British Medical Bulletin

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British Medical Bulletin 60:123-142 (2001)
© 2001 Oxford University Press

Intra-uterine programming of the endocrine pancreas

Abigail L Fowden and David J Hill

Department of Physiology, University of Cambridge, Cambridge, UK
Lawson Health Research Institute, University of Western Ontario, Ontario, Canada

	Abstract

Top Footnotes Abstract Introduction Normal development of the... Factors affecting development of... Long-term consequences Mechanisms of programming... References

 
In altricial species such as the rat and mouse, there is good evidence for the intra-uterine programming of the endocrine pancreas. Changes in the intra-uterine nutritional environment cause alterations in the structure and function of the islets which have life-long effects and predispose the animal to glucose intolerance and diabetes in later life. In rodents, the islets develop relatively late in gestation and undergo substantial remodelling in the period immediately after birth. Hence, the critical window for islet development in these animals is short and readily accessible for experimental manipulation. The short life-span of these species also means that elderly animals can be studied within a reasonable time frame. In precocious species, such as guinea pigs and farm animals, intra-uterine programming of the endocrine pancreas is less well established. In part, this may be due to difficulties in identifying the critical window for development as islet formation and remodelling begin at an earlier stage of gestation and continue for longer after birth. The long life-span of these animals and the relative insulin resistance of adult ruminants compared to other species also make it difficult to establish whether fetal changes in islet development have long-term consequences. In the human, the main phase of islet development occurs during the second trimester, although remodelling occurs throughout late gestation and early childhood. There is, therefore, a relatively long period in which early changes in islet development could be reversed or ameliorated in the human. Although the human epidemiological observations suggest that the fetal origin of adult glucose intolerance is due primarily to changes in insulin sensitivity rather than to defective insulin secretion, subtle changes in islet morphology and function sustained in utero may well contribute to the increased susceptibility to type 2 diabetes observed in adults who were growth-retarded in utero.

	Introduction

Top Footnotes Abstract Introduction Normal development of the... Factors affecting development of... Long-term consequences Mechanisms of programming... References

 
Human epidemiological studies have shown that impaired growth in utero is associated with an increased incidence of glucose intolerance and type 2 diabetes in later life and linked this to poor nutrition during pregnancy and/or early infancy. In part, the changes in glucose tolerance observed in the elderly human populations may be due to alterations in pancreatic endocrine function sustained in utero. The evidence for the intra-uterine programming of islet function is discussed in this chapter.

	Normal development of the endocrine pancreas

Top Footnotes Abstract Introduction Normal development of the... Factors affecting development of... Long-term consequences Mechanisms of programming... References

 
Morphogenesis

Morphogenesis of the endocrine pancreas appears to follow a similar sequence in all mammals although the precise stage of gestation at which the specific events occur may vary amongst species¹. The pancreas develops from two diverticula of the primitive gut which fuse during early embryonic growth to form both the exocrine and endocrine pancreas. The endocrine tissue is derived from epithelial duct cells by rotation of the plane of mitotic division. (Fig. 1). The single immature endocrine cells derived from the duct epithelia multiply and form small knots of cells which bud out of the pancreatic ducts (Fig. 1). In humans, this process of budding is observed as early as 10 weeks of gestation^2,3. The clusters of immature endocrine cells become vascularized by 16 weeks of gestation in humans and are then encapsulated by connective tissue and isolated from the ducts^2,3. At this stage of development, the endocrine cells are still relatively undifferentiated and the cytoplasmic granules co-localize several pancreatic hormones and neuropeptides⁴. During the second half of gestation, the developing islets become innervated and the individual cell types differentiate to contain only a single pancreatic hormone^5,6. The numbers and spatial arrangement of the 4 different endocrine cell types within the islets, therefore, change during the third trimester but, by term, some of the islets have the appearance and topography characteristic of mature adult islets of Langerhans³. In total, the islets account for about 4% of the total pancreas in the normal human infant at birth.

View larger version (42K): [in this window] [in a new window]   Fig. 1 Schematic diagram of the formation of endocrine cells in the fetal pancreas. Duct cells dividing parallel to the lumen undergo endocrine differentiation and bud off from the duct cell to form immature, undifferentiated endocrine cells (stippled granules) which proliferate and differentiate into mature endocrine cells (solid granules).

 
Further re-organization of the pancreatic endocrine tissue occurs after birth, with changes in islet size and topography in most species^1,3,5. The duration of this postnatal period of islet remodelling depends on species and varies from 4 weeks in the rat to 4 years or more in the human infant^3,5. In the rat, the main phase of remodelling occurs around weaning at 2–3 weeks of postnatal age and is associated with a wave of islet cell apoptosis⁷. The mass of endocrine tissue in the neonatal pancreas, therefore, depends on three processes: (i) neogenesis from the duct epithelia; (ii) proliferation of the cells committed to endocrine differentiation; and (iii) apoptosis of the endocrine cells to remodel the developing islets.

Functional development

The pancreatic hormones can be extracted from the fetal pancreas before the various cell types can be distinguished readily^1,8. For most of gestation, the glucagon containing cells predominate and are the first cell type to be identified clearly, mainly in the periphery of the pancreas during early embryonic development^3,8. In most species, -cells appear before ß-cells with - and PP cells becoming detectable later in gestation⁸. By birth, the ratio of - to ß-cells has decreased and closely resembles that seen in adults, at least in humans. The pancreatic content of insulin and glucagon increases with increasing gestational age in parallel with the increase in cell number in several species including the human^5,8,9.

The synthesis and release of the pancreatic hormones in the fetus appears to occur in a manner similar to that observed in the adult¹⁰. In the ß-cells, all the key elements involved in stimulus–secretion coupling in the adult have been identified in the fetus. Insulin secretion occurs by exocytosis of the granules into the intercellular space, where the insulin storage complex breaks down. Pulse chase and immunohistochemical analysis show that prohormones are formed and stored in the granules of the fetal islet cells¹¹. Conversion of pro-insulin to insulin appears to occur in the granules as very little pro-insulin is detected in the fetal circulation. Paracrine interactions between the different endocrine cells in the islet also occur in the fetus as selective ablation of the ß-cells leads to an increase in plasma glucagon in the sheep fetus^10,12.

Insulin and glucagon can be measured in fetal plasma shortly after they are detected in the pancreas (Table 1), while somatostatin and pancreatic polypeptide are present in fetal plasma by term¹⁰. The actual concentrations of the pancreatic hormones in the fetal circulation vary widely amongst species and also change with gestational age. For instance, in late gestation, fetal plasma insulin is 200 µU/ml in the rat but only 10 µU/ml in the pig and horse^10,13. In the majority of species, including the human, insulin and glucagon concentrations rise between mid and late gestation and then remain stable until near term.

