Long-term Metabolic Outcomes Research Articles

Short- and long-term consequences for offspring exposed to maternal diabetes: a review

The prevalence of gestational diabetes mellitus is increasing, as is the worldwide prevalence of type 2 diabetes and obesity, even in children and adolescents. Exposure in utero to maternal diabetes carries several short-term consequences due mainly to maternal hyperglycemia, and consequent fetal hyperinsulinemia. Current evidence also supports the hypothesis that adult health and disease have developmental origins, and that disorders in early-life environments prompt metabolic imprinting that results in a greater risk of negative metabolic outcomes later in life. In particular, exposure in utero to maternal diabetes seems to influence long-term metabolic outcomes, carrying a higher risk of obesity and type 2 diabetes, and thus creating a vicious cycle for future generations. In this paper, the short- and long-term consequences of exposure in utero to hyperglycemia are reviewed, focusing particularly on the long-term metabolic consequences, and investigating the possible pathogenic mechanisms involved.

Surgical treatment of children with total colonic aganglionosis: functional and metabolic long-term outcome

BackgroundTotal colonic aganglionosis (TCA) is a rare variant of Hirschsprung’s disease occurring in 3–10% of the cases. Only few studies reported the long-term clinical and metabolic outcomes of patients with TCA. The aim of this study was to evaluate the functional and metabolic long-term outcomes of children undergoing surgical treatment for TCA.MethodsA 15-year retrospective study was performed. Blood chemistry tests and stool analysis performed at the last follow-up visit were recorded. Height and weight development were assessed using the corresponding percentiles for age. Faecal continence and quality of life were evaluated using a detailed questionnaire.ResultsEleven patients were included in the study. The median age at surgery was 6 months (range: 3–72 months). After histological confirmation, all patients underwent a total colectomy. Ileoanal anastomosis (n = 6), ileorectal anastomosis (n = 1), J-pouch (n = 1) and Duhamel procedure (n = 3) were performed. Temporary ileostomy was closed after a median of 8 weeks in 10/11 patients. After a median follow-up of 78 months (range: 27–199 months), all evaluated patients were continent. Height and weight were appropriate for age in only 5 patients. Vitamin B12 and folic acid serum levels were normal in all examined patients. Ten patients had normal hemoglobin serum levels. Seven patients had low transferrin saturation in serum. Hemoccult tests were negative in all examined patients. Despite complex postoperative courses in some cases, patients and parents showed good overall satisfaction in terms of quality of life.ConclusionThe majority of patients reported a good quality of life. This can result from the adaptation of the patients to certain disease states. The failure to thrive seems to be related with the extent of aganglionosis. The inclusion of these patients in interdisciplinary long-term follow-up care, in which pediatric surgeons, gastroenterologists, and dieticians are involved, is essential.

Liver transaminase levels after intraportal autologous islet transplantation after partial pancreatectomy were associated with long-term metabolic outcomes

AimsTo investigate the changes of post-procedural liver transaminase levels after autologous islet transplantation (ITx), and their associations with glycemic outcomes. MethodsNon-diabetic patients who underwent distal pancreatectomy for benign tumors were enrolled. Islets isolated from the healthy part of the resected pancreas were transplanted via the portal vein. Metabolic parameters were evaluated in the subjects for 5 years. ResultsEight patients completed the study and four developed postoperative diabetes mellitus (PODM). Disposition index (DI) at postoperative 1 year showed prominent difference between the patients who develop PODM or not: DI was preserved in the PODM-free patients (49.7 ± 4.5 to 70.8 ± 14.4, P = 0.182), while it significantly decreased in the PODM patients (69.3 ± 9.9 to 28.5 ± 3.9, P = 0.019). The preoperative liver transaminase levels were not different between the two groups. However, transient increase in liver transaminase levels during the first week after ITx was observed only in the PODM patients, and their peak values demonstrated significant negative correlation with the changes in DI (r = −0.774 for alanine transaminase, r = −0.759 for aspartate transaminase; P < 0.05). ConclusionsElevation of serum transaminases after ITx could be one of the factors determining insulin secretion and PODM.

