Biomedical subjects

F Escrivá

Publications and source records attributed to F Escrivá.

At least 19 recordsLinked to original sources

PubMed2006

Undernutrition does not alter the activation of beta-cell neogenesis and replication in adult rats after partial pancreatectomy.

In previous work, we demonstrated that a 65% protein calorie food restriction started during the third trimester of gestation in rats caused a reduced beta-cell mass at 4 days of life that persisted until adult age. In this study with adult undernourished (U) rats, we investigated 1) whether undernutrition affects the beta-cell growth potential and both beta-cell proliferation and differentiation and 2) the implication of the IGFs, highly responsive to nutritional status, in these processes. To this end, we used the 90% pancreatectomy (Px) procedure in U and control (C) adult rats. The results show that, on day 2 after Px, beta-cell replication was significantly higher in C rats, whereas the beta-cell neogenesis was markedly increased in U/Px rats. Both the serum levels of IGF-I and the liver IGF-I mRNA expression were reduced in adult U rats before and after Px compared with C rats. Pancreatic IGF-I mRNA expression was reduced in U animals on day 0. However, on day 2 after Px, the increase of pancreatic IGF-I mRNA expression was significantly higher in U rats than in C rats. These data suggest that beta-cells still have the capacity to regenerate in the adult U rats, with a higher efficiency than C rats on day 2, and that both beta-cell neogenesis and beta-cell replication are stimulated. The increased pancreatic IGF-I mRNA may be instrumental in these processes.

Age Factors↗

PubMed2005

Maternal food restriction enhances insulin-induced GLUT-4 translocation and insulin signaling pathway in skeletal muscle from suckling rats.

Restriction of protein calories during stages of immaturity has a major influence on glucose metabolism and increases the risk of type 2 diabetes in adulthood. However, it is known that reduction of food intake alleviates insulin resistance. We previously demonstrated an improved insulin-induced glucose uptake in skeletal muscle of chronically undernourished adult rats. The purpose of this work was to investigate whether this condition is present during suckling, a period characterized by physiological insulin resistance as well as elucidate some of the underlying mechanisms. With this aim, 10-d-old pups from food-restricted dams were studied. We showed that undernourished suckling rats are glucose normotolerants, despite their depressed insulin secretion capacity. The content of the main glucose transporters in muscle, GLUT-4 and GLUT-1, was not affected by undernutrition, but fractionation studies showed an improved insulin-stimulated GLUT-4 translocation. p38MAPK protein, implicated in up-regulation of intrinsic activity of translocated GLUT-4, was increased. These changes suggest an improved insulin-induced glucose uptake associated with undernutrition. Insulin receptor content as well as that of both regulatory and catalytic phosphoinositol 3-kinase subunits was increased by food restriction. Insulin receptor substrate-1-associated phosphoinositol 3-kinase activity after insulin was enhanced in undernourished rats, as was phospho-glycogen synthase kinase-3, in line with insulin hypersensitivity. Surprisingly, protein tyrosine phosphatase-1B association with insulin receptor was also increased by undernutrition. These adaptations to a condition of severely limited nutritional resources might result in changes in the development of key tissues and be detrimental later in life, when a correct amount of nutrients is available, as the thrifty phenotype hypothesis predicts.

Animals↗

PubMed2004

Protein-caloric food restriction affects insulin-like growth factor system in fetal Wistar rat.

We have previously shown that fetuses from protein-caloric undernourished pregnant rats (35% of control diet during the last week of pregnancy) at 21.5 d post coitum exhibit increased beta-cell mass. This alteration is correlated with increased insulinemia and total pancreatic insulin content, a pattern similar to that reported in infants of mild diabetic mothers. In this work, we investigated in undernourished fetuses: 1) whether availability of growth factors such as insulin, GH, and IGFs and their binding proteins (IGFBPs) could be implicated in this alteration, and 2) the beta-cell mitogenic response to IGFs in vitro. The results show that maternal undernutrition increases pancreatic IGF-I expression and islet IGF-I receptor content in undernourished fetuses, whereas hepatic IGF-I expression and serum IGF-I levels were decreased. No changes were observed in serum IGF-II, and its expression was diminished in undernourished pancreases and unchanged in the liver, compared with control fetuses. Serum levels and liver and pancreatic mRNA expression of IGFBP-1 were found to be normal in undernourished fetuses, whereas the serum concentration and abundance of IGFBP-2 mRNA in pancreas were increased. Finally, the beta-cell mitogenic response to IGFs in vitro was significantly increased in undernourished fetal islets, compared with controls. In conclusion, in undernourished fetuses the increased beta-cell mass can be related to the stimulation of replicative beta-cell response due to locally increased pancreatic IGF-I mRNA; this effect is perhaps potentiated or favored by the enhanced islet IGF-I receptor content and pancreatic IGFBP-2 gene expression.