View this table: [in this window] [in a new window]   Table 1 The gestational age at which insulin and glucagon are first detected in the fetal pancreas and plasma in different species

 
The fetal - and ß-cells are sensitive to secretogogues in utero¹⁰. Changes in fetal insulin and glucagon secretion have been observed in response to a range of stimuli including metabolites, neurotransmitters and hormones¹⁰. The fetal ß-cell responses to glucose and amino acids show developmental changes with increasing gestational age in both in vivo and in vitro studies^14–16. During late gestation, the fetal ß-cells respond readily to changes in the glucose and amino acid levels and are also affected by circulating catecholamine levels and adverse conditions such as hypoxia and anaesthesia. In contrast, fetal -cells appear to be relatively unresponsive to changes in the glucose level, unlike neonatal or adult -cells¹⁰. However, fetal -cells respond rapidly to changes in the level of amino acids and catecholamines which suggest that it is the glucose sensing mechanisms rather than the synthesis and release of glucagon that may be immature in fetal -cells. In addition, the autonomic nerves to the fetal pancreas are active by late gestation and involved in regulating islet cell responses to stressful stimuli.

Glucose has been shown to stimulate insulin secretion both in the fetus in utero and in in vitro experiments with cultured islet cells in several species^10,13,14,17. The initial in vitro studies also showed that the fetal ß-cell response to glucose was slow and of smaller magnitude than those seen in cultured new-born or adult islet cells^1,10,13. Since the fetal ß-cell responses to amino acids and other secretogogues were similar to those of adult cells in vitro, the poor response to glucose was attributed to immaturity of the glucose sensing mechanisms in the fetal ß-cells^1,13. However, ß-cell function may have been adversely affected in the in vitro studies by the isolation of the islet cells. In unstressed, chronically catheterised fetuses, the ß-cell response to exogenous glucose is relatively rapid with a significant rise in plasma insulin within 5-10 min of raising the fetal glucose concentration¹⁰. With prolonged glucose infusion, the fetal insulin levels continue to rise to a plateau value, but do not show the rapid early phase of the typical biphasic response observed postnatally^10,14. However, since fetal ß-cells would not normally experience sudden or large changes in the glucose level of the type observed during exogenous glucose administration, the apparent immaturity of glucose-stimulated insulin release in utero is not physiologically relevant. Indeed, fetal insulin levels are positively correlated with the glucose level over the range of values normally observed in utero in several species¹⁰. Fetal ß-cells, therefore, show appropriate responses to the changes in glucose levels that occur in utero and have a physiological role in regulating fetal metabolism.

The fetal - and ß-cells have important roles in fetal growth and development¹¹. Insulin secretion from the ß-cells is essential for glucose uptake by the insulin-sensitive tissues of the fetus. Ablation of the fetal ß-cells leads to hyperglycaemia, reduced glucose utilization and, ultimately, growth retardation of the fetus. The fetal ß-cells, therefore, act as sensors of nutrient sufficiency and, via insulin secretion, match the rates of glucose utilization and growth by the fetus to its rate of glucose supply. On the other hand, fetal -cells appears to act as sensors of nutrient insufficiency, particularly of oxygen. Glucagon raises fetal glucose levels and has effects on the fetal cardiovascular system at high concentrations. These changes may help maintain a glucose supply to essential fetal tissues, such as the brain during adverse intra-uterine conditions¹¹.

	Factors affecting development of the endocrine pancreas in utero

Top Footnotes Abstract Introduction Normal development of the... Factors affecting development of... Long-term consequences Mechanisms of programming... References

 
In the human infant, the percentage of islet tissue in the pancreas at birth is positively correlated to birth weight^1,11. In growth retarded and small-for-date infants, the percentage of islet tissue is reduced from 4% to only 2% of the total pancreas. Basal and glucose-stimulated levels of insulin are also low in these infants^5,11. These clinical observations suggest that adverse intra-uterine conditions which lower birth weight also impair development of the fetal endocrine pancreas. In experimental animals, islet development has been shown to be affected by various transcription factors and by the intra-uterine availability of specific metabolites, hormones and growth factors^5,13,17,18. These variables alter both the structural and functional development of the endocrine pancreas, although their specific effects depends on the severity, duration and gestational age at onset of the perturbation.

Transcription factors

The development of ductal epithelial cells into an endocrine lineage, and ultimately into ß-cells, involves a specific sequence of expression of transcription factors¹⁹. One of the most important identified so far is Pdx-1, also known as STF-1, IDX-1 or IPF-1²⁰. In animals with a targeted deletion of Pdx-1, pancreatic buds form but no further differentiation or morphogenesis occurs²¹. However, some ß-cells are found in the pancreatic rudiments, showing that Pdx-1 is not obligatory for ß-cell differentiation and insulin secretion. Expression of Pdx-1 in undifferentiated ductal epithelium is associated with the glucose transporter GLUT 2, which by day 15 of gestation in the fetal rat has been lost from acinar cells, but is retained by developing ß-cells. Pdx-1, therefore, appears to have a dual role, in the induction of an early endocrine cell lineage from ductal epithelial cells, and in the maturation of ß-cells and insulin gene expression. A single deletion of a nucleotide in the human Pdx-1 gene leads to complete pancreatic agenesis²². Thus, control of Pdx-1 expression may be a key step in pancreatic development. Pdx-1 expression is directed by at least two other nuclear transcription factors, hepatocyte nuclear factor 3ß (HNF-3ß) and BETA-2/NeuroD.

Neogenesis of ß-cells is also affected by members of the Pax gene family. Pax-4 and Pax-6 are expressed in the developing pancreas and deletion of Pax-4 in mouse has been shown to cause a complete loss of pancreatic ß-cells and -cells, but an increased number of -cells²³. Conversely, functional deletion of the Pax-6 gene in the mouse decreases the presence of all four endocrine cell types in the pancreas, with the presence of -cells being totally abolished²⁴. Pax-6 has been shown to trans-activate both the glucagon and insulin gene promoters. Mice lacking both Pax-4 and Pax-6 failed to develop any mature endocrine cells in the pancreas. Pax-4 and Pax-6, therefore, appear to be important at a later stage of development than Pdx-1, distinguishing the -cell lineage from the ß- and -cell lines.