FRI-390 - Sustained virologic response leading to improved long-term metabolic outcomes

FRI-390 - Sustained virologic response leading to improved long-term metabolic outcomes

The Energy Costs of Prematurity and the Neonatal Intensive Care Unit (NICU) Experience.

Premature neonates are in an energy deficient state due to (1) oxygen desaturation and hypoxia events, (2) painful and stressful stimuli, (3) illness, and (4) neurodevelopmental energy requirements. Failure to correct energy deficiency in premature infants may lead to adverse effects such as neurodevelopmental delay and negative long-term metabolic and cardiovascular outcomes. The effects of energy dysregulation and the challenges that clinicians in the Neonatal Intensive Care Unit (NICU) face in meeting the premature infant’s metabolic demands are discussed. Specifically, the focus is on the effects of pain and stress on energy homeostasis. Energy deficiency is a complex problem and requires a multi-faceted solution to promote optimum development of premature infants.

Prenatal vitamin D status and offspring's growth, adiposity and metabolic health: a systematic review and meta-analysis.

In this systematic review and meta-analysis of observational studies, we aimed to estimate the associations between prenatal vitamin D status and offspring growth, adiposity and metabolic health. We searched the literature in human studies on prenatal vitamin D status and offspring growth in PubMed, up to July 2017. Studies were selected according to their methodological quality and outcomes of interest (anthropometry, fat mass and diabetes in offspring). The inverse variance method was used to calculate the pooled mean difference (MD) with 95 % CI for continuous outcomes, and the Mantel-Haenszel method was used to calculate the pooled OR with 95 % CI for dichotomous outcomes. In all, thirty observational studies involving 35 032 mother-offspring pairs were included. Vitamin D status was evaluated by circulating 25-hydroxyvitamin D (25(OH)D) level. Low vitamin D status was based on each study's cut-off for low 25(OH)D levels. Low prenatal vitamin D levels were associated with lower birth weight (g) (MD -100·69; 95 % CI -162·25, -39·13), increased risk of small-for-gestational-age (OR 1·55; 95 % CI 1·16, 2·07) and an elevated weight (g) in infant at the age of 9 months (g) (MD 119·75; 95 % CI 32·97, 206·52). No associations were observed between prenatal vitamin D status and other growth parameters at birth, age 1 year, 4-6 years or 9 years, nor with diabetes type 1. Prenatal vitamin D may play a role in infant adiposity and accelerated postnatal growth. The effects of prenatal vitamin D on long-term metabolic health outcomes in children warrant future studies.

A527 - Long-term weight and metabolic outcomes of patients managed through gastric bypass and traditional care in a patient-centered medical home (PCMH)

A527 - Long-term weight and metabolic outcomes of patients managed through gastric bypass and traditional care in a patient-centered medical home (PCMH)

Long-term metabolic follow-up and clinical outcome of 35 patients with maple syrup urine disease.

Maple syrup urine disease (MSUD) is a rare disease that requires a protein-restricted diet for successful management. Little is known, however, about the psychosocial outcome of MSUD patients. This study investigates the relationship between metabolic and clinical parameters and psychosocial outcomes in a cohort of patients with neonatal-onset MSUD. Data on academic achievement, psychological care, family involvement, and biochemical parameters were collected from the medical records of neonatal MSUD patients treated at Necker Hospital (Paris) between 1964 and 2013. Thirty-five MSUD patients with a mean age of 16.3(2.1-49.0)years participated. Metabolic decompensations (plasma leucine >380μmol/L) were more frequent during the first year of life and after 15years, mainly due to infection and dietary noncompliance, respectively. Leucine levels increased significantly in adulthood: 61.5% of adults were independent and achieved adequate social and professional integration; 56% needed occasional or sustained psychological or psychiatric care (8/19, with externalizing, mood, emotional, and anxiety disorders being the most common). Patients needing psychiatric care were significantly older [mean and standard deviation (SD) 22.6 (7.7) years] than patients needing only psychological follow-up [mean (SD) 14.3 (8.9) years]. Patients with psychological follow-up experienced the highest lifetime number of decompensations; 45% of families had difficulty coping with the chronic disease. Parental involvement was negatively associated with the number of lifetime decompensations. Adults had increased levels of plasma leucine, consistent with greater chronic toxicity. Psychological care was associated with age and number of decompensations. In addition, parental involvement appeared to be crucial in the management of MSUD patients.

