Is low birth weight a risk factor for the development of diabetic nephropathy in patients with type 1 diabetes? A population-based case-control study.

OBJECTIVES: To investigate if low birth weight as a consequence of intrauterine malnutrition is a risk factor for the later development of diabetic nephropathy. DESIGN AND SUBJECTS: In a case-control set-up a group of type 1 diabetic subjects with diabetic nephropathy (n = 51) and a matched control group with normal kidney function (n = 51) were compared. Diabetic nephropathy and normal kidney function were defined as urinary albumin excretion rate above 200 microg min-1 and below 20 microg min-1, respectively. The birth weights were all obtained from the midwives' original records. SETTING: The patients were identified from a population-based study of chronic diabetic complications in the Funen County, Denmark. MAIN OUTCOMES: Birth weights according to the presence of diabetic nephropathy. RESULTS: The median (10-90 percentile) birth weights were 3,600 g (2,960-4,274) in the group with diabetic nephropathy and 3,600 g (2,880-4,220) in the group without nephropathy, P = 0.52. In the lower quartile of birth weights the median (10-90 percentile) birth weights were 3,000 g (2,780-3,200) in the group with nephropathy versus 2,850 g (2,250-3,175) in the group without nephropathy, P = 0.07. In the upper quartile the median (10-90 percentile) birth weights were 4,225 g (4,000-4,741) in the nephropathy group and 4,000 g in the group without nephropathy, P = 0.13. We found no significant correlation between birth weights and log urinary albumin excretion rate (r = 0.148, P = 0.14) and no difference in the number of patients with nephropathy in the lower versus upper quartiles of birth weights. CONCLUSION: We found no evidence of low birth weight as a risk factor for the development of diabetic nephropathy.

Prenatal malnutrition-induced hypertension in young rats is prevented by neonatal capsaicin treatment.

Prenatal malnutrition-induced fetal growth retardation in the rat results in elevated arterial blood pressure at adulthood. To test the contribution of cardiovascular sensory C fibers in the hypertensive state, arterial blood pressure was measured in prenatally undernourished rats treated at birth with capsaicin. The effects of the neonatal capsaicin treatment on heart rate and respiratory frequency were also evaluated. Maternal malnutrition resulted in body and brain weights deficits in the offspring that were not modified by neonatal capsaicin treatment. Capsaicin treatment did not change the cardiovascular parameters in normal rats, but prevented the elevation of arterial blood pressure and heart rate in malnourished animals. These results indicate that elevation of arterial blood pressure in prenatally malnourished rats depends on the activity of some sensory unmyelinated C fibers.

Fetal malnutrition and adult chronic disease.

Since the fetal origins of adult disease hypothesis was put forward, more than 30 studies around the world have indicated low-birth-weight (LBW) infants have a higher incidence of hypertension and impaired glucose tolerance. India ranks second in incidence of LBW among South East Asian countries and is experiencing a transition of disease pattern from communicable disease to non-communicable disease. Whether this could be explained in part by LBW infants who experienced better nutrition at a later age is explored here. An earlier cohort with accurate birth weights was traced and enrolled into the study. A sample of 50 LBW and 78 normal birth weight (NBW) individuals are reported on here. Though the odds ratio (OR) estimates of risk factors for coronary heart disease and diabetes tended to be higher in LBWs who were better nourished at the time of the study, they were not statistically different. Similarly, OR estimates for risk factors tended to be higher in LBWs who put on more weight than the median of NBWs, but they were not significant. Logistic regressions with several variables indicated significant influence of body mass index on systolic (P <0.007) and diastolic (P <0.004) blood pressures. Since the risk associations are weak, more studies are needed to put the hypothesis on a firm footing.

The effect of maternal undernutrition on ovine fetal growth.