Animals↗

PubMed2003

Protein calorie restriction has opposite effects on glucose metabolism and insulin gene expression in fetal and adult rat endocrine pancreas.

We previously demonstrated that fetuses from undernourished pregnant rats exhibited increased beta-cell mass and hyperinsulinemia, whereas keeping food restriction until adult age caused reduced beta-cell mass, hypoinsulinemia, and decreased insulin secretion. Because these alterations can be related to insulin availability, we have now investigated early and long-term effects of protein calorie food restriction on insulin mRNA levels as well as the possible mechanisms that could modulate the endogenous insulin mRNA content. We used fetuses at 21.5 days of gestation proceeding from food-restricted rats during the last week of pregnancy and 70-day-old rats undernourished from day 14 of gestation until adult age and with respective controls. Insulin mRNA levels, glucose transporters, and total glycolysis and mitochondrial oxidative fluxes were evaluated. We additionally analyzed undernutrition effects on signals implicated in glucose-mediated insulin gene expression, especially pancreatic duodenal homeobox-1 (PDX-1), stress-activated protein kinase-2 (p38/SAPK2), and phosphatidylinositol 3-kinase. Undernourished fetuses showed increased insulin mRNA, oxidative glucose metabolism, and p38/SAPK2 levels, whereas undernutrition until adult age provoked a decrease in insulin gene expression, oxidative glucose metabolism, and PDX-1 levels. The results indicate that food restriction caused changes in insulin gene expression and content leading to alterations in glucose-stimulated insulin secretion. The molecular events, increased p38/SAPK2 levels in fetuses and decreased PDX-1 levels in adults, seem to be the responsible for the altered insulin mRNA expression. Moreover, because PDX-1 activation appears to be regulated by glucose-derived metabolite(s), the altered glucose oxidation caused by undernutrition could in some manner affect insulin mRNA expression.

Animals↗

PubMed2003

Age-dependent adaptation of the liver thyroid status and recovery of serum levels and hepatic insulin-like growth factor-I expression in neonatal and adult diabetic rats.

The effect of treatment with thyroxine (T(4)) on the hepatic deiodinase (5'D-I) activity and triiodothyronine (T(3)) content and on insulin-like growth factor-I (IGF-I) secretion and mRNA hepatic expression were studied in neonatal and adult diabetic (D) rats and compared with 4 thyroidectomized (Tx) groups: neonatal and adult Tx rats treated or not with T(4). Serum T(3) and T(4) decreased by 92% in both Tx populations and by 80% to 70% in D adults according to the severity of diabetes: -70 mg/kg body weight (BW) (D(70)) or 50 mg/kg BW (D(50)) of streptozotocin (STZ) injected, whereas only a 30% to 33% decrease was found in D neonates. A similar decrease of liver 5'D-I activity and T(3) concentrations was found in neonatal and adult Tx rats, whereas a significant reduction in those parameters was observed only in adult diabetics, either D(70) or D(50), but not in D neonates. Serum levels and liver mRNA expression of IGF-I determined by ribonuclease protection assay, plasma and pituitary growth hormone (GH), plasma insulin, and glycemia were also measured in both D populations. A decrease in circulating IGF-I, previously reported for Tx adult rats, was also found in both D populations. T(4) treatment recovered IGF-I and liver T(3) in both Tx groups and D neonates, but not in D adults. These results show an age-dependent adaptation of the liver thyroid economy in diabetes, as hepatic 5'D-I does not respond to diabetes in neonates and IGF-I is insensitive to T(4) treatment in adult diabetics and suggest a positive correlation between hepatic T(3) content and IGF-I expression in conditions of diabetes and Tx.

Adaptation, Physiological↗

PubMed2002

Influence of hypothyroidism on circulating concentrations and liver expression of IGF-binding proteins mRNA from neonatal and adult rats.