In Vitro fertilization and adverse obstetric and perinatal outcomes

Most IVF-conceived children are healthy, but IVF has also been associated with adverse obstetric and perinatal outcomes as well as congenital anomalies. There is also literature suggesting an association between IVF and neurodevelopmental disorders as well as potentially long-term metabolic outcomes. The main driver for adverse outcomes is the higher risk of multiple gestations in IVF, but as the field moves toward single embryo transfer, the rate of multiple gestations is decreasing. Studies have shown that singleton IVF pregnancies still have a higher incidence of adverse outcomes compared to unassisted singleton pregnancies. Infertility itself may be an independent risk factor. Animal models suggest that epigenetic changes in genes involved in growth and development are altered in IVF during the hormonal stimulation and embryo culture. Further animal research and prospective human data are needed to elucidate the mechanisms by which IVF may contribute to adverse outcomes and to decrease risks.

Long-term Metabolic Outcomes of Functioning Pancreas Transplants in Type 2 Diabetic Recipients

Limited data are available regarding the long-term metabolic outcomes of functioning pancreas transplants in patients with type 2 diabetes mellitus (T2DM). To compare the long-term effects of pancreas transplantation in terms of insulin resistance and β cell function, comparison of metabolic variables was performed between type 1 diabetes mellitus (T1DM) and T2DM patients from 1-month posttransplant to 5 years using generalized, linear-mixed models for repeated measures. Among 217 consecutive patients who underwent pancreas transplantation at our center between August 2004 and January 2015, 193 patients (151 T1DM and 42 T2DM) were included in this study. Throughout the follow-up period, postoperative hemoglobin A1c did not differ significantly between T1DM and T2DM patients, and the levels were constantly below 6% (42 mmol/mol) until 5 years posttransplant, whereas C-peptide was significantly higher in T2DM (P = 0.014). There was no difference in fasting insulin, homeostasis model assessment (HOMA) of insulin resistance, HOMA β cell, or the insulinogenic index between the groups. Furthermore, fasting insulin and HOMA-insulin resistance steadily decreased in both groups during the follow-up period. There was no significant difference in the insulin resistance or β-cell function after pancreas transplantation between T1DM and T2DM patients. We demonstrated that pancreas transplantation is capable of sustaining favorable endocrine functions for more than 5 years in T2DM recipients.

The Pune Rural Intervention in Young Adolescents (PRIYA) study: design and methods of a randomised controlled trial

BackgroundThe Pune Maternal Nutrition Study (PMNS) was established to prospectively study the relationship of maternal nutrition to fetal growth and later cardiometabolic risk in the offspring. High homocysteine and low vitamin B12 levels in pregnancy predicted lower birthweight and higher insulin resistance at 6 years in the offspring. B12 deficiency was widespread in this population, due to low dietary intake. We therefore commenced a community-based intervention study with the underlying hypothesis that vitamin B12 supplementation of adolescent members of the PMNS cohort will improve birth weight, B12 status, and reduce future diabetes risk, in their offspring.MethodsThe individually randomised controlled trial commenced in September 2012, with boys and girls randomized into 3 groups, to receive daily for at least 3 years or until the birth of their first child: 1) vitamin B12 2 μg; or 2) vitamin B12 2 μg plus multiple micronutrients (MMN) plus 20 g of milk powder or 3) placebo. Iron and folic acid is given to all participants. Compliance is assessed by monthly supplement counts. Adverse events are recorded using a standardised questionnaire. The primary outcome is cord blood B12 concentration; based on 180–200 pregnancies in the girls, the study has ~80% power to detect a 0.5 SD change in newborn B12, in the B12 supplementation groups compared with controls, at the 5% significance level. Primary analysis will be by intention to treat.DiscussionOur study tests a primordial prevention strategy through an intergenerational intervention started pre-conceptionally in both boys and girls using physiological doses of micronutrients to improve immediate pregnancy-related and long-term cardio metabolic outcomes. The results will have significant public health implications in a setting with widespread B12 deficiency but relative folate sufficiency. The randomised controlled trial design allows us to be confident that our findings will be causally relevant.Trial registrationISRCTN 32921044, applied on 14/09/2012. CTRI 2012/12/003212, registered on 02/12/2012. Retrospectively registered.

