The use of microindentation for the study of bone properties in type 1 diabetes mellitus patients.

Diabetes mellitus is associated with a higher risk of fracture. In this study, we analysed the bone quality of premenopausal women with type 1 diabetes mellitus by microindentation. No differences in bone quality were identified between patients and healthy controls, suggesting that intensive insulin therapy can preserve bone health. PURPOSE: To compare the bone quality of women with type 1 diabetes mellitus (T1DM) and healthy controls, and to determine the relationship with bone mineral density (BMD). METHODS: This was a cross-sectional study of 45 premenopausal women with T1DM and 21 healthy controls, matched according to age and BMI. Clinical parameters, BMD and bone tissue mechanical properties (assessed using the bone material strength index [BMSi]) were evaluated in each group using microindentation. In T1DM patients, glycosylated haemoglobin (HbA1c), the number of hypoglycaemic events and the status of chronic complications were also analysed. RESULTS: No differences in BMSi or BMD between T1DM patients and healthy controls were identified. In the T1DM patients, the mean HbA1c was 7.52% ± 1.00% and the mean time elapsed since diagnosis was 22.6 ± 12.2 years. Eight patients (17.7%) met the criteria for metabolic syndrome (MetS), and microvascular complications were present in 12 patients (26.7%). Neither the number of features of MetS present nor the presence of microangiopathy was found to be associated with BMSi. CONCLUSIONS: T1DM premenopausal patients showed bone tissue properties comparable to those shown by controls. Further larger-scale studies should be conducted to confirm these results.

Untargeted metabolomics identifies a plasma sphingolipid-related signature associated with lifestyle intervention in prepubertal children with obesity.

OBJECTIVE: Childhood obesity is a strong risk factor for adult obesity and metabolic diseases, including type 2 diabetes and cardiovascular disease. Early lifestyle intervention in children with obesity reduces future disease risk. The objective of this study is to identify metabolic signatures associated with lifestyle intervention in prepubertal children with obesity. METHODS: Thirty-five prepubertal children (7-10 years) with obesity (body mass index (BMI)>2 standard deviations) were enrolled in the study and participated in a 6-month-long lifestyle intervention program. Physiological and biochemical data and blood samples were collected both at baseline and after the intervention. A liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach was applied to obtain a comprehensive profiling of plasma samples, identifying 2581 distinct metabolite. Principal component analysis (PCA) was performed to consolidate all features into 8 principal components. Associations between metabolites and physiological and biochemical variables were investigated. RESULTS: The intervention program significantly decreased mean (95% CI) BMI standard deviation score from 3.56 (3.29-3.84) to 3.11 (2.88-3.34) (P<0.001). PCA identified one component (PC1) significantly altered by the intervention (Bonferroni adjusted P=0.008). A sphingolipid metabolism-related signature was identified as the major contributor to PC1. Sphingolipid metabolites were decreased by the intervention, and included multiple sphingomyelin, ceramide, glycosylsphingosine and sulfatide species. Changes in several sphingolipid metabolites were associated with intervention-induced improvements in HbA1c levels. CONCLUSIONS: Decreased circulating sphingolipid-related metabolites were associated with lifestyle intervention in prepubertal children with obesity, and correlated to improvements in HbA1c.

High prevalence of cardiovascular co-morbidities in patients with symptomatic knee or hand osteoarthritis.

