Adiposity in children born small for gestational age.

Epidemiological studies indicate that children born small for gestational age (SGA) have an increased risk of metabolic and cardiovascular disorders as adults. This suggests that foetal undernutrition leads to permanent metabolic alterations, which predispose to metabolic abnormalities upon exposure to environmental factors such as low physical activity and/or high-energy intake in later life (thrifty phenotype hypothesis). However, this relationship is not restricted to foetal undernutrition or intrauterine growth retardation, but is also found for children born premature, or for high birth weight children. Furthermore, early post-natal nutrition, and more specifically catch-up growth, appear to modulate cardiovascular risk as well. Intrauterine growth retardation can be induced in animal models by energy/protein restriction, or ligation of uterine arteries. In such models, altered glucose homeostasis, including low beta-cell mass, low insulin secretion and insulin resistance is observed after a few weeks of age. In humans, several studies have confirmed that children born SGA have insulin resistance as adolescents and young adults. Alterations of glucose homeostasis and increased lipid oxidation can indeed be observed already in non-diabetic children born SGA at early pubertal stages. These children also have alterations of stature and changes in body composition (increased fat mass), which may contribute to the pathogenesis of insulin resistance. Permanent metabolic changes induced by foetal/early neonatal nutrition (metabolic inprinting) may involve modulation of gene expression through DNA methylation, or alterations of organ structure. It is also possible that events occurring during foetal/neonatal development lead to long-lasting alterations of the hypothalamo-pituitary-adrenal axis or the hypothalamo-pituitary-insulin-like growth factor-1 axis.

Targeting the PI3K p110alpha isoform inhibits medulloblastoma proliferation, chemoresistance, and migration.

PURPOSE: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in medulloblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in medulloblastoma. EXPERIMENTAL DESIGN: The expression pattern and functions of class I(A) PI3K isoforms were investigated in medulloblastoma tumour samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110alpha, p110beta, or p110delta by means of RNA interference or inhibition with isoform-specific PI3K inhibitors. RESULTS: Overexpression of the catalytic p110alpha isoform was detected in a panel of primary medulloblastoma samples and cell lines compared with normal brain tissue. Down-regulation of p110alpha expression by RNA interference impaired the growth of medulloblastoma cells, induced apoptosis, and led to decreased migratory capacity of the cells. This effect was selective, because RNA interference targeting of p110beta or p110delta did not result in a comparable impairment of DAOY cell survival. Isoform-specific p110alpha inhibitors also impaired medulloblastoma cell proliferation and sensitized the cells to chemotherapy. Medulloblastoma cells treated with p110alpha inhibitors further displayed reduced activation of Akt and the ribosomal protein S6 kinase in response to stimulation with hepatocyte growth factor and insulin-like growth factor-I. CONCLUSIONS: Together, our data reveal a novel function of p110alpha in medulloblastoma growth and survival.

A Dose-Response Strategy Reveals Differences between Normal-Weight and Obese Men in Their Metabolic and Inflammatory Responses to a High-Fat Meal.

A dose-response strategy may not only allow investigation of the impact of foods and nutrients on human health but may also reveal differences in the response of individuals to food ingestion based on their metabolic health status. In a randomized crossover study, we challenged 19 normal-weight (BMI: 20-25 kg/m(2)) and 18 obese (BMI: >30 kg/m(2)) men with 500, 1000, and 1500 kcal of a high-fat (HF) meal (60.5% energy from fat). Blood was taken at baseline and up to 6 h postprandially and analyzed for a range of metabolic, inflammatory, and hormonal variables, including plasma glucose, lipids, and C-reactive protein and serum insulin, glucagon-like peptide-1, interleukin-6 (IL-6), and endotoxin. Insulin was the only variable that could differentiate the postprandial response of normal-weight and obese participants at each of the 3 caloric doses. A significant response of the inflammatory marker IL-6 was only observed in the obese group after ingestion of the HF meal containing 1500 kcal [net incremental AUC (iAUC) = 22.9 ± 6.8 pg/mL × 6 h, P = 0.002]. Furthermore, the net iAUC for triglycerides significantly increased from the 1000 to the 1500 kcal meal in the obese group (5.0 ± 0.5 mmol/L × 6 h vs. 6.0 ± 0.5 mmol/L × 6 h; P = 0.015) but not in the normal-weight group (4.3 ± 0.5 mmol/L × 6 h vs. 4.8 ± 0.5 mmol/L × 6 h; P = 0.31). We propose that caloric dose-response studies may contribute to a better understanding of the metabolic impact of food on the human organism. This study was registered at clinicaltrials.gov as NCT01446068.