Transitional hemodynamics in infants of diabetic mothers by targeted neonatal echocardiography, electrocardiography and peripheral flow study

Objective: Metabolic alterations of intrauterine environment in diabetes mellitus (DM) lead to fetal cardiac dysfunctions that can persist after birth. The aim of the study was to assess the cardiovascular adaptation in infants born to diabetic mothers (IDM) with different degrees of glycometabolic control, in relation to revised guidelines for diagnosis of DM and quality improvements in neonatal care. Materials and methods: An observational case-control study was conducted on IDM with gestational, type 1 and type 2 DM. Relevant maternal and neonatal anamnestic, clinical and laboratory data were analyzed. Electrocardiographic and echocardiographic analyses, including structural and systo-diastolic evaluation, were performed. Results: In 68 IDM enrolled, we observed a lower incidence of negative perinatal outcome than expected. Comparing to non-IDM, they presented larger fetal shunts, higher pulmonary pressures, early and atrial wave velocities. At 72 hours, kinesis and heart rate variability remained low. Cerebral blood flow velocities were higher. The most serious impairment of transition was in pregestational IDM. Conclusion: Maternal DM impaired neonatal transitional hemodynamics also in asymptomatic IDM with good glycometabolic control. These results confirm the need for an early cardiologic and cerebrovascular evaluation, to identify IDM with delayed maturation at risk of worse long-term metabolic, cardiovascular, and neurodevelopmental outcome.

Diet-induced modifications to milk composition have long-term effects on offspring growth in rabbits.

It has been clearly demonstrated that the maternal nutritional status during pregnancy and lactation has long-term effects on offspring health. In mammals, milk represents the first maternal support provided to the newborns so that its composition may play a major role in long-term programming. We therefore assessed the effects of maternal high-fat/high-sugar obesogenic (OD) or control (CD) diets on offspring growth and adiposity in the rabbit. Between 7 and 20 wk of age, the BW gain of OD milk-fed rabbits was higher than that of CD milk-fed rabbits ( < 0.05). Body fat mass measurements at 21 wk of age revealed a significant increase in body adiposity as a function of milk ingested during the neonatal period, in both female and male offspring ( < 0.05). A marked weight gain difference was observed according to the milk in both female and male offspring. Moreover, we investigated the composition in major proteins and leptin levels in milk from OD or CD diet-fed dams. Liquid chromatography-mass spectrometry analysis of individual CD skimmed milk samples enabled identification and quantification of the rabbit main milk proteins and of their main phosphorylated isoforms at 2 different stages of lactation (3 and 10 d). Here we show that the OD diet induced a reduction in the whey acidic protein content concomitantly with both an increase in serum albumin and lactoferrin contents and in the phosphorylated isoforms of the main milk proteins. Furthermore, a sharp rise in leptin levels was observed in the milk of OD diet-fed dams on Day 10 of lactation when compared with CD diet animals ( < 0.05). Taken together, these findings provide evidence that lactation is a critical window of development during which exposure to a deleterious diet is highly detrimental to long-term outcomes. Moreover, these insights suggest that it may be possible to prevent at least some of the adverse effects of inadequate maternal nutrition on the long-term metabolic outcomes of the offspring through nutritional interventions applied during the lactation period.

Prediction of Diabetes Remission at Long Term Following Biliopancreatic Diversion.

In obese patients with type 2 diabetes (T2DM), the marked weight loss following bariatric surgery is accompanied in a consistent number of cases by T2DM resolution or control. The clinical need of preoperative parameters reliable in predicting a positive metabolic outcome at long term following the operation has then emerged. A cohort of 135 consecutive T2DM patients with a wide range of body mass index (BMI) at more than 5years following biliopancreatic diversion (BPD) was considered. The 5-year-T2DM resolution, defined as glycosylated hemoglobin (HbA1C) lower than 6.5% without antidiabetic therapy, was related to demographic, anthropometric, and biochemical findings prior to the operation. The long-term metabolic outcome was positively related to baseline BMI values and negatively with the preoperative use of insulin. BMI and insulin therapy at the time of surgery are associated with the probability of T2DM long lasting remission and could be used as solid predictors before surgery. In the overweight and non morbidly obese diabetic patients, bariatric surgery is less efficient in determining long term T2DM resolution than in their morbid obese counterparts.

