Fetal Endocrine Pancreas Research Articles

Maternal hypothyroidism in mice influences glucose metabolism in adult offspring

Aims/hypothesisDuring pregnancy, maternal metabolic disease and hormonal imbalance may alter fetal beta cell development and/or proliferation, thus leading to an increased risk for developing type 2 diabetes in adulthood. Although thyroid hormones play an important role in fetal endocrine pancreas development, the impact of maternal hypothyroidism on glucose homeostasis in adult offspring remains poorly understood.MethodsWe investigated this using a mouse model of hypothyroidism, induced by administration of an iodine-deficient diet supplemented with propylthiouracil during gestation.ResultsHere, we show that, when fed normal chow, adult mice born to hypothyroid mothers were more glucose-tolerant due to beta cell hyperproliferation (two- to threefold increase in Ki67-positive beta cells) and increased insulin sensitivity. However, following 8 weeks of high-fat feeding, these offspring gained 20% more body weight, became profoundly hyperinsulinaemic (with a 50% increase in fasting insulin concentration), insulin-resistant and glucose-intolerant compared with controls from euthyroid mothers. Furthermore, altered glucose metabolism was maintained in a second generation of animals.Conclusions/interpretationTherefore, gestational hypothyroidism induces long-term alterations in endocrine pancreas function, which may have implications for type 2 diabetes prevention in affected individuals.

The impact of IUGR on pancreatic islet development and β-cell function.

Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). IUGR increases the risk of developing type 2 diabetes mellitus (T2DM) throughout life, which indicates that insults from placental insufficiency impair β-cell development during the perinatal period because β-cells have a central role in the regulation of glucose tolerance. The severely IUGR fetal pancreas is characterized by smaller islets, less β-cells, and lower insulin secretion. Because of the important associations among impaired islet growth, β-cell dysfunction, impaired fetal growth, and the propensity for T2DM, significant progress has been made in understanding the pathophysiology of IUGR and programing events in the fetal endocrine pancreas. Animal models of IUGR replicate many of the observations in severe cases of human IUGR and allow us to refine our understanding of the pathophysiology of developmental and functional defects in islet from IUGR fetuses. Almost all models demonstrate a phenotype of progressive loss of β-cell mass and impaired β-cell function. This review will first provide evidence of impaired human islet development and β-cell function associated with IUGR and the impact on glucose homeostasis including the development of glucose intolerance and diabetes in adulthood. We then discuss evidence for the mechanisms regulating β-cell mass and insulin secretion in the IUGR fetus, including the role of hypoxia, catecholamines, nutrients, growth factors, and pancreatic vascularity. We focus on recent evidence from experimental interventions in established models of IUGR to understand better the pathophysiological mechanisms linking placental insufficiency with impaired islet development and β-cell function.

The ontogeny of the endocrine pancreas in the fetal/newborn baboon

Erratic regulation of glucose metabolism including hyperglycemia is a common condition in premature infants and is associated with increased morbidity and mortality. The objective of this study was to examine histological and ultrastructural differences in the endocrine pancreas in fetal (throughout gestation) and neonatal baboons. Twelve fetal baboons were delivered at 125 days (d) gestational age (GA), 140d GA, or 175d GA. Eight animals were delivered at term (185d GA); half were fed for 5 days. Seventy-three nondiabetic adult baboons were used for comparison. Pancreatic tissue was studied using light microscopy, confocal imaging, and electron microscopy. The fetal and neonatal endocrine pancreas islet architecture became more organized as GA advanced. The percent areas of α-β-δ-cell type were similar within each fetal and newborn GA (NS) but were higher than the adults (P<0.05) regardless of GA. The ratio of β cells within the islet (whole and core) increased with gestation (P<0.01). Neonatal baboons, which survived for 5 days (feeding), had a 2.5-fold increase in pancreas weight compared with their counterparts killed at birth (P=0.01). Endocrine cells were also found in exocrine ductal and acinar cells in 125, 140 and 175d GA fetuses. Subpopulation of tissue that coexpressed trypsin and glucagon/insulin shows the presence of cells with mixed endo-exocrine lineage in fetuses. In summary, the fetal endocrine pancreas has no prevalence of a α-β-δ-cell type with larger endocrine cell percent areas than adults. Cells with mixed endocrine/exocrine phenotype occur during fetal development. Developmental differences may play a role in glucose homeostasis during the neonatal period and may have long-term implications.