OBJECTIVES: To evaluate the frequency of cardiovascular events (CVEs) and metabolic syndrome (MetS) in patients with symptomatic knee or hand osteoarthritis (OA). METHOD: A cross-sectional study conducted by rheumatologists in a primary care setting. Consecutive symptomatic patients with primary knee or hand OA were included and patients with soft tissue conditions served as the control group. Hypertension, diabetes mellitus, obesity, dyslipidaemia, and CVEs consisting of myocardial infarction, angina, or cerebrovascular disease were recorded. RESULTS: A total of 254 OA patients (184 with knee OA and 70 with hand OA) and 254 control patients were included. The frequency of obesity was higher in all OA groups and hypertension was more frequent in knee OA. MetS was significantly more frequent in patients with OA as a whole group and in knee or hand OA groups separately (p < 0.001, p = 0.002, and p = 0.007, respectively, vs. control group), with odds ratio (OR) 2.4, 95% confidence interval (CI) 1.26-4.55 in the OA group, OR 2.29, 95% CI 1.15-4.54 in the knee OA group, and OR 2.67, 95% CI 1.15-6.19 in the hand OA group. A higher prevalence of CVEs in the three OA groups was observed compared with the control group. CONCLUSIONS: A high frequency of MetS and CVEs was observed in OA patients in a primary care setting.

Bariatric surgery: to whom and when?

Bariatric surgery is the most effective treatment for obesity. Its effects go beyond weight loss, in a high percentage of cases achieving remission of comorbidities associated with obesity and reducing mortality. However, not all patients achieve satisfactory weight loss or resolution of comorbidities and perioperative complications are a constant risk. Correct preoperative evaluation is essential to predict the likelihood of success and choose the most appropriate surgical technique for this purpose. The aim of this review was to ascertain which obese subjects will benefit from bariatric surgery taking into account body mass index, age, comorbidities, risk of complications and the impact of different bariatric surgery techniques.

Obesity and type 1 diabetes mellitus management.

Patients with type 1 diabetes mellitus (T1DM) traditionally had a low body mass index and microangiopathic complications were common. The Diabetes Control and Complications Trial, published in 1993, demonstrated that therapy aimed at maintaining HbA1c levels as close to normal as feasible reduced the incidence of microangiopathy. Since then, the use of intensive insulin therapy to optimise metabolic control became generalised, with two main side effects: a higher rate of severe hypoglycaemia and increased weight gain. Approximately 50% of patients with T1DM are currently obese or overweight, which reduces or nullifies the benefits of good metabolic control, and which has other negative consequences; therefore, strategies to achieve weight control in patients with T1DM are necessary. At present, treatment with GLP-1 and SGLT-2 inhibitors has yielded promising short-term results that need to be confirmed in studies with larger numbers of patients and long-term follow-up. It is possible that, in coming years, the applicability of bariatric surgery in obese patients with T1DM will be similar to that of the general population or T2DM.

Different clinical presentation of Klinefelter's syndrome in monozygotic twins.

There is a wide variability in the clinical presentation of Klinefelter's syndrome. We report the case of a 45-year-old man who was incidentally diagnosed a 47,XXY/46,XY karyotype in a bone marrow aspiration (case 1). He presented hypogonadic features with undetectable testosterone levels and a height in accordance with mid-parental height. He had a monozygous sibling (case 2) who did not show clinical signs of hypogonadism and whose height exceeded mid-parental height. Both patients had presented language disorders since childhood. The karyotype of lymphocytes in peripheral blood of both subjects was compatible with mosaic Klinefelter's syndrome (46,XY/47,XXY). Testosterone replacement was initiated in case 1. Lack of testicular involvement due to mosaicism and the overexpression of the SHOX gene in case 2 could explain the marked differences in phenotype in these homozygous twins.

Role of A1c in the postpartum screening of women with gestational diabetes.