Overall and cause-specific mortality in GH-deficient adults on GH replacement.

OBJECTIVE: Hypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients. DESIGN: In KIMS (Pfizer International Metabolic Database) 13,983 GH-deficient patients with 69,056 patient-years of follow-up were available. METHODS: This study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to P<0.05. RESULTS: All-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04-1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushing's disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044). CONCLUSIONS: GH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment.

Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.

Background- Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown. Methods and Results- We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and β-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding-induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. Conclusions- Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy.

Mastoparan, a novel mitogen for Swiss 3T3 cells, stimulates pertussis toxin-sensitive arachidonic acid release without inositol phosphate accumulation

Mastoparan, a basic tetradecapeptide isolated from wasp venom, is a novel mitogen for Swiss 3T3 cells. This peptide induced DNA synthesis in synergy with insulin in a concentration-dependent manner; half-maximum and maximum responses were achieved at 14 and 17 microM, respectively. Mastoparan also stimulated DNA synthesis in the presence of other growth promoting factors including bombesin, insulin-like growth factor-1, and platelet-derived growth factor. The synergistic mitogenic stimulation by mastoparan can be dissociated from activation of phospholipase C. Mastoparan did not stimulate phosphoinositide breakdown, Ca2+ mobilization or protein kinase C-mediated phosphorylation of a major cellular substrate or transmodulation of the epidermal growth factor receptor. In contrast, mastoparan stimulated arachidonic acid release, prostaglandin E2 production, and enhanced cAMP accumulation in the presence of forskolin. These responses were inhibited by prior treatment with pertussis toxin. Hence, mastoparan stimulates arachidonic acid release via a pertussis toxin-sensitive G protein in Swiss 3T3 cells. Arachidonic acid, like mastoparan, stimulated DNA synthesis in the presence of insulin. The ability of mastoparan to stimulate mitogenesis was reduced by pertussis toxin treatment. These results demonstrate, for the first time, that mastoparan stimulates reinitiation of DNA synthesis in Swiss 3T3 cells and indicate that this peptide may be a useful probe to elucidate signal transduction mechanisms in mitogenesis.