A New Role for GPR103b in the Peripheral Regulation of Adipogenesis

The activation of G protein-coupled receptor 103 (GPR103) by its endogenous peptidic ligands, QRFPs, is involved in the central regulation of feeding by increasing food intake, body weight, and fat mass after intracerebroventricular injection in mice. However, the role of GPR103 in regulating peripheral metabolic pathways has not yet been explored. The present study aimed to investigate the role of GPR103 in adipogenesis and lipid metabolism using 3T3-L1 adipocyte cells. Our results show that differentiated 3T3-L1 cells expressed the GPR103b subtype mRNA and protein, as well as QRFP mRNA. QRFP-43 and 26 induced an increase in triglyceride accumulation of 50 and 41%, respectively, and elicited a dose-dependent increase in fatty acid uptake, by up to approximately 60% at the highest concentration, in 3T3-L1-differentiated cells. QRFP-43 and 26 inhibited isoproterenol (ISO)-induced lipolysis in a dose-dependent manner, with IC50s of 2.3 1.2 and 1.1 1.0 nM, respectively. The expression of genes involved in lipid uptake (FATP1, CD36, LPL, ACSL1, PPAR, and C/EBP), was increased by 2to 3-fold following treatment with QRFP. The effects of QRFP on ISO-induced lipolysis and fatty acid uptake were abolished when GPR103b was silenced. In a mouse model of diet-induced obesity, the expression of GPR103b in epididymal fat pads was elevated by 16-fold whereas that of QRFP was reduced by 46% compared to lean mice. Furthermore, QRFP was bioactive in omental adipocytes from obese individuals, inhibiting ISO-induced lipolysis in these cells. Our results suggest that GPR103b and QRFP work in an autocrine/paracrine manner to regulate adipogenesis. Foxa1 and Foxa2 Maintain the Metabolic and Secretory Features of the Mature -Cell Nan Gao, John Le Lay, Wei Qin, Nicolai Doliba, Jonathan Schug, Alan J. Fox, Olga Smirnova, Franz M. Matschinsky, and Klaus H. Kaestner (Mol Endocrinol, published June 9, 2010, 10.1210/me.2009-0513) ABSTRACT Foxa1 and Foxa2 play both redundant and distinct roles in early pancreas development. We demonstrate here that inducible ablation of both transcription factors in mature mouse -cells leads to impaired glucose homeostasis and insulin secretion. The defects in both glucose-stimulated insulin secretion and intracellular calcium oscillation are more pronounced than those in -cells lacking only Foxa2. Unexpectedly, in contrast to the severe reduction of -cell-enriched factors contributing to metabolic and secretory pathways, expression of a large number of genes that are involved in neural differentiation and function is significantly elevated. We further demonstrate that expression of carbohydrate response element-binding protein (ChREBP or Mlxipl), an important transcriptional regulator of carbohydrate metabolism, is significantly affected in compound Foxa1/a2 mutant -cells. ChREBP expression is directly controlled by Foxa1 and Foxa2 in both the fetal endocrine pancreas as well as mature islets. These data demonstrate that Foxa1 and Foxa2 play crucial roles in the development and maintenance of -cell-specific secretory and metabolic pathways. 3564 Abstracts Translational Highlights from MOLECULAR ENDOCRINOLOGY J Clin Endocrinol Metab, July 2010, 95(7):3563–3564Foxa1 and Foxa2 play both redundant and distinct roles in early pancreas development. We demonstrate here that inducible ablation of both transcription factors in mature mouse -cells leads to impaired glucose homeostasis and insulin secretion. The defects in both glucose-stimulated insulin secretion and intracellular calcium oscillation are more pronounced than those in -cells lacking only Foxa2. Unexpectedly, in contrast to the severe reduction of -cell-enriched factors contributing to metabolic and secretory pathways, expression of a large number of genes that are involved in neural differentiation and function is significantly elevated. We further demonstrate that expression of carbohydrate response element-binding protein (ChREBP or Mlxipl), an important transcriptional regulator of carbohydrate metabolism, is significantly affected in compound Foxa1/a2 mutant -cells. ChREBP expression is directly controlled by Foxa1 and Foxa2 in both the fetal endocrine pancreas as well as mature islets. These data demonstrate that Foxa1 and Foxa2 play crucial roles in the development and maintenance of -cell-specific secretory and metabolic pathways. 3564 Abstracts Translational Highlights from MOLECULAR ENDOCRINOLOGY J Clin Endocrinol Metab, July 2010, 95(7):3563–3564