Genetic lesions within transcription factors governing pancreatic development have been found to underlie some forms of diabetes. Maturity-onset diabetes of the young (MODY), a form of type-2 diabetes, is a monogenic disease with autosomal dominant inheritance, and is characterized by an early onset of failure of insulin secretion²⁵. The known genes that are involved in MODY are hepatocyte nuclear factor 4 (HNF-4) (MODY 1)²⁶, glucokinase (MODY 2)^27,28, HNF-1 (MODY 3)²⁹, and Pdx-1 (MODY 4)³⁰. MODY 4 has been observed in patients carrying a heterozygous mutation in Pdx-1. The resulting phenotype differed widely between individuals, some being normal others being glucose intolerant, suggesting that penetrance of this mutation was not complete. The expression of the HNF factors were first found in the liver, but a role in the pancreas now also seems likely, as, in MODY 3, there is an impaired insulin secretion³¹. A family of patients with MODY1 has been described with mutations in HNF-4 who developed diabetes requiring insulin therapy in 30% of cases²⁶. Such patients demonstrate primary defects in the mechanisms releasing insulin in the ß-cells^32,33.

Availability of nutrients

Development of fetal islet cells have been shown to be dependent on the availability of glucose and amino acids in both in vivo and in vitro studies^{5,10,13,14,15,34}. Cultured islet cells from fetal rats require both glucose and amino acids for normal development³⁵. At 17–18 days of gestation, amino acids appear to be more important than glucose whereas, by term, glucose has become the critical factor in islet development in vitro^1,5,13. Similarly, in mice, glucose availability to the islet cells has a more pronounced effect on their development postnatally than prenatally³⁶. This developmental shift in nutrient dependence is consistent with the changes in nutrition that occur at birth. Prenatally, amino acid levels are high and glucose levels are low, whereas postnatally glucose is more plentiful than amino acids.

In vivo, islet development is altered by both decreases and increases in nutrient availability. In rats, maternal metabolic perturbations induced by diabetes or reductions in dietary intake of protein or calories during pregnancy alter development of the ß-cells in the fetal islets^{5,13,18,37–39}. Feeding a low protein (LP) isocalorific diet (8% protein) to pregnant rats changes amino acid profiles but has little, if any, effect on glycaemia in the fetus and mother¹³. In late gestation, the fetal islets from LP rats were smaller and contained less ß-cells and insulin than those from control animals fed a normal diet (20% protein) during pregnancy^18,38. Protein deprivation during pregnancy, therefore, alters the balance between neogenesis, proliferation and apoptosis in the fetal islets⁴⁰. Proliferation of the existing islet cells was reduced while apoptosis was increased in the fetal islets of LP rats⁴⁰. The cell cycle of the fetal islet cells was also lengthened in these circumstances⁴⁰. The fetal islets from the LP animals were also poorly vascularized and released less insulin in response to secretogogues such as glucose and amino acids^38,41. The reductions in islet cell proliferation and amino acid stimulated insulin release were maintained when fetal islets from LP rats were cultured for 7 days^13,42. Protein deprivation in utero, therefore, induces permanent changes in the growth and function of the fetal islet cells.

Reduction in total calorific intake during pregnancy also affects development of the fetal endocrine pancreas but in a different manner to that seen with protein deprivation. Like protein deprivation, reducing calorific intake by 50% for the last 7 days of pregnancy in rats leads to decreases in ß-cell mass and insulin content of the fetal pancreas^13,42. However, this reduction in ß-cell mass appears to be due to reduced neogenesis and a smaller number of islets rather than to lower rates of ß-cell proliferation as occurs with protein deprivation⁴². In pregnant sheep, prolonged maternal hypoglycaemia induced by insulin infusion leads to a reduced fetal insulin level and a decrease in glucose-stimulated insulin release¹⁴. Restricting nutrient availability either in total or of glucose, in particular, therefore reduces fetal ß-cell mass and increases the - to ß-cell ratio in the fetal islets during development.

Raising fetal glucose levels by maternal diabetes induces changes in islet development which are determined by the severity of the diabetes (see also Van Assche et al, this issue). Moderate maternal diabetes in rats leads to an increase in the fetal pancreatic insulin content, enhanced insulin secretion in response to glucose and greater proliferation of the islet cells^13,35. Similar increases in insulin secretion are seen in sheep fetuses in which maternal glucose levels were raised periodically by pulsatile glucose infusion¹⁵. On the other hand, severe diabetes or maintained experimental maternal hyperglycaemia leads to a decrease in the insulin content and degranulation of the ß-cells in fetal sheep and rats^12,34,35. These fetuses also have low circulating insulin levels and a reduced ß-cell response to exogenous glucose. A reduced ß-cell mass and degranulation of the ß-cells has also been observed in an infant of a severely diabetic women¹. These observations suggest that severe, prolonged hyperglycaemia in utero has adverse effects on pancreatic endocrine development and leads to ß-cell exhaustion.

Glucose availability, therefore, appears to have an important role in islet development in vivo. However, since maternal amino acid levels are also altered by maternal diabetes, calorific restriction and experimental hypoglycaemia, some of the apparent effects of variations in glycaemia may be due, in part, to changes in amino acid profile. Certainly, for most of gestation, amino acids appear to be more important than glucose in stimulating ß-cell proliferation in vitro^13,42. In addition, replacement of a single amino acid, taurine, in the drinking water of pregnant rats fed 8% protein prevented the reduction in ß-cell mass and pancreatic insulin content in the fetuses in late gestation³⁷. Some of the changes in islet development may be due to the nutritionally-induced alterations in exposure to hormones and growth factors⁴³. For instance, maternal protein deprivation reduces placental 11ß hydroxysteroid dehydrogenase activity which, in turn, increases fetal exposure to maternal glucocorticoids⁴⁴.

Availability of hormones and growth factors

Pancreatic islet development has been shown to be influenced by a number of growth factors including the protein complex, ilotrophin, the fibroblast growth factor (FGF) family, platelet derived growth factor, transforming growth factor- (TGF-) and the insulin-like growth factors, IGF-I and IGF-II⁴⁵. Islet neogenesis associated protein (INGAP), part of the ilotrophin complex, is believed to initiate duct cell proliferation and endocrine cell differentiation. INGAP, TGF- and platelet derived growth factor have all been identified in the fetal pancreas, but little is known about their ontogeny or control during islet development^19,45. Much more is known about the IGFs and FGFs.