Modifications in maternal nutrition during pregnancy can significantly disrupt fetal growth and subsequent post-natal health and survival. This study investigated the effects of undernutrition on fetal growth and the potential mechanisms involved. Tissue from pregnant ewes (n=27) was investigated on days 45, 90 and 135 of gestation (term = approximately 150 days). The thoracic girth (P<0.05) was greater in fetuses from nutrient restricted ewes on day 45 and there was also a trend towards an increased gut weight (P<0.08). By day 90, the fetal brain and thymus weight were lighter in underfed than in well-fed animals whilst the weight of the fetal ovaries was heavier (P<0.05). On day 135 the fetal heart, pancreas, thymus, gut and kidney weights were lighter in undernourished ewes (P<0.05). When expressed as a percentage of fetal body weight, significance was retained in the heart, pancreas and thymus (P<0.05). Bone growth was also affected. At day 90 the fetal femur and metatarsal were longer in underfed mothers (P<0.05). In contrast, the fetal humerus and scapula were shorter in underfed than in well-fed animals on day 135 (P<0.05) when the weight of the semitendinosus muscle (P<0.05) was also reduced. The fall in fetal glucose (P<0.1), insulin (P<0.01) and IGF-I (P<0.01) levels in underfed ewes on day 135 may have compromised fetal growth. Fetal plasma IGF binding protein-2 also increased between days 90 and 135 in underfed ewes (P<0.03), whilst levels were unaltered in well-fed animals. Although maternal and fetal plasma IGF-I levels increased with gestation (P<0.01) and the placentome morphology altered in all ewes (P<0.05), the fall in placental mass (P<0.05), amniotic and allantoic glucose concentrations (P<0.05) and maternal plasma glucose and insulin levels (P<0.05) in underfed ewes in late gestation may have compromised fetal substrate delivery. These perturbations in fetal development may have significant implications on adult health and carcass conformation, raising important health and economic issues in medical and agricultural sectors.

Dysregulation of the adipoinsular axis -- a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming.

Obesity and its related disorders are the most prevalent health problems in the Western world. Using the paradigm of fetal programming we developed a rodent model which displays the phenotype of obesity and metabolic disorders commonly observed in human populations. We apply maternal undernutrition throughout gestation, generating a nutrient-deprived intrauterine environment to induce fetal programming. Maternal undernutrition results in fetal growth retardation and in significantly decreased body weight at birth. Programmed offspring develop hyperphagia, obesity, hypertension, hyperleptinemia and hyperinsulinism during adult life and postnatal hypercaloric nutrition amplifies the metabolic abnormalities induced by fetal programming. The adipoinsular axis has been proposed as a primary candidate for linking the status of body fat mass to the function of the pancreatic beta-cells. We therefore investigated the relationship between circulating plasma concentrations of leptin and insulin and immunoreactivity in the endocrine pancreas for leptin and leptin receptor (OB-R) in genetically normal rats that were programmed to become obese during adult life. Virgin Wistar rats were time mated and randomly assigned to receive food either available ad libitum (AD group) or at 30% of the ad libitum available intake (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring (AD 6.13+/-0.04 g, UN 4.02+/-0.03 g, P<0.001). At weaning, offspring were assigned to one of two diets (a standard control diet or a hypercaloric diet consisting of 30% fat) for the remainder of the study. At the time of death (125 days of age), UN offspring had elevated (P<0.005) fasting plasma insulin (AD control 1.417+/-0.15 ng/ml, UN control 2.493+/-0.33 ng/ml, AD hypercaloric 1.70+/-0.17 ng/ml, UN hypercaloric 2.608+/-0.41 ng/ml) and leptin (AD control 8.8+/-1.6 ng/ml, UN control 14.32+/-1.9 ng/ml, AD hypercaloric 15.11+/-1.8 ng/ml, UN hypercaloric 30.18+/-5.3 ng/ml) concentrations, which were further increased (P<0.05) by postnatal hypercaloric nutrition. The elevated plasma insulin and leptin concentrations were paralleled by increased immunolabeling for leptin in the peripheral cells of the pancreatic islets. Dual immunofluorescence histochemistry for somatostatin and leptin revealed that leptin was co-localized in the pancreatic delta-cells. OB-R immunoreactivity was evenly distributed throughout the pancreatic islets and was not changed by programming nor hypercaloric nutrition. Our data suggest that reduced substrate supply during fetal development can trigger permanent dysregulation of the adipoinsular feedback system leading to hyperleptinemia, hyperinsulinism and compensatory leptin production by pancreatic delta-cells in a further attempt to reduce insulin hypersecretion in the progression to adipogenic diabetes.