Autocrine secretion of IGF2 regulates adult ß cell functional plasticity

In the pathogenesis of type 2 diabetes, hyperglycemia appears when ß cell mass and insulin secretory capacity are no longer sufficient to compensate for insulin resistance. The reduction in ß cell mass results from increased apoptosis. Therefore, finding strategies to preserve ß cell mass and function may be useful for the treatment or prevention of diabetes. Glucagon-like peptide-1 (GLP-1) protects ß cells against apoptosis, increases their glucose competence, and induces their proliferation. Previous studies in the lab of Prof. Bernard Thorens showed that the GLP-1 anti- apoptotic effect was mediated by robust up-regulation of IGF-1R expression, and this was paralleled with an increase in Akt phosphorylation. This effect was dependent not only on increased IGF-1R expression but also on the autocrine secretion of insulin-like growth factor 2 (IGF2). They also demonstrated that GLP-1 up-regulated IGF-1R expression by a protein a kinase A-dependent translational control mechanism. The main aim of this PhD work has been to further investigate the role of the IGF2/IGF-1 Receptor autocrine loop in ß cell function and to determine the physiological role of IGF2 in ß cell plasticity and its regulation by nutrients. This PhD thesis is divided in 3 chapters. The first chapter describes the role of IGF2/IGF-1R autocrine loop in ß cell glucose competence and proliferation. Here using MIN6 cells and primary mouse islets as an experimental model we demonstrated that the glucose competence of these cells was dependent on the level of IGF-1R expression and on IGF2 secretion. Furthermore, we showed that GLP-1-induced primary ß cell proliferation was significantly reduced by Igf-lr gene inactivation and by IGF2 immunoneutralization or knockdown. In the second chapter we examined the role of this IGF2/IGF-1R autocrine loop on the ß cell functional plasticity during ageing, pregnancy, and in response to acute induction of insulin resistance using mice with ß cell-specific inactivation of ig/2. Here we showed a gender-dependent role of ß cell IGF2 in ageing and high fat diet-induced metabolic stress; we demonstrated that the autocrine secretion of IGF2 is essential for ß cell mass adaptation during pregnancy. Further we also showed that this autocrine loop plays an important role in ß cell expansion in response to acute induction of insulin resistance. The aim of the third chapter was to investigate whether we can modulate the expression and secretion of IGF2 by nutrients in order to increase the activity of autocrine loop. Here we showed that glutamine induces IGF2 biosynthesis and its fast secretion through the regulated pathway, a mechanism enhanced in the presence of glucose. Furthermore, we demonstrated that glutamine-mediated Akt phosphorylation is dependent on IGF2 secretion, indicating that glutamine controls the activity of the IGF2/IGF1R autocrine loop through IGF2 up-regulation. In summary, this PhD work highlights that autocrine secretion of IGF2 is required for compensatory ß cell adaptation to ageing, pregnancy, and insulin resistance. Moreover IGF2/IGF1R autocrine loop is regulated by two feeding-related cues, GLP-1 to increase IGF-1R expression and glutamine to control IGF2 biosynthesis and secretion. -- Dans le diabète de type 2, lorsque la sécrétion d'insuline des cellules Beta du pancréas n'est plus suffisante pour compenser la résistance à l'insuline, une hyperglycémie est observée. Cette baisse de sécrétion d'insuline est Causée par la diminution de la masse de cellules Beta suite à l'augmentation du phénomène de mort cellulaire ou « apoptose ». En diabétologie, une des stratégies médicales concerne la préservation des cellules Beta du pancréas. Une des protéines intervenant dans cette fonction est GLP-1 (Glucagon-like peptide-1). GLP-1 est capable de protéger les cellules Beta contre la mort cellulaire et d'induire leur prolifération. Des études précédemment menées dans le laboratoire du Professeur Bernard Thorens ont montrées que l'activité « anti-apoptotique » de GLP-1 est le résultat l'une augmentation de l'expression du gène IGF-1R sous la dépendance de la sécrétion autocrine d'IGF2 (Insulin-Like Growth Factor). Le but de mon travail de thèse aura été d'étudier le mécanisme de la régulation de GLP-1 par IGF2 et plus précisément de déterminer le rôle physiologique d'IGF2 dans la plasticité des cellules ß ainsi que sa régulation par les nutriments. Ce manuscrit est ainsi divisé en trois chapitres : Le premier chapitre décrit la fonction d'IGF2/IGF- R1 dans la réponse des cellules Beta au glucose ainsi que dans leur capacité à proliférer. Dans ce chapitre nous avons montré l'importance du niveau d'expression d'IGFR-1 et de la sécrétion d'IGF2 dans la régulation du métabolisme du glucose. Dans un deuxième chapitre, nous étudions la boucle de régulation IGF2/IGF-R1 sur la plasticité des cellules Beta lors du vieillissement, de la grossesse ainsi que dans un modèle de souris résistantes à l'insuline. Cette étude met en évidence un dimorphisme sexuel dans le rôle d'IGF2 lors du vieillissement et lors d'un stress métabolique. Nous montrons également l'importance d'IGF2 pour l'adaptation des cellules Beta tout au long de la grossesse ou lors du phénomène de résistance à l'insuline. Dans un troisième chapitre, nous mettons en évidence la possibilité de moduler l'expression et la sécrétion d'IGF2 par les nutriments. En conclusion, ce travail de thèse aura permis de mettre en évidence l'importance d'IGF2 dans la plasticité des cellules ß, une plasticité indispensable lors du vieillissement, de la grossesse ou encore dans le cas d'une résistance à l'insuline.

