expansion of the beta cell mass has been shown to take place in the second half of prenatal development, from

Conclusions

Regulation of beta cell mass is a process that in utero depends on a precisely timed cascade of transcription factors, which initiates and promotes pancreas development starting from a multipotent endodermal cell population. Many intrinsic and extrinsic growth factors contribute to physiological pancreas development. Lack of adequate nutrition, quantitative as well as qualitative alterations, leads to IUGR associated with a reduced beta cell mass. Beta cell mass reduction can either be present

References (67)

  • B. Blondeau et al.

    Age-dependent inability of the endocrine pancreas to adapt to pregnancy: a long-term consequence of perinatal malnutrition in the rat

    Endocrinology

    (1999)
  • F.H. Bloomfield et al.

    Brief undernutrition in late-gestation sheep programs the hypothalamic-pituitary-adrenal axis in adult offspring

    Endocrinology

    (2003)
  • T. Bock et al.

    Increased islet volume but unchanged islet number in ob/ob mice

    Diabetes

    (2003)
  • C. Bonal et al.

    Experimental models of beta-cell regeneration

    Biochem. Soc. Trans.

    (2008)
  • B. Breant et al.

    Nutrition, glucocorticoids and pancreas development

    Horm. Res.

    (2006)
  • A. Chamson-Reig et al.

    Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific

    J. Endocrinol.

    (2006)
  • S. Dahri et al.

    Islet function in offspring of mothers on low-protein diet during gestation

    Diabetes

    (1991)
  • M. de Onis

    Measuring nutritional status in relation to mortality

    Bull. World Health Org.

    (2000)
  • A. de Vries et al.

    Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function

    J. Clin. Invest.

    (2007)
  • J.C. Devedjian et al.

    Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes

    J. Clin. Invest.

    (2000)
  • M.Y. Donath et al.

    Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes

    Diabetes

    (1999)
  • Y. Dor et al.

    Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation

    Nature

    (2004)
  • O. Dumortier et al.

    Different mechanisms operating during different critical time-windows reduce rat fetal beta cell mass due to a maternal low-protein or low-energy diet

    Diabetologia

    (2007)
  • B. Duvillie et al.

    Phenotypic alterations in insulin-deficient mutant mice

    Proc. Natl. Acad. Sci. U.S.A.

    (1997)
  • Y. Fujitani et al.

    Targeted deletion of a cis-regulatory region reveals differential gene dosage requirements for Pdx1 in foregut organ differentiation and pancreas formation

    Genes Dev.

    (2006)
  • A. Garofano et al.

    In utero undernutrition impairs rat beta-cell development

    Diabetologia

    (1997)
  • A. Garofano et al.

    Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat

    Diabetologia

    (1998)
  • A. Garofano et al.

    Effect of ageing on beta-cell mass and function in rats malnourished during the perinatal period

    Diabetologia

    (1999)
  • M. George et al.

    Beta cell expression of IGF-I leads to recovery from type 1 diabetes

    J. Clin. Invest.

    (2002)
  • S. Georgia et al.

    p27 Regulates the transition of beta-cells from quiescence to proliferation

    Diabetes

    (2006)
  • E. Gesina et al.

    Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

    Diabetologia

    (2006)
  • E. Gesina et al.

    Dissecting the role of glucocorticoids on pancreas development

    Diabetes

    (2004)
  • P.D. Gluckman et al.

    Effect of in utero and early-life conditions on adult health and disease

    N. Engl. J. Med.

    (2008)
  • Cited by (53)

    • The adaptation of maternal energy metabolism to lactation and its underlying mechanisms

      2022, Molecular and Cellular Endocrinology
      Citation Excerpt :

      It is noteworthy that pregnant rats subjected to a protein-restricted diet also show the abolishment of the 1st phase of insulin secretion and altered calcium handling (de Siqueira et al., 2018). Excessive corticosterone levels found in food-restricted pregnant rats can account for this modulation (Schwitzgebel et al., 2009). Additional studies from our laboratory also provided new insights into the mechanisms underlying the control of the maternal pancreatic β-cell mass after delivery.

    • The effects of early- or mid-gestation nutrient restriction on bovine fetal pancreatic development

      2020, Domestic Animal Endocrinology
      Citation Excerpt :

      Fetuses of dams on the nutrient-restricted diet at any point in gestation observed decreased beta cell number and increased number of apoptotic cells, and particularly in animals that experience nutrient restriction closer to harvest. In nutrient-restricted rats, the offspring exhibited reduced beta cell mass at birth and by 21 d of age [25], a finding that occurred as well in offspring of protein-restricted rats [26,27]. Conversely, in overfeeding models of maternal nutrition in sheep, fetal beta cell mass growth is accelerated [17] or beta cell number is reduced [20].

    • Gestational glucocorticoid exposure disrupts glucose homeostasis that is accompanied by increased endoglin and DPP-4 activity instead of GSK-3 in rats

      2018, Environmental Toxicology and Pharmacology
      Citation Excerpt :

      Decreased body weight and food intake shown in this study are consistent with previous study that reported that gestational GC exposure led to weight loss (Gomes et al., 2014) and reduced food intake in animal studies (Holness and Sugden, 2001). In addition, gestational GC-induced adverse birth outcome in the present study is in consonance with previous findings in experimental animals (Schwitzgebel et al., 2009). Adverse prenatal environment such as exposure to excess GC have been reported to lead to metabolic imprinting including intrauterine growth restriction (IUGR) characterized by low birth weight and negative impact on the placenta that is needed to sustain foetal growth which are predictive of increased development of CMD such as IR, type 2 diabetes, obesity and hypertension in later life of offsprings (Seckl, 2004; Cunningham et al., 2010).

    • The hypothalamic transcriptional response to stress is severely impaired in offspring exposed to adverse nutrition during gestation

      2017, Neuroscience
      Citation Excerpt :

      Abnormalities of gestational growth can result from several different causes. However, intrauterine growth restriction, resulting in offspring born small for gestational age, is most frequently linked with problems of placental blood flow impacting fetal nutrient transfer, which can be modeled in rodents via a maternal low-protein diet, caloric restriction or uterine artery ligation (Schwitzgebel et al., 2009). In contrast, excess gestational growth, resulting in offspring born large for gestational age, is strongly associated with excess maternal weight gain and maternal overnutrition, which we model in mice with a maternal high-fat diet.

    • Skeletal muscle Sirt3 expression and mitochondrial respiration are regulated by a prenatal low-protein diet

      2015, Journal of Nutritional Biochemistry
      Citation Excerpt :

      Intrauterine growth retardation (IUGR) is linked to the development of type 2 diabetes mellitus (T2DM) [1–5].

    • Early Origins of Health and Disease

      2015, Glucose Intake and Utilization in Pre-Diabetes and Diabetes: Implications for Cardiovascular Disease
    View all citing articles on Scopus
    View full text