Exogenous FGF-1 was able to increase the insulin content of fetal rat 'islet-like structures'⁴⁶ which suggests that it may potentiate ß-cell generation. However, FGF-7 may be a more potent inducer of ß-cell neogenesis. Systemic injection of FGF-7 into adult rats for up to 2 weeks caused a rapid increase in DNA synthesis within the ductal epithelium which was seen within 24 h⁴⁷. Pancreatic duct hyperplasia followed, but not a progression to increased numbers of endocrine cells. When FGF-7 was expressed within the embryonic liver of transgenic mice, driven by an ApoE promoter, pancreatic duct hyperplasia was seen, with increased numbers of ductal cells containing immunoreactive insulin⁴⁸. The ability of circulating FGF-7 to promote ß-cell neogenesis in the embryo, but only cause ductal cell proliferation in the adult, suggests that additional growth factors are necessary to complete the neogenic process in utero. In neonatal rats, FGF-7 immunoreactivity is predominantly associated with stroma around the vascular endothelium of capillaries and ducts⁴⁹. This is consistent with its reported origins within mesenchymal tissues of other organs during embryogenesis, while target cells expressing the FGF-4 receptor are located within adjacent epithelia⁵⁰.

The fetal pancreas expresses IGF-I, IGF-II and IGF binding protein 3 during late gestation⁵¹. As in other fetal tissues, IGF-II is the predominant IGF in the pancreas and is localised to the islets and duct epithelial cells^45,52. Both IGF-I and IGF-II are mitogens in the fetal pancreas and lead to an increase in islet cell mass⁵¹. Transgenic IGF-II mice which over-express IGF-II in utero are larger at birth and show abnormalities in pancreatic endocrine development⁵³. The fetal islets are irregular in shape and 5 times greater in area than in controls. The islets of fetuses expressing the transgene also had a higher - to ß-cell ratio and altered topography of the endocrine cell types within the islet. In addition, the number of fetal islet cells proliferating increased from the normal value of 11% to 20% in those with high IGF-II levels. There was also decreased apoptosis in the fetal islets of the transgenic animals⁵³.

Neonatally, pancreatic IGF-II gene expression declines in parallel with the major wave of developmental apoptosis⁴⁰. When circulating IGF-II levels are maintained in mice after birth by transgenic expression of IGF-II by specific non-pancreatic tissues, the wave of apoptosis in the islets is prevented⁷. The islets from the neonates with raised IGF-II levels were larger and had a higher proliferation rate than the wild-type controls. IGF-II has also been shown to increase islet cell survival in neonatal rats exposed to cytokines which normally induce cell death⁴⁵. IGF-II, therefore, appears to be cytoprotective and prevents the developmental apoptosis normally associated with ß-cell turnover in neonatal life. Its actions appear to be both paracrine and endocrine and, by altering the balance between proliferation and apoptosis, it has a major influence on the ß-cell mass of the developing pancreas.

Expression of the IGFs in utero is regulated by a number of factors including nutrient and hormone concentrations^11,45. In vitro, release of IGF-I and IGF-II by cultured fetal rat islets is stimulated by glucose and amino acids⁵¹. In vivo, fetal undernutrition induced by maternal dietary restriction or placental insufficiency reduces expression of both IGF genes in a variety of fetal tissues^42–44. In rats fed a LP diet during pregnancy, gene expression for IGF-II but not IGF-I was reduced by 40% in the fetal pancreas during late gestation⁴⁰. In addition, increased fetal glucocorticoid exposure has been used to suppress IGF-II and IGF-I gene expression in a developmental and tissue specific manner, although little is known about the effects of natural or synthetic glucocorticoids on pancreatic IGF gene expression⁴³. Insulin itself is also believed to regulate fetal IGF production. In fetal sheep, insulin raises IGF-I levels while conversely IGF-I suppresses insulin concentrations⁴³. There may, therefore, be intra-islet feedback regulation of insulin and IGF-I secretion which maintains the circulating insulin levels while stimulating an increase in insulin synthesis and ß-cell mass during late gestation.

In many fetal tissues, glucocorticoids have an important role in regulating cell proliferation and differentiation, especially during the prepartum period when fetal tissues are maturing in preparation for extra-uterine life⁴³. In part, these maturational effects of the glucocorticoids are mediated through changes in IGF gene expression and/or thyroid hormone status. However, little is known about the effects of the glucocorticoids or thyroid hormones on the structural development of the fetal endocrine pancreas. Manipulation of the fetal hypothalamic-pituitary-adrenal or thyroid axes appears to have little effect on basal or glucose stimulated insulin levels in fetal sheep¹⁰. In contrast, removal of the pituitary hormones by fetal decapitation or hypophysectomy increases fetal insulin levels and enhances insulin secretion in response to glucose in fetal rabbits and pigs^1,10. A functional hypothalamic pituitary link is also essential for the proliferation of fetal ß-cells in the infant of the moderately diabetic women¹. However, changes in pancreatic innervation in the absence of cerebral tissue may also contribute to the abnormalities in pancreatic endocrine function observed after fetal decapitation and in human anencephalics.

	Long-term consequences

Top Footnotes Abstract Introduction Normal development of the... Factors affecting development of... Long-term consequences Mechanisms of programming... References

 
Intra-uterine changes in pancreatic endocrine development have long-term consequences for islet function and the regulation of glycaemia in the postnatal animal. The specific effects that abnormalities in fetal islet development have postnatally depend, in part, on the nutritional and hormonal environment experienced after birth. For instance, the poor vascularization of the fetal islets in LP rats is maintained at 3 months of postnatal age if protein restriction continues during lactation, but is ameliorated if the LP neonates are fostered at birth onto rats fed normally during pregnancy and lactation⁵⁴. On the other hand, the pancreatic insulin content is low at 3 months of postnatal age in animals, protein deprived in utero, irrespective of whether they were suckling by LP or normally fed rats during lactation^13,42. Abnormalities in islet development sustained in utero can also be unmasked by conditions, such as pregnancy, ageing and obesity, which increase the demand for insulin.

Juvenile animals

At 3 months of age, rats exposed solely to low protein in utero still have abnormalities in the structure and function of the endocrine pancreas. Although the vascularity of the islets appeared to be restored to normal, the islets were bigger and contained less insulin than controls^41,54. In vitro, the islets from the 3-month-old rats, protein deprived in utero, were less responsive to amino acids but responded normally to glucose^17,18,38,43. However, in vivo, these rats had lower insulin concentrations after an oral glucose load in the female, but not the male animals³⁸. The LP females also had higher basal glucagon concentrations at 3 months of age⁵⁵. These observations indicate that male but not female animals are able to recuperate from protein deprivation in utero when given a normal diet after birth. They also suggest that the prenatal programming of postnatal islet function may be sex linked and related to differences in exposure to sex steroids in utero.