Insulin and insulin-like growth factor I receptors utilize different G protein signaling components.

We examined the role of heterotrimeric G protein signaling components in insulin and insulin-like growth factor I (IGF-I) action. In HIRcB cells and in 3T3L1 adipocytes, treatment with the Galpha(i) inhibitor (pertussis toxin) or microinjection of the Gbetagamma inhibitor (glutathione S-transferase-betaARK) inhibited IGF-I and lysophosphatidic acid-stimulated mitogenesis but had no effect on epidermal growth factor (EGF) or insulin action. In basal state, Galpha(i) and Gbeta were associated with the IGF-I receptor (IGF-IR), and after ligand stimulation the association of IGF-IR with Galpha(i) increased concomitantly with a decrease in Gbeta association. No association of Galpha(i) was found with either the insulin or EGF receptor. Microinjection of anti-beta-arrestin-1 antibody specifically inhibited IGF-I mitogenic action but had no effect on EGF or insulin action. beta-Arrestin-1 was associated with the receptors for IGF-I, insulin, and EGF in a ligand-dependent manner. We demonstrated that Galpha(i), betagamma subunits, and beta-arrestin-1 all play a critical role in IGF-I mitogenic signaling. In contrast, neither metabolic, such as GLUT4 translocation, nor mitogenic signaling by insulin is dependent on these protein components. These results suggest that insulin receptors and IGF-IRs can function as G protein-coupled receptors and engage different G protein partners for downstream signaling.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

An SH2 domain-containing 5' inositolphosphatase inhibits insulin-induced GLUT4 translocation and growth factor-induced actin filament rearrangement.

Tyrosine kinase receptors lead to rapid activation of phosphatidylinositol 3-kinase (PI3 kinase) and the subsequent formation of phosphatidylinositides (PtdIns) 3,4-P2 and PtdIns 3,4, 5-P3, which are thought to be involved in signaling for glucose transporter GLUT4 translocation, cytoskeletal rearrangement, and DNA synthesis. However, the specific role of each of these PtdIns in insulin and growth factor signaling is still mainly unknown. Therefore, we assessed, in the current study, the effect of SH2-containing inositol phosphatase (SHIP) expression on these biological effects. SHIP is a 5' phosphatase that decreases the intracellular levels of PtdIns 3,4,5-P3. Expression of SHIP after nuclear microinjection in 3T3-L1 adipocytes inhibited insulin-induced GLUT4 translocation by 100 +/- 21% (mean +/- the standard error) at submaximal (3 ng/ml) and 64 +/- 5% at maximal (10 ng/ml) insulin concentrations (P < 0.05 and P < 0.001, respectively). A catalytically inactive mutant of SHIP had no effect on insulin-induced GLUT4 translocation. Furthermore, SHIP also abolished GLUT4 translocation induced by a membrane-targeted catalytic subunit of PI3 kinase. In addition, insulin-, insulin-like growth factor I (IGF-I)-, and platelet-derived growth factor-induced cytoskeletal rearrangement, i.e., membrane ruffling, was significantly inhibited (78 +/- 10, 64 +/- 3, and 62 +/- 5%, respectively; P < 0.05 for all) in 3T3-L1 adipocytes. In a rat fibroblast cell line overexpressing the human insulin receptor (HIRc-B), SHIP inhibited membrane ruffling induced by insulin and IGF-I by 76 +/- 3% (P < 0.001) and 68 +/- 5% (P < 0.005), respectively. However, growth factor-induced stress fiber breakdown was not affected by SHIP expression. Finally, SHIP decreased significantly growth factor-induced mitogen-activated protein kinase activation and DNA synthesis. Expression of the catalytically inactive mutant had no effect on these cellular responses. In summary, our results show that expression of SHIP inhibits insulin-induced GLUT4 translocation, growth factor-induced membrane ruffling, and DNA synthesis, indicating that PtdIns 3,4,5-P3 is the key phospholipid product mediating these biological actions.