Foxa1 and Foxa2 Maintain the Metabolic and Secretory Features of the Mature β-Cell

Foxa1 and Foxa2 play both redundant and distinct roles in early pancreas development. We demonstrate here that inducible ablation of both transcription factors in mature mouse beta-cells leads to impaired glucose homeostasis and insulin secretion. The defects in both glucose-stimulated insulin secretion and intracellular calcium oscillation are more pronounced than those in beta-cells lacking only Foxa2. Unexpectedly, in contrast to the severe reduction of beta-cell-enriched factors contributing to metabolic and secretory pathways, expression of a large number of genes that are involved in neural differentiation and function is significantly elevated. We further demonstrate that expression of carbohydrate response element-binding protein (ChREBP or Mlxipl), an important transcriptional regulator of carbohydrate metabolism, is significantly affected in compound Foxa1/a2 mutant beta-cells. ChREBP expression is directly controlled by Foxa1 and Foxa2 in both the fetal endocrine pancreas as well as mature islets. These data demonstrate that Foxa1 and Foxa2 play crucial roles in the development and maintenance of beta-cell-specific secretory and metabolic pathways.

Foxa1 and Foxa2 Maintain the Metabolic and Secretory Features of the Mature β-Cell

Foxa1 and Foxa2 play both redundant and distinct roles in early pancreas development. We demonstrate here that inducible ablation of both transcription factors in mature mouse beta-cells leads to impaired glucose homeostasis and insulin secretion. The defects in both glucose-stimulated insulin secretion and intracellular calcium oscillation are more pronounced than those in beta-cells lacking only Foxa2. Unexpectedly, in contrast to the severe reduction of beta-cell-enriched factors contributing to metabolic and secretory pathways, expression of a large number of genes that are involved in neural differentiation and function is significantly elevated. We further demonstrate that expression of carbohydrate response element-binding protein (ChREBP or Mlxipl), an important transcriptional regulator of carbohydrate metabolism, is significantly affected in compound Foxa1/a2 mutant beta-cells. ChREBP expression is directly controlled by Foxa1 and Foxa2 in both the fetal endocrine pancreas as well as mature islets. These data demonstrate that Foxa1 and Foxa2 play crucial roles in the development and maintenance of beta-cell-specific secretory and metabolic pathways.

Transcription factor expression in the developing human fetal endocrine pancreas

Morphological changes that occur during pancreatic endocrine cell differentiation have been shown in rodent systems to be dependent on sequential alterations in transcription factor expression. However, similar data for humans have been limited. The aim of the present study was to provide a connection between pancreatic morphology, transcription factor gene expression and protein localisation during human fetal development. Human fetal pancreases were examined at early (8-12 weeks of fetal age), middle (14-16 weeks) and late (19-21 weeks) stages, using immunohistological, microarray and qRT-PCR analyses. We observed a significant decrease in pancreatic duodenal homeobox 1 (PDX-1)(+)/cytokeratin 19(+) cells (p < 0.001), with a simultaneous increase in PDX-1(+)/insulin(+) cells from 8 to 21 weeks (p < 0.05). Increased PDX-1/insulin co-localisation within islet clusters was noted, while no co-expression of PDX-1 with glucagon was found, suggesting that loss of PDX-1 is essential for alpha cell formation. Given that neurogenin 3 (NGN3) expression is critical for establishing the endocrine cell programme in the rodent pancreas, we examined its expression pattern and co-localisation in PDX-1(+), insulin(+) and glucagon(+) cells. Co-localisation of NGN3 with PDX-1, insulin and glucagon was noted during early development, with significant decreases in middle and late stages (p < 0.001). Our microarray and co-localisation analyses of transcription factors linked to NGN3 demonstrated that ISL1 transcription factor (ISL1), neurogenic differentiation 1 (NEUROD1), NK2 related transcription factor related, locus 2 (NKX2-2) and paired box gene 6 (PAX6) were upregulated during development and present in all four endocrine cell types, while NK6 related transcription factor related, locus 1 (NKX6-1) was expressed exclusively in beta cells. This study is an important step towards identifying key molecular factors involved in development of the human fetal endocrine pancreas.