When protein deprivation was maintained during pregnancy and lactation, the changes in the islets of the 3-month-old rats were more extensive^5,13,38,39. In addition to larger islets and a reduced insulin content^13,38, the pancreas had fewer blood vessels per unit volume and a lower blood flow⁵⁴. The insulin response to amino acids and glucose was also reduced both in vitro and in vivo in males and females⁴². Similarly, offspring of mothers with restricted calorie intake during pregnancy and lactation had fewer ß-cells and secreted less insulin in response to oral glucose administration at 3 months of age⁵⁶. However, with intra-uterine calorie restriction, it appeared to be the males rather than the females that were adversely affected^13,42. In contrast, offspring of diabetic mothers appear to have a morphologically normal pancreas and normal concentrations of insulin and glucose at 3 months of age under basal conditions⁵⁵. However, insulin levels were raised in these animals in response to glucose administration in vivo. The abnormalities in islet development sustained in utero were, therefore, maintained to a greater or lesser extent in all three experimental models (low protein, low calorie, diabetes) used to investigate the intra-uterine programming of the islet function. However, the changes in insulin secretion were rarely associated with alterations in glucose tolerance at 3 months of age because of compensatory changes in insulin sensitivity of the peripheral tissues^39,55,56.

Pregnancy

During normal pregnancy, there is increased ß-cell proliferation, enhanced insulin synthesis and a lower threshold for glucose-stimulated insulin secretion¹³. In females, protein deprived either solely in utero or during pregnancy and lactation, ß-cell proliferation is reduced during pregnancy and the islet cell mass and pancreatic insulin content are low at the end of gestation compared with controls. In some, but not all studies, the insulin response to oral glucose was also smaller than normal in pregnant rats protein deprived in early life¹³. Reduced ß-cell proliferation was also observed during pregnancy in the female offspring of rats deprived of calories during pregnancy⁴². In female rats, deprivation of either protein or calories during fetal and early postnatal life therefore leads to gestational diabetes with lower insulin and higher glucose levels than during normal pregnancy. Gestational diabetes also occurs in the female offspring of diabetic rats³⁵.

Ageing

In contrast to juvenile animals, glucose intolerance is common in elderly rats (11–15 months) which have been deprived of protein or calories or treated with dexamethasone during early life^{13,17,43,55,58}. However, in the majority of these studies, the glucose intolerance was the result of insulin resistance rather than defective insulin secretion^39,55,58. Insulopenia was observed only in the rats deprived of calories pre- and postnatally and in females, but not males, protein restricted during early life. Nutritional manipulations in utero may, therefore, accelerate the ageing process so that, by 11–15 months, there is less difference in islet function between control and manipulated animals than seen at 3 months.

In the human population, glucose intolerance is also more frequent in adults older than 50 years who were either small at birth or were calorie deprived during mid to late gestation. Like the animal studies, glucose intolerance in the older human population appeared to be more closely related to insulin insensitivity than insulopenia. However, the basal and glucose-stimulated levels of pro-insulin and 32-33 split pro-insulin were elevated in elderly men who were small at birth or calorie deprived in utero¹⁷. The prohormone convertases in the insulin granules may, therefore, be adversely affected by the intra-uterine environment but only lead to abnormalities in pro-insulin cleavage later in life.

Transgenerational effects

The gestational diabetes that occurs in female offspring (second generation) of rats exposed to metabolic abnormalities during pregnancy in the first generation leads to fetal hyperglycaemia and hypoinsulinaemia in the fetuses in late gestation (third generation). There are also reductions in the volume density of the ß-cells and pancreatic insulin content as well as changes in islet size distribution in the fetuses of this third generation⁴². Adults of the third generation, particularly the females, are glucose intolerant and develop type 2 diabetes and its complications in later life¹³. Overall, it takes at least three generations to reverse the effects of moderate malnutrition during pregnancy. However, normalization of glycaemia in the first generation, stretozotocin-induced, diabetic rats by islet cell transplants prevents these transgenerational effects^13,35.

	Mechanisms of programming pancreatic endocrine function

Top Footnotes Abstract Introduction Normal development of the... Factors affecting development of... Long-term consequences Mechanisms of programming... References

 
There are a wide range of structural and functional changes that can occur in the endocrine pancreas during fetal development that could lead to changes in islet function in later life (Table 2). The changes in the vascularity and vascular reactivity in the islets that occur in response to early protein deprivation may be due to alterations in both locally produced and blood-borne growth factors such as FGF, VEGF and IGFs^41,45,54. The endothelium of the islet capillaries expresses a unique nitric oxide (NO) synthetase which is regulated by the glucose concentration⁵⁴. Since NO production in other vascular beds appears to be programmed in utero⁴², the low blood flow of the adult pancreas of offspring protein deprived in early life may be due to diminished endothelial NO activity in the islets. The low vessel density and blood flow to the pancreas will reduce exposure of the islets to metabolic stimuli and blood-borne growth factors which may limit insulin secretion and postnatal ß-cell proliferation with long term consequences for adult ß-cell function.

View this table: [in this window] [in a new window]   Table 2 Processes within the pancreatic ß-cell that may be programmed in utero

 

View larger version (33K): [in this window] [in a new window]   Fig. 2 Diagram of stimulus-secretion coupling in the pancreatic ß-cell illustrating the processes which may be programmed in utero. 1. Abundance of the glucose transporter-GLUT 2. 2. Abundance and activity of glucokinase. 3. Abundance and activity of uncoupling protein (UCP)-2. 4. ATP-dependent K+ channels responsible for the potential difference () across the cell membrane. 5. Voltage sensitive Ca2+ channels responsible for Ca2+ entry and [Ca2+]i. 6. Abundance and activity of prohormone convertases which metabolise pro-insulin to insulin.

 
Changes in the pancreatic innervation induced in utero may also contribute to the changes in adult islet function. In other tissues, the number of nerve fibres and the activity of these nerves are determined by the nutritional and hormonal environment in utero⁴⁴. Circulating catecholamine concentrations are also known to be higher in growth-retarded fetuses than in those normally grown¹⁰. Furthermore, there is evidence for increased sympathetic activity in adult men who were small at birth. Certainly, the observation that insulin release is suppressed in vivo but not in vitro in juvenile rats which were protein deprived in utero^13,42 suggests that changes in pancreatic innervation or circulating catecholamine levels may be important in regulating insulin secretion in vivo.