OBJECTIVE: This study aimed to determine whether A1c detects a different prediabetes prevalence in women with a history of gestational diabetes mellitus (GDM) compared to those diagnosed with oral glucose tolerance test (OGTT) and the influence of haemoglobin concentrations on A1c levels. DESIGN AND PATIENTS: We evaluated carbohydrate metabolism status by performing OGTT and A1c tests in 141 postpartum women with prior GDM in the first year post-delivery. RESULTS: The overall prevalence of prediabetes was 41.8%. Prevalence of isolated A1c 5.7-6.4%, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) was 10.6%, 7.1%, and 9.2%, respectively. Isolated A1c 5.7-6.4% was associated with Caucasian origin (66.7% versus 32.6%, p = 0.02) and with higher LDL cholesterol concentrations (123 ± 28.4 mg/dl versus 101.6 ± 19.2 mg/dl, p = 0.037) compared with patients diagnosed by OGTT (IFG or IGT). Women with postpartum anaemia had similar A1c levels to those with normal haemoglobin concentrations (5.5% ± 0.6% versus 5.4% ± 0.4%, p = 0.237). CONCLUSIONS: Use of A1c in postpartum screening of women with GDM detected an additional 10.6% of patients with prediabetes and a more adverse lipid profile. Haemoglobin concentrations did not influence A1c values.

Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine.

Cystinuria is a classic heritable aminoaciduria that involves the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine. Six missense mutations in the human rBAT gene, which is involved in high-affinity transport of cystine and dibasic amino acids in kidney and intestine, segregate with cystinuria. These mutations account for 30% of the cystinuria chromosomes studied. Homozygosity for the most common mutation (M467T) was detected in three cystinuric siblings. Mutation M467T nearly abolished the amino acid transport activity induced by rBAT in Xenopus oocytes. These results establish rBAT as a cystinuria gene.

[Chronic complications in type 1 diabetes mellitus. Analysis of a cohort of 291 patients with a mean evolution time of 15 years]. / Complicaciones crónicas en la diabetes mellitus tipo 1. Análisis de una cohorte de 291 pacientes con un tiempo medio de evolución de 15 años.

BACKGROUND AND OBJECTIVE: Micro- and macrovascular complications are the main cause of morbidity and mortality in type 1 diabetes mellitus (T1D). Given the scarcity of data on the subject in our population, we have analyzed the prevalence of vascular complications and possible risk factors in a cohort of T1D patients. PATIENTS AND METHODS: A cross-sectional study including patients aged 18 and over diagnosed of T1D with at least 6 months' evolution, seen in the Hospital del Mar, Barcelona and Hospital de Granollers during 2008 was carried out. RESULTS: We recruited 291 patients (166 men) with a mean age of 38 years and a T1D duration of 15.3 years. There was one or more diabetes-related vascular complications in 110 (37.8%) patients. Of these, 104 (35.7%) had microvascular complications, 22 (7.6%) macrovascular, and 16 (5.5%) both. Patients with microvascular complications had a higher prevalence of tobacco use (57% smokers Vs. 47.5%, P<.05), dyslipidemia (65.4% Vs. 28.3%, P <.05), hypertension (43.3% Vs. 23.5%, P <.05) and metabolic syndrome (41.3% Vs. 18.7%, P<.001). Moreover, they were older, had a longer duration of diabetes and higher values of glycosylated hemoglobin, triglycerides and systolic blood pressure. In the logistic regression analysis, diabetes duration (OR: 1.19 [95%CI: 1.07-1.32], P=.002), glycosylated hemoglobin levels (OR: 3.33 [95%CI: 1.58-7.03], P=.002) and the absence of metabolic syndrome (OR: 0.04 [95% CI:0.002-0.72], P=.03) showed an independent association with microangiopathy. Patients with T1D and macroangiopathy had longer diabetes duration (23.3±12.6 years Vs. 14.7±10.9 years, in patients without complications, P <.001), higher prevalence of metabolic syndrome (50% Vs. 24.9%, in patients without complications, P=.011) and were more frequently receiving lipid lowering treatment (59.1% Vs. 27.1%, in patients without complications, P=.002). In the multiple regression model, only diabetes duration (OR: 1.047 [95% CI: 1.01-1.09], P=.019) remained independently associated with macroangiopathy. CONCLUSIONS: More than 1/3 of the T1D patients suffered a diabetes-related complication, mainly microvascular, at the time of the study. Diabetes duration and metabolic syndrome are the two mostly strongly related factors to chronic complications of DM1.