Associations of maternal BMI and insulin resistance with the maternal metabolome and newborn outcomes.

Maternal obesity increases the risk for large-for-gestational-age birth and excess newborn adiposity, which are associated with adverse long-term metabolic outcomes in offspring, probably due to effects mediated through the intrauterine environment. We aimed to characterise the maternal metabolic milieu associated with maternal BMI and its relationship to newborn birthweight and adiposity. Fasting and 1h serum samples were collected from 400 European-ancestry mothers in the Hyperglycaemia and Adverse Pregnancy Outcome Study who underwent an OGTT at ∼28weeks gestation and whose offspring had anthropometric measurements at birth. Metabolomics assays were performed using biochemical analyses of conventional clinical metabolites, targeted MS-based measurement of amino acids and acylcarnitines and non-targeted GC/MS. Per-metabolite analyses demonstrated broad associations with maternal BMI at fasting and 1h for lipids, amino acids and their metabolites together with carbohydrates and organic acids. Similar metabolite classes were associated with insulin resistance with unique associations including branched-chain amino acids. Pathway analyses indicated overlapping and unique associations with maternal BMI and insulin resistance. Network analyses demonstrated collective associations of maternal metabolite subnetworks with maternal BMI and newborn size and adiposity, including communities of acylcarnitines, lipids and related metabolites, and carbohydrates and organic acids. Random forest analyses demonstrated contribution of lipids and lipid-related metabolites to the association of maternal BMI with newborn outcomes. Higher maternal BMI and insulin resistance are associated with broad-based changes in maternal metabolites, with lipids and lipid-related metabolites accounting, in part, for the association of maternal BMI with newborn size at birth.

Adipokine Pattern After Bariatric Surgery: Beyond the Weight Loss.

Besides the role in energy storing and body health isolating, adipose tissue produces proteins, the so-called adipokines, with pro-inflammatory or anti-inflammatory actions that contribute to metabolic control and to appetite and energy expenditure regulation. The marked adipose tissue loss following bariatric surgery corresponds to a rearrangement of serum adipokine pattern, with increase of anti-inflammatory and decrease of pro-inflammatory agents. This might play a relevant role in the postoperative improvement of metabolic conditions. However, after surgically induced weight loss, other investigations failed to evidence significant modifications of serum concentration of some adipokines. This review speculates that the composition of adipose tissue lost could influence postoperative changes in some adipokine concentration and that an adequate adipokine pattern plays a pivotal role for the long-term metabolic outcome.

Long-term Functional, Urodynamic, and Metabolic Outcome of a Modified Orthotopic Neobladder Created With a Short Ileal Segment: Our 5-year Experience

To assess the long-term functional, urodynamic, and metabolic outcomes of our modified neobladder. In this prospective study from January 2010 to October 2014, 42 consecutive male patients with bladder tumor underwent radical cystectomy and orthotopic urinary diversion with modified ileal neobladder using 25 cm ileal segment. During follow-up, functional outcome, urodynamic studies, metabolic parameters, and renal parameters were assessed at regular intervals. Complications were graded as early (<3 months) or late (>3 months). There were no perioperative deaths. At a mean follow-up of 27.2 months, good or satisfactory daytime and nighttime continence were achieved in 100% and 93.8% of patients, respectively. Mean maximal bladder capacity was 588 mL at 3 years. Mean resting pressure and voiding pressures were 20.1 cm H2O and 34.6 cm H2O at 3 years, respectively. Good bladder compliance was achieved in all patients by 1 year. Mean maximum urine flow rate (Qmax) was 18.5 mL at 3 years. Postvoid residual volume was insignificant in all the patients and none of the patients were on clean intermittent self-catheterization. None of the patients developed severe metabolic acidosis. Vitamin B12 levels were within normal range in all patients. Early complications were seen in 12 patients (28.6%), whereas late complications were observed in 5 patients (12%). Our results demonstrate that our modified technique of using a short ileal segment to create a near-spherical, compliant, low-pressure reservoir provides an acceptable, safe, and functional alternative to the standard Hautmann neobladder.