The changes in islet morphology induced by nutritional manipulation in utero have been well documented. In particular, the changes in topography and the - to ß-cell ratio in the islets will affect the local intra-islet regulatory mechanisms and, thereby, alter islet cell responsiveness to physiological stimuli both in utero and subsequently. However, the relative contribution of neogenesis, proliferation and apoptosis to the overall changes in islet cell mass and morphology remain unknown and probably differ with the severity, duration and specific nature of the nutritional deficit. Environmental programming may act prior to the generation of endocrine pancreatic cells, at the level of pre-endocrine stem cells within the pancreatic ducts or islets, or even before pancreas formation in the embryo. Using stem cell markers commonly found in preneuronal lineages, such as the intermediary filament protein, nestin, putative pre-endocrine stem cells have been identified both in the pancreatic ducts and within the islets, where they persist in low numbers into adult life⁵⁹. When juvenile rat pancreatic ducts were isolated and allowed to grow as cystic structures in vitro, nestin mRNA was detected by RT-PCR after 10 days in culture, before the appearance of insulin-expressing cells. Feeding a low protein diet to pregnant rats significantly reduces the proportion of nestin-expressing stem cells both in the pancreatic ducts and islets of the neonates which suggests a possible environmental limitation of stem cell number and, hence, tissue plasticity in later life.

Much less is known about the intra-uterine programming of the cellular mechanisms controlling the synthesis and release of islet hormones. In the ß-cells, activation of insulin synthesis is cAMP dependent. Fetal islets from rat protein deprived during pregnancy release less insulin in response to theophylline and produce less cAMP in response to glucose than controls^13,38. Together, these findings suggest that there may be nutritionally-induced changes in the adenyl cyclase system which limits insulin synthesis and, ultimately, reduces the insulin response to glucose. The insulin gene contains multiple transcriptional elements that respond to glucose and no single mutation of the rat insulin promotor removes glucose sensitivity⁶⁰. Nutritional and hormonally induced changes in promotor usage in utero may alter the translatability of insulin mRNA with consequences for adult insulin secretion. Developmental changes in promotor usage are known to occur with other genes in utero and have been shown to be hormone-dependent⁴⁴. In humans, allelic variations in the insulin promotor leads to different insulin genotypes which have been related to birth weight and adult insulin resistance and type 2 diabetes⁶¹. However, recent studies have indicated that differences in insulin genotype are unlikely to account for much of the association between low birth weight and adult abnormalities in the insulin–glucose relationship⁶². The changes in circulating pro-insulin and 32-33 split pro-insulin seen in elderly human populations that were small at birth or undernourished in utero suggests that the final stages of insulin synthesis may be affected by intra-uterine conditions. In particular, the activity of prohormone convertase 2 (PC2) may be reduced in these circumstances (Fig. 2). Neonatal concentrations of 32-33 split pro-insulin are known to be related to maternal intake of energy and protein during pregnancy¹⁶ which indicates that PC2 activity may be nutritionally regulated in utero. However, the factors regulating PC activity in utero and the extent to which intra-uterine changes in this enzyme activity persist after birth remain unknown.

Finally, stimulus–secretion coupling in the pancreatic endocrine cells may be permanently altered by the intra-uterine environment. There are at least 5 points at which glucose stimulated insulin secretion could be programmed in utero (Fig. 2). Glucose is taken up into the ß-cell via the GLUT 2 transporter and is then metabolised by glucokinase before entering the citric acid cycle (Fig. 2). GLUT 2 and glucokinase have been identified in the fetal islets from early in gestation in rats and humans^19,36,63. In human fetal islets, inhibition of GLUT 2 activity reduces insulin release³⁶. However, in mice, knockout of GLUT 2 has no effect on the fetal islets which suggests that other glucose transporters may be active in utero in this species⁶³. In contrast, disruption of the pancreatic glucokinase gene leads to hypoinsulinaemia and growth retardation at birth in both mice and humans^36,64. Pancreatic glucokinase, therefore, appears to be active as a glucose sensor in utero and involved in insulin secretion. Total pancreatic glucokinase activity is reduced in 3-month-old rats deprived in early life⁶⁵, but little is known about the nutritional or hormonal influences on pancreatic glucokinase and GLUT 2 before birth⁶⁶.

Glucose metabolism by the ß-cell leads to ATP production which, in turn, closes the ATP-dependent K⁺ channel (Fig. 2). Depolarisation of the ß-cell results and leads to opening of the voltage-sensitive Ca²⁺ channels. The consequent rise in intracellular Ca²⁺ concentration activates exocytosis and the final release of insulin (Fig. 2). Production of ATP via the citric acid cycle depends, in part, on mitochondrial UCP2 abundance. Disruption of the UCP2 gene in mice leads to hyperinsulinaemia and increases sensitivity to glucose (Lowell B, personal communication). In other fetal tissues, such as brown fat and skeletal muscle, UCP is developmentally regulated and responsive to changes in the availability of nutrients and hormones in the fetus⁴⁴. Patch clamping of the K⁺ and Ca²⁺ channels in fetal ß-cells showed that their characteristics were similar to those in adults and that the immaturity of glucose-stimulated insulin response in cultured fetal ß- cells was upstream of these ion channels^67–69. Developmental and hormonally induced changes in abundance of K⁺ and Ca²⁺ channels have been observed in several fetal and adult tissues^68,69, but nothing is known about the control of these channels in the pancreatic ß-cells. Manipulation of pancreatic UCP2 and/or ion channel abundances during intra-uterine growth could, therefore, provide a mechanism of permanently altering ß-cell sensitivity to glucose and other secretogogues (Fig. 2).

	Footnotes

Top Footnotes Abstract Introduction Normal development of the... Factors affecting development of... Long-term consequences Mechanisms of programming... References

 
Correspondence to: Dr Abigail L Fowden, Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK

	References

Top Footnotes Abstract Introduction Normal development of the... Factors affecting development of... Long-term consequences Mechanisms of programming... References

 