Dissociation from BiP and retrotranslocation of unassembled immunoglobulin light chains are tightly coupled to proteasome activity.

Unassembled immunoglobulin light chains expressed by the mouse plasmacytoma cell line NS1 (kappa(NS1)) are degraded in vivo with a half-life of 50-60 min in a way that closely resembles endoplasmic reticulum (ER)-associated degradation (). Here we show that the peptide aldehydes MG132 and PS1 and the specific proteasome inhibitor lactacystin effectively increased the half-life of kappa(NS1), arguing for a proteasome-mediated degradation pathway. Subcellular fractionation and protease protection assays have indicated an ER localization of kappa(NS1) upon proteasome inhibition. This was independently confirmed by the analysis of the folding state of kappa(NS1) and size fractionation experiments showing that the immunoglobulin light chain remained bound to the ER chaperone BiP when the activity of the proteasome was blocked. Moreover, kinetic studies performed in lactacystin-treated cells revealed a time-dependent increase in the physical stability of the BiP-kappa(NS1) complex, suggesting that additional proteins are present in the older complex. Together, our data support a model for ER-associated degradation in which both the release of a soluble nonglycosylated protein from BiP and its retrotranslocation out of the ER are tightly coupled with proteasome activity.

Influence of catch up growth on spatial learning and memory in a mouse model of intrauterine growth restriction.

BACKGROUND: Intrauterine growth restriction (IUGR) and rapid postnatal weight gain or catch up growth (CUG) increase the susceptibility to metabolic syndrome during adult life. Longitudinal studies have also revealed a high incidence of learning difficulties in children with IUGR. The aim of the present study was to investigate the effect of nutrition and CUG on learning memory in an IUGR animal model. We hypothesized that synaptic protein expression and transcription, an essential mechanism for memory consolidation, might be affected by intrauterine undernutrition. METHODS: IUGR was induced by 50% maternal caloric undernutrition throughout late gestation. During the suckling period, dams were either fed ad libitum or food restricted. The pups were divided into: Normal prenatal diet-Normal postnatal diet (NN), Restricted prenatal diet- Normal postnatal diet + catch up growth (RN+), Normal prenatal diet-Restricted postnatal diet (NR) and Restricted prenatal diet-Restricted postnatal diet (RR). At 4 weeks of age, memory was assessed via a water maze test. To evaluate synaptic function, 2 specific synaptic proteins (postsynaptic density-95 [PSD95], synaptophysin) as well as insulin receptors (IR) were tested by Western Blot and quantitative polymerase chain reaction (qPCR). Brain-derived neurotrophic factor and serum insulin levels were also studied. RESULTS AND CONCLUSIONS: The RN+ group presented a learning curve similar to the NN animals. The RR animals without CUG showed learning disabilities. PSD95 was lower in the RR group than in the NN and RN+ mice. In contrast, synaptophysin was similar in all groups. IR showed an inverse expression pattern to that of the PSD95. In conclusion, perinatal nutrition plays an important role in learning. CUG after a period of prenatal malnutrition seems to improve learning skills. The functional alterations observed might be related to lower PSD95 activity and a possible dysfunction in the hormone regulation of synaptic plasticity.

Clinical Value of Thyrotropin Receptor Antibodies for the Differential Diagnosis of Interferon Induced Thyroiditis.