Foxa2 Controls Vesicle Docking and Insulin Secretion in Mature β Cells

The winged-helix transcription factor Foxa2 regulates Pdx1 gene expression and fetal endocrine pancreas development. We show here by inducible gene ablation that Foxa2 inactivation in mature beta cells induces hyperinsulinemic hypoglycemia in Foxa2(loxP/loxP),Pdx1-CreERT2 adult mice. Mutant beta cells exhibited a markedly increased pool of docked insulin granules, some of which were engaged in sequential or compound exocytosis, consistent with increased first-phase glucose-stimulated insulin secretion. Expression of multiple genes involved in vesicular trafficking, membrane targeting, and fuel-secretion pathways is dependent on Foxa2. In addition, impaired cytosolic Ca(2+) oscillations and elevated intracellular cyclic AMP production accompanied this secretory defect and were likely contributors to the sensitization of the exocytotic machinery. Thus, in the absence of Foxa2, alterations in intracellular second-messenger signaling redistribute the insulin granules into the readily releasable pool. We conclude that Foxa2 is required for both fetal pancreas development and the function of mature beta cells.

Maturation of pancreatic β-cell function in the fetal horse during late gestation

At birth, the endocrine pancreas becomes more directly involved in the control of glycaemia than in utero. However, compared with other tissues, relatively little is known about the maturational changes that occur in the fetal endocrine pancreas in preparation for extrauterine life. This study examined the pancreatic beta-cell response to exogenous administration of glucose and arginine in fetal horses with respect to their gestational age and concentration of cortisol, the hormone responsible for prepartum maturation of other fetal tissues. Glucose administration had no effect on fetal insulin secretion between 175 and 230 days of gestation but evoked a rapid insulin response in fetuses closer to term (290-327 days). In late gestation, the beta-cell response was more rapid and greater in magnitude in fetuses with basal cortisol levels higher than 15 ng/ml than in those with lower cortisol values at the time of glucose administration. The fetal beta-cell response to arginine was unaffected by the rise in fetal plasma cortisol towards term. These findings show that there are maturational changes in pancreatic beta-cell function in fetal horses as cortisol levels rise close to term. Primarily, these prepartum maturational changes were in the mechanisms of glucose-stimulated insulin secretion, which would enable the beta cells to regulate glycaemia at the higher glucose levels observed postnatally.

Taurine Supplementation of a Low Protein Diet Fed to Rat Dams Normalizes the Vascularization of the Fetal Endocrine Pancreas

In rats, an isoenergetic low protein diet (LP) given throughout gestation perturbs the development of the endocrine pancreas by reducing beta-cell mass and islet vascularization at birth. Taurine, an important amino acid during development, has been found to be low in fetal and maternal plasma. When added to a LP diet, taurine normalizes beta-cell mass. Therefore, we investigated the ability of taurine to correct altered islet vascularization. Rats were given 20% [control (C)] or 8% (LP) protein in the diet with or without supplementation with 25 g/L taurine (T) in drinking water (C+T and LP+T) during gestation and lactation. Immunostaining for vascular endothelial growth factor (VEGF) and fetal liver kinase-1 (Flk-1), a VEGF receptor, was performed on fetal and neonatal pancreatic sections. Blood vessel density and blood vessel number were analyzed morphometrically on semi-thin sections. Taurine supplementation restored a normal volume and numerical density of vessels in fetal islets. The number of cells showing immunoreactivity for VEGF and Flk-1 was reduced by 33 and 45%, respectively, in islet cells from LP fetuses. In 1-mo-old pups, VEGF-positive cells remained decreased by nearly 22%. Both VEGF and Flk-1 were restored in pancreatic endocrine cells of fetuses and pups given taurine. The LP diet induced a threefold overexpression of Flk-1 in ductal cells, which contain precursors of beta cells. However, taurine supplementation was without effect. In conclusion, underexpression of VEGF and Flk-1 is associated with the lower fetal islet vascularization induced by the maternal malnutrition. The addition of taurine to the maternal diet prevents such damage and has a potential role in islet vasculogenesis.