Performance and hormonal profile in broiler chickens fed with different energy levels during post restriction period

The aim of this work was to investigate the influence of diet energy level on performance and hormonal profiles of broilers during post restriction period. It was a split-plot experiment, and the main treatments were in a 2x2 factorial scheme. Birds were fed restricted to 30% of the ad libitum intake, from 7 to 14 days of age. After the restriction period, birds were fed ad libitum with diets containing low (2,900 kcal ME/kg) or high (3,200 kcal ME/kg) energy until 49 days of age. Broilers fed with high energy ration showed lower feed intake and better feed conversion and decreased carcass protein; however, abdominal fat pad, and total carcass fat were not affected by ration energy levels or feeding program. Neither diet energy level nor feed restriction program changed body weight at 49 days. The profile of insulin-like growth factor-1 (IGF-1) was reduced during the feed restriction period, but increased at refeeding period. Feeding program and ration energy level did not affect T3, T4 and growth hormone serum concentrations. Feed restriction at 30% of ad libitum intake is not enough to promote changes on carcass quality, related to fat deposition, and on metabolic hormone levels, except IGF-1 seric level that has rapid increase after feed restriction.

Épidémiologie et physiopathologie de la rétinopathie du prématuré [Epidemiology and pathophysiology of retinopathy of prematurity].

Retinopathy of prematurity (ROP) is a major cause of visual impairment in premature infants. It is characterized by an arrest in normal retinal vascular development associated with microvascular degeneration, followed by an abnormal hypoxiainduced neovascularization. Recent studies point out that ROP is a multifactorial disease, implicating both oxygen-dependent and oxygen-independent mechanisms. Oxygen-dependent factors leading to microvascular degeneration include generation of reactive oxygen species and suppression of specific oxygen-regulated vascular survival factors, such as vascular endothelial growth factor (VEGF) and erythropoietin. The other major mechanism for the initial capillary loss is oxygen-independent and implicates a deficit in growth factor IGF-1/IGFBP3. The proliferative, second phase of ROP is triggered by increases in vascular growth factors concentrations, in an attempt to compensate for the hypoxic retina. Novel signaling pathways for vascular repair, implicating both metabolite signaling and inflammatory lipids signaling, represent new therapeutic avenues for ROP.

Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled study.

Patients with chronic obstructive pulmonary disease (COPD) often develop weight loss, which is associated with increased mortality. Recombinant human growth hormone (rhGH) treatment has been proposed to improve nitrogen balance and to increase muscle strength in these patients. The aim of this study was to assess the effects of rhGH administration on the nutritional status, resting metabolism, muscle strength, exercise tolerance, dyspnea, and subjective well-being of underweight patients with stable COPD. Sixteen patients attending a pulmonary rehabilitation program (age: 66 +/- 9 yr; weight: 77 +/- 7% of ideal body weight; FEV1: 39 +/- 13% of predicted) were randomly treated daily with either 0.15 IU/kg rhGH or placebo during 3 wk in a double-blind fashion. Measurements were made at the beginning (DO) and at the end (D21) of treatment and 2 mo later (D81). Body weight was similar in the two groups during the study, but lean body mass was significantly higher in the rhGH group at D21 (p < 0.01) and D81 (p < 0.05). The increase in lean body mass was 2.3 +/- 1.6 kg in the rhGH group and 1.1 +/- 0.9 kg in the control group at D21 and 1.9 +/- 1.6 kg in the rhGH group and 0.7 +/- 2.1 kg in the control group at D81. At D21, the resting energy expenditure was increased in the rhGH group (107.8% of DO, p < 0.001 compared with the control group). At D21 and D81, the changes in maximal respiratory pressures, handgrip strength, maximal exercise capacity, and subjective well-being were similar in the two groups. At D21, the 6-min walking distance decreased in the rhGH group (-13 +/- 31%) and increased in the control group (+10 +/- 14%; p < 0.01). We conclude that the daily administration of 0.15 IU/kg rhGH during 3 wk increases lean body mass but does not improve muscle strength or exercise tolerance in underweight patients with COPD.