OBJECTIVE: The clinical value of thyrotropin receptor antibodies for the differential diagnosis of thyrotoxicosis induced by pegylated interferon-alpha remains unknown. We analyzed the diagnostic accuracy of thyrotropin receptor antibodies in the differential diagnosis of thyrotoxicosis in patients with chronic hepatitis C (CHC) receiving pegylated interferon-alpha plus ribavirin. METHODS: Retrospective analysis of 274 patients with CHC receiving pegylated interferon-alpha plus ribavirin. Interferon-induced thyrotoxicosis was classified according to clinical guidelines as Graves disease, autoimmune and non- autoimmune destructive thyroiditis. RESULTS: 48 (17.5%) patients developed hypothyroidism, 17 (6.2%) thyrotoxicosis (6 non- autoimmune destructive thyroiditis, 8 autoimmune destructive thyroiditis and 3 Graves disease) and 22 "de novo" thyrotropin receptor antibodies (all Graves disease, 2 of the 8 autoimmune destructive thyroiditis and 17 with normal thyroid function). The sensitivity and specificity of thyrotropin receptor antibodies for Graves disease diagnosis in patients with thyrotoxicosis were 100 and 85%, respectively. Patients with destructive thyroiditis developed hypothyroidism in 87.5% of autoimmune cases and in none of those with a non- autoimmune etiology (p<0.001). CONCLUSION: Thyrotropin receptor antibodies determination cannot replace thyroid scintigraphy for the differential diagnosis of thyrotoxicosis in CHC patients treated with pegylated interferon.

Evidence for posttranscriptional regulation of GLUT4 expression in muscle and adipose tissue from streptozotocin-induced diabetic and benfluorex-treated rats.

In this study we explored the expression of GLUT4 glucose carriers in muscle and adipose tissues from streptozotocin-induced diabetic and benfluorex-treated rats. In nondiabetic rats, benfluorex treatment decreased GLUT4 protein content in muscle and brown adipose tissue, with no change in GLUT4 mRNA. This effect occurred in the presence of normal circulating levels of insulin and glucose. Seventeen days after streptozotocin injection, diabetic rats showed a decreased GLUT4 protein content in adipose tissues and in both red and white skeletal muscle. Diabetic rats showed decreased GLUT4 mRNA levels in white and brown adipose tissue, whereas messenger concentrations remained unaltered in red and white fibers of skeletal muscle. The interaction of benfluorex and diabetes on GLUT4 protein expression showed a tissue-specific pattern. Benfluorex treatment to some extent prevented the decrease in GLUT4 protein in white and brown adipose tissue and in white muscle associated with diabetes. In contrast, diabetes and benfluorex caused an additive decrease in GLUT4 expression in red skeletal muscle. The effects of benfluorex on GLUT4 content in tissues from diabetic rats occurred in the absence of alterations in GLUT4 mRNA levels, suggesting a modification of translational or posttranslational steps. Benfluorex did not ameliorate the hyperglycemia of diabetic rats. Our results indicate that red and white skeletal muscle respond to diabetes and benfluorex in a heterogeneous manner, which suggests the existence of differences in the mechanisms that regulate GLUT4 expression. Furthermore, our data indicate that GLUT4 expression in muscle and adipose tissue can be regulated by modification of translational or posttranslational steps.

Reduction of islet amylin expression and basal secretion by adenovirus-mediated delivery of amylin antisense cDNA.

Reduction of amylin content and secretion in rat islets was attempted by transduction with an adenovirus bearing a 0.2-kb fragment of rat amylin cDNA inserted in the antisense orientation (AdCMV-alpha amylin). Exposure of islets to AdCMV-alpha amylin at a multiplicity of infection (moi) of 200 (1.2 x 10(7) pfu/ml) reduced amylin mRNA levels by 37 +/- 5% (p < 0.005), whereas infection with an adenovirus expressing the reporter gene of beta-galactosidase (AdCMV-lacz) did not modify amylin expression. Transduction with the antisense construct was specifically associated with the decrease (30 +/- 6%; p < 0.001) in the amylin content. Insulin content was unaltered in AdCMV-alpha amylin islets compared to AdCMV-lacz-transduced or untransduced cells. Basal amylin secretion (2.8 mM glucose) was 36 +/- 3% (p < 0.005) lower in AdCMV-alpha amylin islets than in untransduced or AdCMV-lacz-transduced islets. In contrast, no difference in amylin secretion in response to high glucose concentrations (16.7 mM) was detected in AdCMV-alpha amylin-transduced islets. Thus, a reduction of amylin content and basal secretion in islet cells can be achieved by the adenovirus-mediated expression of antisense RNA.