Lifetime consequences of abnormal fetal pancreatic development

There is ample evidence that an adverse intrauterine environment has harmful consequences for health in later life. Maternal diabetes and experimentally induced hyperglycaemia result in asymmetric overgrowth, which is associated with an increased insulin secretion and hyperplasia of the insulin-producing B-cells in the fetuses. In adult life, a reduced insulin secretion is found. In contrast, intrauterine growth restriction is associated with low insulin secretion and a delayed development of the insulin-producing B-cells. These perinatal alterations may induce a deficient adaptation of the endocrine pancreas and insulin resistance in later life. Intrauterine growth restriction in human pregnancy is mainly due to a reduced uteroplacental blood flow or to maternal undernutrition or malnutrition. However, intrauterine growth restriction can be present in severe diabetes complicated by vasculopathy and nephropathy. In animal models, intrauterine growth retardation can be obtained through pharmacological (streptozotocin), dietary (semi-starvation, low protein diet) or surgical (intrauterine artery ligation) manipulation of the maternal animal. The endocrine pancreas and more specifically the insulin-producing B-cells play an important role in the adaptation to an adverse intrauterine milieu and the consequences in later life. The long-term consequences of an unfavourable intrauterine environment are of major importance worldwide. Concerted efforts are needed to explore how these long-term effects can be prevented. This review will consist of two parts. In the first part, we discuss the long-term consequences in relation to the development of the fetal endocrine pancreas and fetal growth in the human; in the second part, we focus on animal models with disturbed fetal and pancreatic development and the consequences for later life.

Lifetime consequences of abnormal fetal pancreatic development.

There is ample evidence that an adverse intrauterine environment has harmful consequences for health in later life. Maternal diabetes and experimentally induced hyperglycaemia result in asymmetric overgrowth, which is associated with an increased insulin secretion and hyperplasia of the insulin-producing B-cells in the fetuses. In adult life, a reduced insulin secretion is found. In contrast, intrauterine growth restriction is associated with low insulin secretion and a delayed development of the insulin-producing B-cells. These perinatal alterations may induce a deficient adaptation of the endocrine pancreas and insulin resistance in later life. Intrauterine growth restriction in human pregnancy is mainly due to a reduced uteroplacental blood flow or to maternal undernutrition or malnutrition. However, intrauterine growth restriction can be present in severe diabetes complicated by vasculopathy and nephropathy. In animal models, intrauterine growth retardation can be obtained through pharmacological (streptozotocin), dietary (semi-starvation, low protein diet) or surgical (intrauterine artery ligation) manipulation of the maternal animal. The endocrine pancreas and more specifically the insulin-producing B-cells play an important role in the adaptation to an adverse intrauterine milieu and the consequences in later life. The long-term consequences of an unfavourable intrauterine environment are of major importance worldwide. Concerted efforts are needed to explore how these long-term effects can be prevented. This review will consist of two parts. In the first part, we discuss the long-term consequences in relation to the development of the fetal endocrine pancreas and fetal growth in the human; in the second part, we focus on animal models with disturbed fetal and pancreatic development and the consequences for later life.

The Transplanted Fetal Endocrine Pancreas Undergoes an Inherent Sequential Differentiation Similar to That in the Native Pancreas