[The immune system of the hunter-gatherer meets poverty and excess]. / Jägarens-samlarens immunsystem möter fattigdom och överflöd.

The immune system is closely integrated with the neuroendocrine system, and infection-induced increases in cytokines such as IL-1, IL-6 and TNF have numerous effects on the central nervous system. These include stimulation of the hypothalamus-pituitary-adrenal (HPA) axis, as well as of leptin production. The increase in leptin causes loss of appetite, which may be deleterious for children who are living under conditions of poverty, have frequent infections and are often already undernourished. These cytokines may also be involved in problems of obesity, since they activate the HPA-axis and since TNF is produced by fat cells and can cause insulin resistance. The immune system originally developed for hunter-gatherers may not be well adapted to the pathology of poverty or that of excess.

Retinoids and their receptors in vertebrate embryogenesis.

Vitamin A and its derivatives, the retinoids, participate in formation of diverse embryonic structures, including face, heart, eye, limb and nervous system. Studies of retinoid-deficient and -treated embryos, and of receptor null mutants, provide evidence that this participation involves interactions between retinoids and their receptors. Targeted retinoid application and retinoid deficiency, using in ovo avian embryos, has identified early cardiogenic contributions, including cardiocyte gene expression and differentiation, heart tube fusion and laterality, and segmental identity. Also useful is a mammalian model, which targets retinoid deficiency to distinct gestational windows, circumventing limitations of traditional deficiency studies and current null mutant technologies. Rat embryos made deficient in retinoids during gestational d 11.5-13.5 exhibit specific cardiac, limb, ocular and nervous system deficits. That many of the anomalies previously reported in retinoid receptor null mutants are observed in deficiency confirms that ligand-receptor interactions are essential for embryonic development. Other defects are novel, reemphasizing the functional redundancy of retinoid receptors and that retinoid receptors have multiple and overlapping contributions to morphogenesis.

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.

In utero undernutrition impairs rat beta-cell development.

The role of nutrition on the development of the endocrine pancreas was studied in a rat model obtained by maternal food restriction. A 50% food restriction was applied to female rats from day 15 of pregnancy and resulted in intrauterine growth-retardation (IUGR) in the offspring. At day 1 postnatal, beta-cell mass was significantly decreased in IUGR pups as compared to controls (0.70 +/- 0.06 vs 1.07 +/- 0.06 mg, p < 0.0001), as well as insulin content. This change in beta-cell mass can be attributed to a reduced number of islets, since the density of insulin-positive aggregates in pancreatic sections of IUGR rats was 20% lower than in controls. Proliferative capacity of beta cells, as measured by 5-bromo-2-deoxyuridine (BrdU) labelling index, was not altered in growth-retarded animals. Body as well as pancreatic weight were fully recovered in IUGR pups after 21 days of normal feeding by control mothers. However, these animals retained a 25% decrease in insulin content, 40% decrease in beta-cell mass (1.58 +/- 0.18 vs 2.78 +/- 0.42 mg, p < 0.001) and a strong reduction in the density of insulin positive aggregates per cm2, as compared to controls, suggesting that the total islet number was likely to be reduced. Beta-cell proliferative capacity remained normal. In conclusion, in utero undernutrition in rats does not impede postnatal growth but durably impairs beta-cell development. Impairment of beta-cell differentiation might be suggested.

Lifelong consequences of metabolic adaptations in utero?

Dr. Phillips argues that insulin resistance in adult life may be the price the developing fetus has to pay in return for a short-term successful adaptation to undernutrition in utero. The concept is interesting, and, indeed, challenging. There is, however, a strong need for expansion of the existing knowledge of the possible developmental mechanisms involved, especially against the background of the obvious diagnostic and therapeutic gains in this particular group of patients.