1. Van Assche FA, Aerts L. The fetal endocrine pancreas. Contrib Gynecol Obstet 1979; 5: 44–57[Medline]
2. Bonwens L, Lu WG, De Krijgar RR. Proliferation and differentiation in the human fetal endocrine pancreas. Diabetologia 1997; 40: 398–404[Web of Science][Medline]
3. Robb P. The development of the islets of Langerhans in the human foetus. Quart J Exp Physiol 1961; 46: 335–43
4. De Krijgar RR, Aanstoot HJ, Kranenburg G, Reishard M, Visser WJ, Bruining GJ. The mid gestational human fetal pancreas contains cells coexpressing islet hormones. Dev Biol 1992; 153: 368–75[Web of Science][Medline]
5. Hellerstrom L, Swenne I. Functional maturation and proliferation of fetal pancreatic beta cells. Diabetes 1991; 40 (Suppl 2): 89–93
6. Portela-Gomes GM, Johansson H, Olding L, Grimelius L. Co-localization of neuroendocrine hormones in the human fetal pancreas. Eur J Endocrinol 1999; 141: 526–33[Abstract]
7. Hill DJ, Strutt B, Arany E, Zaina S, Conkell S, Graham CF. Increased and persistent circulating insulin-like growth factor II in neonatal transgenic mice suppresses developmental apoptosis in the pancreatic islets. Endocrinology 2000; 141: 1151–7[Abstract/Free Full Text]
8. Reddy S, Elliott RB. Ontogenic development of peptide hormones in the mammalian fetal pancreas. Experientia 1988; 44: 1–9[Web of Science][Medline]
9. Mally MI, Otonkosk T, Lopez AD, Haycock A. Developmental gene expression in the human fetal pancreas. Pediatr Res 1994; 36: 537–44[Web of Science][Medline]
10. Fowden AL. Pancreatic endocrine function and carbohydrate metabolism in the fetus. In: Abrecht E, Pepe GJ. (eds) Research in Perinatal Medicine IV. Ithaca, NY: Perinatology Press, 1985; 71–90
11. Fowden AL. Endocrine regulation of fetal growth. Reprod Fertil Dev 1995; 7: 351–63[Medline]
12. Lips JP, Acuk WJ, Crevels J, Eskes TK. Chronic hyperglycaemia and insulin concentrations in fetal lambs. Am J Obstet Gynecol 1988; 159: 247–51[Web of Science][Medline]
13. Dahri S, Reusen B, Remacle C, Hoet JJ. Nutritional influences on pancreatic development – potential links with non-insulin-dependent diabetes. Proc Nutr Soc 1995; 54: 345–56[Web of Science][Medline]
14. Aldoretta PW, Carver TD, Hay WW. Maturation of glucose stimulated insulin secretion in fetal sheep. Biol Neonate 1998; 73: 375–86[Web of Science][Medline]
15. Carver TD, Anderson SM, Aldoretta PW, Hay WW. Effect of low-level basal plus marked pulsatile hyperglycaemia on insulin secretion in fetal sheep. Am J Physiol 1996; 271: E865–71[Abstract/Free Full Text]
16. Godfrey KM, Robinson S, Hales CN, Barker DJP, Osmond C, Taylor KP. Nutrition in pregnancy and the concentrations of proinsulin, 32/33 split proinsulin, insulin and C-peptide in cord plasma. Diabet Med 1996; 13: 868–73[Web of Science][Medline]
17. Hales CN, Desai M, Ozanne SE, Crowther NJ. Fishing in the stream of diabetes: from measuring insulin to the control of fetal organogenesis. Biochem Soc Trans 1996; 24: 341–50[Web of Science][Medline]
18. Berney DM, Desai M, Palmer DJ et al. The effects of maternal protein deprivation on the fetal rat pancreas: major structural changes and their recuperation. J Pathol 1997; 183: 109–15[Web of Science][Medline]
19. Nielsen JH, Serup P. Molecular basis for islet development, growth and regeneration. Curr Opin Endocrinol Diabetes 1998; 5: 97–107
20. Sander M, German S. The ßcell transcription factors and development of the pancreas. J Mol Med 1997; 75: 327–40[Web of Science][Medline]
21. Offield MF, Jetton TL, Labosky PA et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 1996; 122: 983–95[Abstract]
22. Stoffers DA, Zinkin FT, Stanojevik V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single deletion in the human IPF-1 coding region. Nat Genet 1997; 15: 106–10[Web of Science][Medline]
23. Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P. The Pax-4 gene is essential for the differentiation of insulin-producing ß-cells in mammalian pancreas. Nature 1997; 386: 399–402[Medline]
24. St-Onge L, Sosa-Pineda B, Chowdhury K, Mansouri A, Gruss P. Pax6 is required for differentiation of glucagon-producing cells in mouse pancreas. Nature 1997; 387: 406–8[Medline]
25. Velho G, Froguel P. Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young. Eur J Endocrinol 1998; 138: 233–9[Abstract]
26. Yamagata K, Furuta H, Oda N et al. Mutations in the hepatocyte nuclear factor 4 alpha gene in maturity-onset diabetes of the young (MODY1). Nature 1996; 384: 468–70
27. Froguel P, Vaxillaire M, Sun F et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 1992; 356: 162–4[Medline]
28. Velho G, Blanché H, Vaxillaire M et al. Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia 1997; 40: 217–24[Web of Science][Medline]
29. Vaxillaire M, Rouard M, Yamagata K et al. Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity onset diabetes of the young (MODY 3). Hum Mol Genet 1997; 6: 583–6[Abstract/Free Full Text]
30. Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type 2 diabetes mellitus (MODY4) linked to IPF1. Nat Genet 1997; 17: 138–9[Web of Science][Medline]
31. Byrne MM, Sturis J, Menzel S et al. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes mellitus susceptibility gene MODY on chromosome 12. Diabetes 1996; 45: 1503–10[Abstract]
32. Byrne MM, Sturis J, Fajans SS et al. Altered secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 1995; 44: 699–704[Abstract]
33. Herman WH, Fajans SS, Ortiz FJ et al. Abnormal insulin secretion, not insulin resistance, is the genetic or primary defect of MODY in the RW pedigree. Diabetes 1994; 43: 40–6[Abstract]
34. Carver TD, Anderson SM, Aldoretta PE, Esler AL, Hay WW. Glucose suppression of insulin secretion in chronically hyperinsulinaemic fetal sheep. Pediatr Res 1995; 38: 754–62[Web of Science][Medline]
35. Kervan A, Guillaume M, Frost A. The endocrine pancreas of the fetus from diabetic pregnant rats. Diabetologia 1975; 15: 387–93
36. Terauchi Y, Kubota N, Tamemoto H et al. Insulin effect during embryogenesis determines fetal growth: A possible molecular link between birth weight and susceptibility to type 2 diabetes. Diabetes 2000; 49: 82–6[Abstract]
37. Cherif H, Rensens B, Ahn MJ, Hoet JJ, Remacle C. Effect of taurine on the insulin secretion of islets of fetus from dams fed a low protein diet. Endocrinology 1998; 159: 341–8