This study examines, at the ultrastructural level, whether the fetal porcine endocrine pancreas (insulin, glucagon, somatostatin, and pancreatic polypeptide [PP]- and islet amyloid polypeptide [IAPP]-containing cells) develops normally after transplantation under the kidney capsule in athymic mice. We have thus used an in vivo pig-to-mouse model for the differentiation of the endocrine pancreas removed from its normal milieu. Islet-like cell clusters (ICCs) were prepared from the fetal porcine pancreas as previously described and transplanted under the renal capsule of athymic mice. At various times after transplantation, the endocrine pancreas was removed and the level of differentiation was compared with the native pancreas of the same biological age. At the ultrastructural level, several sequential steps could be identified based on the morphology and hormone content of the secretory granules of the endocrine cell examined. Applying this approach, we could demonstrate that the ontogeny of the transplanted fetal pig pancreas follows the same sequential differentiation as the native pancreas. The process seems to be under stringent control, apparently directly related to the biological age of the tissue, and independent not only of the new environment under the kidney capsule but also of the adult and xenogeneic milieu provided after transplantation to the athymic nude mouse. Therefore, all four major hormone-producing cells seem to develop normally after transplantation when compared with the development in the native pancreas. IAPP was produced by the pluripotent fetal endocrine cells as well as the adult alpha-, beta-, and delta-cell granules in the native pancreas; however, in the transplanted pancreas, IAPP expression was demonstrated only in beta-cells, delta-cells, and PP cells. No IAPP was found in granules of the alpha-cell lineage. The results suggest a sequential differentiation of all four major types of islet cells from a common pluripotent progenitor cell, which seems to be located in the pancreatic ducts. Therefore, the results presented strongly suggest that the ontogeny of the four major endocrine islet cells is determined by genetic information carried by the progenitor cells and not by the systemic or local environment.

Fetal growth and long-term consequences in animal models of growth retardation

Perturbations of the maternal environment involve an abnormal intrauterine milieu for the developing fetus. The altered fuel supply (depends on substrate availability, placental transport of nutrients and uteroplacental blood flow) from mother to fetus induces alterations in the development of the fetal endocrine pancreas and adaptations of the fetal metabolism to the altered intrauterine environment, resulting in intrauterine growth retardation. The alterations induced by maternal diabetes or maternal malnutrition (protein-calorie or protein deprivation) have consequences for the offspring, persisting into adulthood and into the next generation.

The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats

Diabetes of the mother during pregnancy induces structural and functional adaptations in the fetal endocrine pancreas. We have previously shown in our experimental rat model, that the impact of this abnormal intra-uterine milieu leads, in the adult offspring, to a disturbance of the glucose homeostasis and to the development of gestational diabetes. The aim of the present work is to investigate wether these functional differences can be explained by structural differences at the level of the endocrine pancreas. Therefore the size and the structure of the endocrine pancreas, as well as the contribution of the insulin-, glucagon-, somatostatin- and PP-cells, were investigated morphometrically in the adult youngsters of mildly and of severely diabetic mothers, since both display a disturbed glucose tolerance but with divergent characteristics. Also the adaptation of their endocrine pancreas to pregnancy was measured and compared to that of a control pregnancy. In the offspring of mildly diabetic mothers, the size of the endocrine pancreas and the distribution of the islets of Langerhans are normal. Also the doubling of the endocrine mass during pregnancy is similar to controls. The high proportion of A-cells, especially in relation to a normal B-cell mass and the low amount of PP-cells, might play a role in the impairment of the insulin response in these animals and in the development of gestational diabetes. In the offspring of severely diabetic mothers a clear hypertrophy of the endocrine pancreas is noted, which is mainly due to the presence of numerous small islets and which does not increase further during pregnancy. In these animals, the size of the endocrine pancreas and of the B-cell mass have reached `pregnant' values without pregnancy, which coincides with an exaggerated insulin output and peripheral insulin resistance, as during normal pregnancy. No further increase in islet mass is seen during pregnancy, which is associated with gestational diabetes.

New Immunosuppressive Drugs and Their Role in the Prevention of Islet Xenograft Rejection

Islet transplantation offers an attractive future means to treat diabetes as long as prevention of xenograft rejection can be accomplished. This review analyses the role of 5 new immunosuppressive drugs [tacrolimus, sirolimus, mycophenolate mofetil, gusperimus (15-deoxyspergualin) and leflunomide] in the context of islet xenotransplantation. Although cytotoxic T cells are the major effector cells in allogeneic islet rejection, macrophages serve as important contributing effector cells in xenogeneic islet rejection. All the drugs discussed in this review inhibit T cell activation, and several of them also inhibit B cells. In addition, gusperimus has been found to inhibit macrophages. All the drugs have, at least in some animal model, delayed islet xenograft rejection. Synergistic, or at least additive, protective effects have been observed when 2 or more of the drugs have been used in combination. Assessment of the relative efficacy of the various drugs is made difficult by the use of different models in the various studies performed. In the future, several drugs should be examined in a single model. The efficacy of the various drugs in controlling autoimmune beta cell damage after transplantation remains poorly known. One of the drugs, tacrolimus, has the disadvantage of being diabetogenic in animals and humans. The other drugs do not disturb glucose homeostasis, at least in humans. Mycophenolate mofetil and leflunomide are antiproliferative drugs, a feature that might be disadvantageous in fetal endocrine pancreas transplantation. Although several of the newly available drugs show considerable promise in the prevention of islet xenograft rejection, the search for even better immunosuppressive drugs must continue.