Impact of different criteria on type 2 diabetes remission rate after bariatric surgery.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) achieve similar type 2 diabetes mellitus (T2DM) remission rates. Since a great variability exists in defining T2DM remission, an expert panel proposed partial and complete remission criteria that include the maintenance of fasting plasma glucose (FPG) and glycosylated hemoglobin (A1c) objectives for at least 1 year. The 2-year T2DM remission rate and time needed to reach it after LSG or LRYGB were compared using different remission criteria. METHODS: This was a prospective cohort study of 55 T2DM subjects operated on with LSG (n = 21) or LRYGB (n = 34). Four models for defining remission were used: Buchwald criteria (FPG <100 mg/dl or A1c <6 %), American Diabetes Association (ADA) complete (FPG <100 mg/dl plus A1c <6 % maintained for at least 1 year), ADA partial (FPG <125 mg/dl with A1c <6.5 % maintained for at least 1 year), and ADA complete without time requirement. RESULTS: Both groups were comparable, except for higher A1c levels in the LSG group. The remission rate ranged from 43.6 % using ADA complete remission to 92.7 % with Buchwald criteria, with no differences between surgical procedures. Differences were found in the time to achieve remission only when ADA complete remission criteria (5.1 ± 2.9 months LRYGB and 9.0 ± 3.8 months LSG, p = 0.014) and ADA without time requirement criteria (4.9 ± 2.7 months LRYGB and 8.4 ± 3.9 months LSG, p = 0.005) were used. CONCLUSIONS: T2DM remission rate varies widely depending on the criteria used for its definition. Remission occurred sooner after LRYGB when the strictest criteria to define remission were used.

Efficacy of treatment for hyperglycemic crisis in elderly diabetic patients in a day hospital.

BACKGROUND: The purpose of this prospective cohort study was to compare the costs of day hospital (DH) care for hyperglycemic crisis in elderly diabetic patients with those of conventional hospitalization (CH). Secondary objectives were to compare these two clinical scenarios in terms of glycemic control, number of emergency and outpatient visits, readmissions, hypoglycemic episodes, and nosocomial morbidity. METHODS: The study population comprised diabetic patients aged >74 years consecutively admitted to a tertiary teaching hospital in Spain for hyperglycemic crisis (sustained hyperglycemia [>300 mg/dL] for at least 3 days with or without ketosis). The patients were assigned to DH or CH care according to time of admission and were followed for 6 months after discharge. Exclusion criteria were ketoacidosis, hyperosmolar crisis, hemodynamic instability, severe intercurrent illness, social deprivation, or Katz index >D. RESULTS: Sixty-four diabetic patients on DH care and 36 on CH care were included, with no differences in baseline characteristics. The average cost per patient was 1,345.1±793.6 € in the DH group and 2,212.4±982.5 € in the CH group (P<0.001). There were no differences in number of subjects with mild hypoglycemia during follow-up (45.3% DH versus 33.3% CH, P=0.24), nor in the percentage of patients achieving a glycated hemoglobin (HbA(1c)) <8% (67.2% DH versus 58.3% CH, P=0.375). Readmissions for hyperglycemic crisis and pressure ulcer rates were significantly higher in the CH group. CONCLUSION: DH care for hyperglycemic crises is more cost-effective than CH care, with a net saving of 1,418.4 € per case, lower number of readmissions and pressure ulcer rates, and similar short-term glycemic control and hypoglycemia rates.

Cerebral salt wasting syndrome: review.

Hyponatremia is the most frequent electrolyte disorder in critically neurological patients. Cerebral salt wasting syndrome (CSW) is defined as a renal loss of sodium during intracranial disease leading to hyponatremia and a decrease in extracellular fluid volume. The pathogenesis of this disorder is still not completely understood. Sympathetic responses as well as some natriuretic factors play a role in this syndrome. Distinction between SIADH and CSW might be difficult. The essential point is the volemic state. It is necessary to rule out other intermediate causes. Treatment requires volume replacement and maintenance of a positive salt balance. Mineral corticoids may be useful in complicated cases.

In utero undernutrition reduces diabetes incidence in non-obese diabetic mice.

AIMS/HYPOTHESIS: Observational studies in humans suggest that low birthweight may decrease the risk of type 1 diabetes, but the mechanism is unknown. We hypothesised that antenatal undernutrition would decrease the incidence of type 1 diabetes in non-obese diabetic (NOD) mice. MATERIALS AND METHODS: A 40% restriction of energy intake was applied to pregnant NOD dams from day 12.5 to day 18.5 of gestation, resulting in intrauterine growth retardation of offspring. All mice were fed a standard diet after weaning. Control and undernourished female offspring were followed to assess diabetes incidence. Male NOD mice were treated with cyclophosphamide to accelerate development of diabetes. Glucose homeostasis, body composition and pancreatic histology were compared in control and undernourished offspring. RESULTS: Mean birthweight was lower in undernourished than in control mice (p = 0.00003). At 24 weeks of age, the cumulative incidence of spontaneous diabetes in female mice was 73% in control and 48% in undernourished mice (p = 0.003). In cyclophosphamide-treated male mice, antenatal undernutrition also tended to reduce the development of diabetes (p = 0.058). Maternal leptin levels were lower in undernourished dams on day 18.5 of pregnancy (p = 0.039), while postnatal leptin levels were significantly higher in undernourished offspring at 4, 20 and 27 weeks of life (p < 0.05). Beta cell mass was similar in both groups (control = 0.4 mg; undernourished = 0.54 mg; p = 0.24). Histological evidence of apoptosis at 20 weeks was greater in control than in undernourished mice (control = 6.3 +/- 1.4%; undernourished = 4.2 +/- 0.3%, p = 0.05). CONCLUSIONS/INTERPRETATION: Antenatal undernutrition reduces the incidence of diabetes in NOD mice, perhaps via alterations in apoptosis.

Reductions in caloric intake and early postnatal growth prevent glucose intolerance and obesity associated with low birthweight.

AIMS/HYPOTHESIS: Low birthweight (LBW) and rapid postnatal weight gain, or catch-up growth, are independent risk factors for the development of obesity and diabetes during adult life. Individuals who are both small at birth and have postnatal catch-up growth are at the highest risk. We hypothesised that dietary interventions designed to attenuate catch-up growth in LBW subjects may have long-term beneficial consequences. MATERIALS AND METHODS: We used our previously described mouse model of LBW-associated diabetes, created by restricting maternal food intake to 50% during the last week of gestation. Control (C) dams and dams that had been subjected to undernutrition (U) were then provided either chow ad libitum after delivery or 50% food restriction on a per-day basis from delivery until weaning. We designated the resulting four groups control-control (CC), undernutrition-control (UC), control-undernutriton (CU) and undernutrition-undernutrition (UU), indicating the prenatal and postnatal experimental conditions, respectively. Carbohydrate metabolism and adiposity were assessed prospectively in offspring until age 6 months. RESULTS: Males that were small at birth and exhibited early postnatal catch-up growth developed glucose intolerance and obesity by age 6 months. In contrast, LBW mice without catch-up growth (UU) remained smaller than controls (CC), and glucose intolerance and obesity was prevented. Similarly, mice with normal birthweight that had blunted catch-up growth (CU) were leaner and had better tolerance test than CC mice. Catch-up growth during the first week of life correlated better than birthweight with glucose, fat mass and glucose tolerance up to 6 months of age. CONCLUSIONS/INTERPRETATION: Prevention of early catch-up growth reversed the development of glucose intolerance and obesity in our mouse model of LBW-associated diabetes.