Long-term clinical and functional impact of biliopancreatic diversion on type 2 diabetes in morbidly and non–morbidly obese patients

SettingObesity surgery has been proposed as a treatment option for diabetic patients with body mass index (BMI)<35 kg/m2, but the efficacy of metabolic surgery has not been conclusively determined. ObjectivesTo evaluate the long-term metabolic outcome of non–morbidly obese (NMO) patients with type 2 diabetes (T2D) after biliopancreatic diversion (BPD). Material and methodsTwo groups of T2D patients with different degree of obesity (NMO, 17 cases, BMI 25–35 kg/m2; and morbidly obese [MO], 13 cases, BMI>35 kg/m2) were studied before and at 1 and 5 years after BPD in a university hospital setting. Insulin secretion was assessed by acute insulin response (AIR) to intravenous glucose and by insulinogenic index (IGI). ResultsIn all MO patients, T2D was remitted or controlled (1 case) at 1 year and results were maintained at 5 years; AIR (μU/mL) and IGI (μU/mg) improved (P<.001) at 1 year (from .1±3.1 to 18.52±21.9, and from 6.0±8.5 to 9.1±22.8, respectively) with a further increase (to 24.8±25.5 and to 14.3±13.8, respectively) at 5 years. Within the NMO group, T2D was remitted in 1/17 and controlled in 14/17 patients at 1 year, and in 2/17 and in 4/17 patients at 5 years, respectively; AIR (μU/mL) and IGI (μU/mg) remained unchanged throughout the postoperative period (from .31±9.26 to 1.5±2.8 at 1 yr and to .4±3.29 at 5 yr for AIR, and from 2.2±4.9 to 1.3±9.0 at 1 yr and to 2.3±3.3 at 5 yr for IGI). ConclusionsAfter BPD, restoration of β-cell secretion/production plays a pivotal role in determining postoperative T2D remission.

Long-Term Metabolic Outcomes 5 to 20 Years After Biliopancreatic Diversion.

Biliopancreatic diversion (BPD) is a complex bariatric operation requiring meticulous surveillance which has impeded its broad adoption. Improvements in surgical care and technique, better teaching programs, and stringent norms for follow-up have contributed to increased safety of BPD for patients with BMI <50, achieving better long-term results than other bariatric operations. Here we report 20-year outcomes of 2615 consecutive patients (median 8) having open BPD with duodenal switch (DS) between 1992 and 2010. Chart of 92 % of patients with complete clinical, biochemical, and physical examinations completed before 2013 was reviewed. The research was conducted at Academic Medical Center, Quebec City. There was total mortality of 4.7 %, equivalent to that of the general population of Quebec. Incident diabetes (38.8 %) was cured in 93.4 % (blood glucose <6 mmol/l; HbA1c <6.5 %) with 4 % relapse rate after mean 9.6 years with no new cases. Dyslipidemia (24.2 %) was cured in 80 %. Hypertension (60 %) was cured in 64 % and improved in 31 %. Mean weight loss of 55.3 kg (71 % excess weight loss (EWL); 20 BMI units) was maintained for 5 to 20 years. Operative mortality was reduced from 1.3 % in 1992 to 0.2 % during 2005-2010, with cumulated rate surgical mortality of 0.5, revision rate 3, and reoperations in 13 %. Nutritional deficiencies were present in 2 % for calcium, iron, and vitamin A. Side effects were considered minor by the great majority of patients, rating global satisfaction as 4.5/5 (91 % "satisfied"). BPD deserves more consideration as a primary procedure for eligible patients in experienced centers with sufficient resources for delivering high-quality care and long-term follow-up.

Effect of pre- and postnatal growth and post-weaning activity on glucose metabolism in the offspring.

Maternal caloric restriction during late gestation reduces birth weight, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (∼147 days), compared with mothers fed to 100% of requirements. Offspring were reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reduced maternal plasma glucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity.