L. Aerts

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.

Evidence for an insulin resistance in the adult offspring of pregnant streptozotocin-diabetic rats

SummaryOur previous work has suggested the presence of an insulin resistance in the adult offspring of streptozotocindiabetic pregnant rats. In this study we used the euglycaemic hyperinsulinaemic clamp technique with an isotope-dilution method to define and quantify this postulated insulin resistance in adult offspring of streptozotocin-diabetic rats. Under basal conditions, these rats had a lower body weight than control rats, but their glucose and insulin concentrations were normal. During the hyperinsulinaemic clamp, the steady-state glucose infusion rate was significantly lower in the offspring of streptozotocin-diabetic rats than in both ageand weight-matched controls, indicating insulin resistance. Basal peripheral tissue glucose utilization was normal in the offspring of streptozotocin-diabetic rats, but the dose-response curve was shifted to the right: insulin concentrations causing half-maximal stimulation of glucose utilization were increased by about 60% in the offspring of diabetic rats; the maximal stimulation of glucose utilization, however, was unaltered. Basal hepatic glucose production was normal, but again, half-maximal suppression of glucose production occurred at insulin concentrations 50% higher than in control rats; in addition, the maximal suppression of glucose production was significantly decreased, even at insulin concentrations of 5700 μU/ml. These data are evidence for an insulin resistance in the adult offspring of streptozotocin-diabetic rats, characterized by: (1) a decreased insulin sensitivity by peripheral glucose-utilizing tissues, and, (2) a decreased sensitivity and responsiveness of the liver.

Fetal growth restriction and consequences for the offspring in animal models.

Objective: In the present review we discuss rat models in which intra-uterine growth restriction is obtained through pharmacological (streptozotocin), dietary (global food restriction, low protein diet), or surgical (uterine artery ligation) manipulation of the maternal animal. Methods: A MEDLINE search was performed on rat models of intrauterine growth restriction (IUGR), ie, streptozotocin, food restriction, low protein diet, or uterine artery ligation and pregnancy and fetal programming, long-term effects or adult offspring. Results: We address the impact of the different maternal conditions for the fetal and neonatal development. The rat models we concentrate on were all associated with fetal hypoinsulinemia and intrauterine growth restriction. Both fetus and neonate adapt to the altered perinatal environment. Some of these adaptations may predispose the offspring to the development of insulin resistance, cardiovascular disease, obesity, and even overt diabetes in later life. Conclusion: The adaptations of the fetal metabolism to the altered intrauterine environment have consequences for the offspring, persisting into adulthood and into the next generation.

Intra-uterine transmission of disease.

Fetal development is dependent on maternal supply of fuels and building blocks. Disturbed maternal metabolism or inappropriate maternal nutrition confronts the fetus with an unfavourable intra-uterine milieu. Structural and functional adaptations occur during development and maturation of organs. Consequences of these fetal alterations persist postnatally and may result in metabolic alterations throughout life. Gestational diabetes can occur in these offspring and transmit the effect to the next generation. These alterations in fetal development can be associated with fetal macrosomia (maternal diabetes) or fetal growth-restriction (maternal/fetal malnutrition). The relation between birth weight and later metabolic disease therefore is U-shaped. Adult metabolic condition is thus to a considerable extent programmed in utero, fetal and neonatal weight being symptoms of disturbed fetal development. This concept of intra-uterine programming of disease is illustrated with a review of epidemiological human studies and experimental animal studies.

The diabetic intrauterine milieu has a long-lasting effect on insulin secretion by B cells and on insulin uptake by target tissues

From our previous work, it appears that fetal development in the abnormal intrauterine milieu of a mother with diabetes results in impaired glucose tolerance in adult life. In adult Wistar rats that were the offspring of mildly or severely diabetic mothers, in vitro islet stimulation and in vivo insulin uptake studies were undertaken to distinguish between alterations in glucose sensitivity and insulin secretion at the B cell level and alterations in insulin sensitivity and uptake at the level of the peripheral tissues. Insulin output after glucose stimulation by isolated islets was lower than normal in the rats of mothers with mild diabetes and higher than normal in the animals of severely diabetic mothers, confirming the results of previous in vivo studies. Insulin binding by the liver was normal in both groups. Insulin uptake by the kidney was normal in rats with mildly diabetic mothers but was increased in rats of severely diabetic mothers, suggesting decreased uptake of insulin by the peripheral tissues. Impaired glucose tolerance in rats of mildly diabetic mothers, resulting from decreased responsiveness to glucose, is interpreted as a consequence of hyperactivity of these B cells during the intrauterine life. Impaired glucose tolerance in rats of severely diabetic mothers, associated with insulin hypersecretion and decreased insulin uptake by the peripheral tissues might result from intrauterine alterations of the peripheral receptor or postreceptor system induced by the abnormal intrauterine milieu. These data on experimental diabetes in the rat demonstrate that the maternal diabetic environment exerts a diabetogenic influence on the offspring.

Taurine and taurine-deficiency in the perinatal period

Abstract Taurine, a non-protein sulfur amino-acid, is the most abundant free amino-acid in the body and plays an important role in several essential biological processes. Apart from its role in cholesterol degradation, it acts as neurotransmitter, and has a function as osmoregulator and antioxydant in most body tissues. During pregnancy, taurine accumulates in the maternal tissues, to be released in the perinatal period to the fetus via the placenta and to the newborn via the maternal milk. It is accumulated especially in the fetal and neonatal brain. Low maternal taurine levels result in low fetal taurine levels. Taurine-deficiency in the mother leads to growth retardation of the offspring, and to impaired perinatal development of the central nervous system and of the endocrine pancreas. The adult offspring of taurine-deficient mothers display signs of impaired neurological function, impaired glucose tolerance and vascular dysfunction; they may develop gestational diabetes and transmit the effects to the next generation. This transgeneration effect of taurine-deficiency in the perinatal period fits into the concept of fetal origin of adult disease.

Ultrastructural changes of the endocrine pancreas in pregnant rats

SummaryThe ultramicroscopic appearence of the B-cell of the pregnant rat suggests hyperinsulinism of the individual beta cell. In pregnant rats the B-cell contains an increased volume and an increased number of light granules as well as enlarged mitochondria.

Long-Term Effect of Diabetes and Pregnancy in the Rat

Islet hyperplasia and B-cell degranulation were found in the fetuses of the third generation from mothers (second generation) born to a diabetic mother (first generation) regardless of the origin of the father, while pancreatic islets were normal in fetuses from control mothers, even when the father was an offspring of a diabetic mother. These data support the hypothesis that in our experimental model overstimulation of the fetal endocrine pancreas results in long-term consequences to the third generation.

In Vivo Glucose Utilization by Individual Tissues in Virgin and Pregnant Offspring of Severely Diabetic Rats

Adult offspring of diabetic rats or SDF rats are characterized by insulin resistance in the liver and extrahepatic tissues; this insulin resistance does not worsen during pregnancy. In this study, we determined the glucose metabolic index in tissues of anesthetized virgin and pregnant control and SDF rats in basal conditions and during a euglycemic hyperinsulinemic clamp. Tissues comprised insulin-sensitive tissues (five skeletal muscles, diaphragm, and periovarian white adipose tissue) and control tissues (duodenum and cerebrum). In addition, this study measured the GMI of placenta and fetuses. In basal conditions, SDF rats showed a slight decrease (9–29%) in the GMI of skeletal muscles compared with control rats; it was not altered by pregnancy in any of the tissues. During physiological hyperinsulinemia, virgin SDF rats exhibited a 25–70% decrease in the GMI of skeletal muscles compared with control rats; this decrease was not observed in diaphragm, or in adipose tissue in which the GMI was found to be increased. During pregnancy, SDF rats did not show an additional drop in the GMI of skeletal muscles, whereas the GMI of both skeletal muscles and adipose tissue was clearly diminished (25–60%) in control rats. The GMI of skeletal muscles was therefore comparable in pregnant control rats and SDF rats. The placental, but not fetal, GMI was increased by 24% during hyperinsulinemia in control rats; the placental and fetal GMIs, in basal and hyperinsulinemic conditions, were similar in control rats and SDF rats. In conclusion, skeletal muscles, but not white adipose tissue, are involved in the peripheral insulin resistance of the SDF rats. However, pregnancy does not induce a further decrease in glucose utilization by skeletal muscles in SDF rats.

Immunocytochemical study of the endocrine pancreas in the rat during normal pregnancy and during experimental diabetic pregnancy

SummaryThe distribution of different celltypes (A, B, D and PP cells) of the endocrine pancreas was studied in both the normal and in the experimental diabetic non-pregnant and pregnant rat. In the normal rat the head (juxta duodenal part) of the pancreas contained more PP cells than the tail (12.5±1.1 versus 5.2±2.2) but fewer glucagon cells (19.0 ±3.5 versus 14.3±3.6). This difference disappeared during pregnancy, when the total B cell mass increased (2.05 versus 0.82). In the diabetic rat no difference was found in the number of endocrine cells between the tail and the juxta duodenal part of the pancreas. Unlike the non-diabetic rat, the number of B cells did not increase in the pancreas of the pregnant diabetic rat. An absolute increase in the number of glucagon (A) cells was demonstrated in the islets of the pregnant diabetic rat as compared to the non-diabetic rat (35 versus 21.2).