Contrasted impact of maternal rat food restriction on the fetal endocrine pancreas.

The effects of food restriction of the mother (65% restriction of ad libitum food intake) on fetal and maternal insulin secretion and islet function were studied at 21 days gestation in three different rat populations: 1) undernourished from 0-7 days gestation, 2) undernourished from 7-14 days gestation, and 3) undernourished from 14-21 days gestation. The body weights of mothers were decreased in groups 2 and 3 vs. those in control fed pregnant animals, and no changes in basal parameters were found in any group. A glucose tolerance test in mothers from group 3 showed a mild intolerance to glucose and a decreased islet insulin content, although islet stimulation in vitro with glucose alone or plus arginine showed a normal insulin secretory response. Body weight was decreased in fetuses from the three groups (P < 0.01), and pancreas weight was reduced only in group 3. Insulinemia was increased in groups 2 and 3, and pancreatic insulin content increased only in group 3. However, fetuses from mothers of group 3 showed increased islet insulin content, increased response of insulin in vitro to glucose or glucose plus arginine, and hypertrophy of beta-cell mass. These results indicate, first, that the development of the fetal pancreas depends on a balanced maternal glucose homeostasis and, second, that adaptive maternal changes to undernutrition seem to induce alterations on the fetal endocrine pancreas, especially when food restriction is applied during the last week of gestation.

Contrasted Impact of Maternal Rat Food Restriction on the Fetal Endocrine Pancreas

Contrasted Impact of Maternal Rat Food Restriction on the Fetal Endocrine Pancreas

Proliferation and differentiation in the human fetal endocrine pancreas.

The morphogenesis and growth of the endocrine pancreas has not been well investigated in man although it represents an important issue in diabetology. We examined human fetal pancreas from 12 to 41 weeks of gestation immunocytochemically to evaluate proliferative activity with the Ki-67 marker, and cytodifferentiation with cytokeratin 19 (ductal cells), synaptophysin (all endocrine cells), and insulin, glucagon, somatostatin and pancreatic polypeptide (islet cell types). Ki-67 labelling was found in all these cell types but was much higher in ductal cells than in islet cells. An intermediate population expressed synaptophysin but lacked islet hormones. With increasing gestational age the Ki-67 labelling index decreased from 17 to 4% in ductal cells, from 9 to 1% in synaptophysin-positive cells, and from 3 to 0.1% in insulin- or glucagon-positive cells. From 12 to 16 weeks, all epithelial cells including the endocrine islet cells expressed cytokeratin 19. Thereafter cytokeratin 19 expression decreased and eventually disappeared from most islet cells, whereas strong expression remained in the ductal cells. We show that differentiated human islet cells have only very limited proliferative capacity, and we demonstrate the existence of transitional differentiation stages between ductal and islet cells.

The influence of sub-optimal protein nutrition on insulin hypersecretion evoked by high-energy/high-fat feeding in rats

Low (8%) protein feeding during pregnancy impairs the functional development of the fetal endocrine pancreas. Continued low-protein feeding post-natally decreases pancreatic insulin content and secretion, whereas transfer to standard diet evoked β-cell recuperation. Glucose-stimulated insulin secretion (GSIS) and insulin action were examined in vivo at 28 days after transfer from 8% protein diet to a high-energy/high-fat/standard (20%)-protein diet (HEF diet). HEF feeding dramatically enhanced GSIS after intravenous glucose in control rats, but not in rats previously maintained on the low-protein diet. However, glucose disappearance after intravenous glucose, and glucose production and whole-body glucose disposal during euglycaemic-hyperinsulinaemic clamps were unaffected by prior protein malnutrition. In conclusion, impaired insulin secretion after protein malnutrition is exacerbated by high-energy/high-fat feeding, but this response is not linked to enhanced whole-body insulin resistance.