Developmental toxicity of in utero exposure to toluene on malnourished and well nourished rats.

The aim of the present study was to investigate the effects of toluene on fetal development in well nourished and malnourished rats. Long-term behavioural consequences after in utero exposure were also studied. Toluene (1.2 g/kg s.c.) was administered daily to well nourished and to malnourished (food restricted to 50% of ad libitum intake) pregnant rats, during the second (8-15 days) or the third week of pregnancy (14-20 days). Offspring were evaluated for malformations, development of the skeleton, prenatal growth of the brain and liver, postnatal growth and long lasting behavioural effects. In utero exposure to toluene during the third week of pregnancy resulted in low body weight at birth, which persisted in the male offspring into adulthood. Malnutrition increased fetal susceptibility to the effects of toluene as indicated by evaluation of the development of the skeleton. Behavioral tests performed when the pups were 30 and 90 days old showed effects of in utero malnutrition (increased ambulation and worse performance in a shuttle box), but no behavioural effects related to toluene exposure were detected. These data indicate that in utero exposure to toluene can have long lasting effects on body growth and that maternal malnutrition increases the risk for toluene fetotoxicity.

Mating behaviour of male rats following pre- and early postnatal undernutrition: a comparison of two outbred stocks.

Developing rats of two outbred stocks (Lister and Wistar) were either well-nourished or were undernourished by feeding their mothers a restricted quantity of food during pregnancy and lactation. All rats were fed ad lib from 25 days. Beginning at 14 months, the mating behaviour of males was investigated in five tests at weekly intervals using ovariectomised females brought into behavioural oestrus using injections of oestradiol and progesterone. Lister males were tested with Lister females, and Wistar males with Wistar females. Early life undernutrition reduced the numbers of non-penetrative mounts and shortened the latency to ejaculate in rats of the Lister but not the Wistar stock. Mount latency was reduced by early undernutrition in the Wistar stock, but was unaffected in the Lister stock. These results indicate that the effects of early life undernutrition on male mating behaviour differ in detail from one stock of rat to another. In general, however, the results suggest that infantile undernutrition facilitates, rather than impairs, the sexual behaviour of male rats in "middle-age."

Effects of undernutrition on gliogenesis and glial maturation in rat corpus callosum.

Rats were undernourished by halving the mother's food intake from the sixth day of pregnancy onwards and through lactation. At weaning, the young rats were restricted to half the normal weight of food. A combination of light and electron microscopic techniques was used to study the effects of this regime on gliogenesis and glial maturation in the corpus callosum of animals aged between 15 and 48 days. A disturbance of neuroglial proliferation was suggested by the finding of an increased proportion of astroglia relative to oligodendroglia in the 15-day-old undernourished rats, indicating a delay in the acquisition of cells produced relatively late in development. Impaired differentiation of oligodendroglia was suggested by the finding in treated animals of increased light oligodendrocytes at 15 days and a deficit of dark oligodendrocytes at 48 days, relative to controls. The previously observed retardation in myelin acquisition seems thus to be related to a delay in the differentiation of oligodendroglia, although it seems likely that the proliferation of these cells is also disturbed in undernutrition.

Effects of undernutrition on myelination in rat corpus callosum.

Rats were undernourished by halving the mother's food intake from the sixth day of pregnancy onwards and through lactation. Subsequently, the young animals were maintained up to 48 days on half the normal diet. The effects of this regime of treatment on myelination in the corpus callosum were investigated by light and electron microscopy. In comparison with controls, the percentage of axons myelinated at 15, 21, and 48 days was reduced in undernourished rats. The number of lamellae constituting the myelin sheath was also reduced at 15 and 21 days, but at 48 days no difference was seen between control and treated rats, suggesting that a catch-up in myelination had occurred. A linear relationship between myelin sheath thickness and axonal diameter was observed in both groups of animals. However, a long-term effect on axonal growth was suggested by findings in the 48-day undernourished animals; in comparison with controls, axonal diameter was reduced, relative to myelin sheath thickness.