38. Dahri S, Snoeck A, Reuse-Billen B, Remacle C, Hoet JJ. Islet function in offspring of mothers on low protein diet during late gestation. Diabetes 1991; 40 (Suppl 2): 115–20
39. Ozanne SE, Hales CN. The long term consequences of intra-uterine protein malnutrition for glucose metabolism. Proc Nutr Soc 1999; 58: 615–9[Web of Science][Medline]
40. Petrik J, Reusens B, Avany E et al. A low protein diet alters the balance of islet cell replication and apoptosis in the fetus and is associated with a reduced pancreatic expression of insulin-like growth factor-II. Endocrinology 1999; 140: 4861–73[Abstract/Free Full Text]
41. Snoeck A, Remacle C, Reises B, Hoet JJ. Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. Biol Neonate 1990; 57: 107–18[Web of Science][Medline]
42. Hoet JJ, Hanson MA. Intrauterine nutrition: its importance during critical periods for cardiovascular and endocrine development. J Physiol 1999; 514: 617–27[Abstract/Free Full Text]
43. Fowden AL, Forhead AJ. The role of hormones in intrauterine development. In: Barker DJP. (ed) Fetal Origins of Cardiovascular and Like Disease. New York: Marcel Decker, 2000; 199–228
44. Fowden AL, Li J, Forhead AJ. Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance? Proc Nutr Soc 1998; 57: 113–22[Web of Science][Medline]
45. Hill DJ, Petrik J, Arany E. Growth factors and the regulation of fetal growth. Diabetes Care 1998; 21 (Suppl 2): B60–9
46. Oberg-Welsh C, Welsh M. Effects of certain growth factors on in vitro maturation of rat fetal islet-like structures. Pancreas 1996; 12: 334–9[Web of Science][Medline]
47. Yi ES, Yin S, Harclerode DL et al. Keratinocyte growth factor induces pancreatic ductal epithelial proliferation. Am J Pathol 1994; 145: 80–5[Abstract]
48. Nguyen HQ, Danilenko DM, Bucay N et al. Expression of keratinocyte growth factor in embryonic liver of transgenic mice causes changes in epithelial growth and differentiation resulting in polycystic kidneys and other organ malformations. Oncogene 1996; 12: 2109–19[Web of Science][Medline]
49. Arany E, Petrik J, Hill DJ. Fibroblast growth factors and beta cell neogenesis in the developing rat pancreata. J Endocrinol 1998; 156 (Suppl): P104
50. Rubin JS, Bottaro DP, Chedid M et al. Keratinocyte growth factor. Cell Biol Int 1995; 19: 399–411[Web of Science][Medline]
51. Hill DJ, Hogg J, Peptrik J, Arany EI, Hai VK. Cellular distribution and ontogeny of insulin-like growth factors (IGFs) and IGF binding protein messenger RNAs and peptides in developing rat pancreas. J Endocrinol 1999; 160: 305–17[Abstract]
52. Hiettinen PJ, Otonkoski J, Voutilainer R. Insulin-like growth factor-II and transforming growth-factor alpha in developing human fetal pancreatic islets. J Endocrinol 1993; 138: 127–36[Abstract/Free Full Text]
53. Petrik J, Pell JM, Arany E et al. Over expression on insulin-like growth factor II in transgenic mice is associated with pancreatic islet cell hyperplasia. Endocrinology 1999; 140: 2353–63[Abstract/Free Full Text]
54. Iglesisa-Barreiva V, Ahn M-T, Reutens B, Dahri S, Hoet JJ, Remacle C. Pre and postnatal low protein diet affect pancreatic islet blood flow and insulin release in adult rats. Endocrinology 1996; 137: 3797–801[Abstract]
55. Ozanne SE, Smith GD, Tikerpae J, Hales CN. Altered regulation of hepatic glucose output in male offspring of protein-malnourished rat dams. Am J Physiol 1996; 270: E559–64[Abstract/Free Full Text]
56. Hogg J, Han VR, Clemmons DR, Hill DJ. Interactions of nutrients, insulin-like growth factors (IGFs) and IGF-binding proteins in the regulation DNA synthesis by isolated fetal rat islets of Langerhans. J Endocrinol 1993; 138: 401–12[Abstract/Free Full Text]
57. Desai M, Byrne CD, Meeran K, Martinez ND, Bloom SR, Hales CN. Regulation of hepatic enzymes and insulin levels in offspring of rat dams fed a reduced protein diet. Am J Physiol 1997; 273: G899–904[Abstract/Free Full Text]
58. Nyirendi MJ, Lindsay RS, Kenyon CJ, Burchell A, Seckl JR. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and cause glucose intolerance in adult offspring. J Clin Invest 1998; 101: 2174–81[Web of Science][Medline]
59. Hunziker E, Stein M. Nestin-expressing cell in the pancreatic islets of Langerhans. Biochem Biophys Res Commun 2000; 271: 116–9[Web of Science][Medline]
60. German MS, Wang J. The insulin gene contains multiple transcriptional elements that respond to glucose. Mol Cell Biol 1994; 14: 4067–75[Abstract/Free Full Text]
61. Dunger DB, Ong KKL, Huxtable SJ et al. Association of the INS VNTR with size at birth. Nat Genet 1998; 19: 98–100[Web of Science][Medline]
62. Ong KKL, Phillips DIW, Fall C et al. The insulin gene VNTR, type 2 diabetes and birth weight. Nat Genet 1999; 21: 262–3[Web of Science][Medline]
63. Guilliam M-T, Hummler E, Schaerer E et al. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking GLUT-2. Nat Genet 1997; 17: 327–30[Web of Science][Medline]
64. Hattersley AJ, Tooke J. The fetal insulin hypothesis in an alternate explanation of the association of low birthweight with diabetes and vascular disease. Lancet 1999; 353: 1789–92[Web of Science][Medline]
65. Garafano A, Czernillow P, Breant B. Effect of ageing on beta cell mass and function in rats malnourished during the perinatal period. Diabetologia 1999; 42: 711–8[Web of Science][Medline]
66. Jorns A, Tiedge M, Lenzen S. Nutrient-dependent distribution of insulin and glucokinase immunoactivities in rat pancreatic beta cells. Virchows Arch 1999; 434: 75–82[Web of Science][Medline]
67. Kornel L, Prancan AV, Kanamarlapudi N, Hynes J, Kuzianik E. Study on the mechanisms of glucocorticoid induced hypertension: glucocorticoid increase transmembrane Ca²⁺ influx in vascular smooth muscle in vitro. Endocr Res 1995; 21: 203–10
68. Rorsman P, Arklanmar P, Bokvist K et al. Failure of glucose to elicit a normal secretary response in fetal pancreatic beta cells results from glucose insensitivity of the ATP regulated K⁺ channels. Proc Natl Acad Sci USA 1989; 86: 4505–9[Abstract/Free Full Text]
69. Szep Y, Iqbal Z. Glucocorticoid action on depolarization dependent calcium influx in brain synaptosomes. Neuroendocrinology 1994; 59: 457–65[Web of Science][Medline]

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