The aim of this work was to study the influence of the endocrine balance between thyroid hormones, insulin and growth hormone (GH) on the regulation of insulin-like growth factor binding proteins (IGFBPs), complementing a study previously reported for insulin-like growth factors (IGFs) in similar populations. Serum concentrations of IGFBPs-1 to -3 were assayed by Western ligand blot and their mRNA expression in the liver assayed by RNase protection assay in the hypothyroid populations: thyroidectomized and mercapto-1-methylimidazole (MMI)-treated neonates, and thyroidectomized adult rats at different periods after thyroidectomy. Serum concentrations of insulin, GH and IGF-I were increased in thyroidectomized neonates and decreased in the other populations. IGFBPs-1 and -2 increased 79% and 50% respectively in thyroidectomized neonatal rats compared with control at 15 days after thyroidectomy, whereas only IGFBP-2 increased (87%) in MMI-treated neonates, which had low serum insulin and GH compared with control on the same days. In thyroidectomized adult rats, IGFBPs-1 and -2 decreased 60% compared with controls on all days studied. Furthermore, when streptozotocin was administered to thyroidectomized neonates and insulin was given to thyroidectomized adult rats to restore insulin to control values in both groups, a differential regulation was found for IGFBPs-1 and -2. The transcriptionally induced decrease in IGFBP-3 (20-25% compared with control in neonates and 50% in adult rats), however, seemed to be regulated by GH and IGF-I. The similarity of changes in IGFBPs found in hypothyroid, undernourished and streptozotocin-induced diabetic neonatal rats suggests that the regulatory effect of insulin or GH on the IGFBPs requires the reduced biologically active thyroid hormone that is found in these three populations.

Animals↗

PubMed2001

Influence of type II 5' deiodinase on TSH content in diabetic rats.

The influence of hypothalamic and pituitary type II 5'deiodinase (5'D-II) activities and T3 content on pituitary TSH content was investigated in streptozotocin (STZ)-induced diabetic rats (D). The results show, first, that hypothalamic and pituitary 5'D-II activities were lower in neonatal D rats versus control (C) rats, and the normal developmental pattern was altered. Secondly, when D and C rats were thyroidectomized (Tx) at 25 days of age (D+Tx, C+Tx), pituitary and hypothalamic 5'D-II activities increased ten days later in both populations vs. intact rats, but the percentage of increase was smaller in D+Tx than in C+Tx. The hypothalamic T3 to T4 ratios were also decreased in D+Tx animals (0.38) as compared to C+Tx rats (1.64). The hypothalamic T3 content was reduced by 30% in D as compared to C rats and by 80% in D+Tx as compared to C+Tx rats, showing a defect in hypothalamic T4 deiodination. Pituitary TSH content increased after Tx in D+Tx, but not in C+Tx. These results in diabetic rats indicate that the hypothalamic and pituitary 5'D-II activity and hypothalamic T3 content are affected by diabetes and play a role in the regulation of pituitary TSH content.

Animals↗

PubMed2001

Different role of insulin in GLUT-1 and -4 regulation in heart and skeletal muscle during perinatal hypothyroidism.

Two groups of hypothyroid rats were used; one group was given 2-mercapto-1-methylimidazole (MMI) treatment in the drinking water of the mothers and was killed at 2 and 4 days of life, and the other group was given similar MMI treatment and then was thyroidectomized at 5 days of life and killed at 8 or 20 days. Serum insulin, growth hormone (GH), and insulin-like growth factor I (IGF-I) were decreased in MMI-treated rats but increased in MMI-treated plus thyroidectomized rats. No significant reduction of thyroid hormones was observed in 2-day-old MMI rats. Protein and mRNA expression of GLUT-1 increased, and those of GLUT-4 decreased, in the heart in all populations independent of changes in insulin, GH, and IGF-I levels. However, GLUT-4 protein and mRNA expression in quadriceps and gastrocnemius skeletal muscles decreased at 4 days and increased at 8 and 20 days of life in parallel with insulin, GH, and IGF-I levels. GLUT-1 in the skeletal muscles seemed regulated posttranscriptionally and presented a decrease of mRNA expression in all stages studied. A differential sensitivity to insulin regulation of GLUT-1 and GLUT-4 glucose transporters seems to be one of the causes for the tissue-specific regulation of these glucose transporters in heart and skeletal muscles during the perinatal period.

Animals↗

PubMed2001

Glucose uptake and glucose transporter proteins in skeletal muscle from undernourished rats.

Undernutrition in rats impairs secretion of insulin but maintains glucose normotolerance, because muscle tissue presents an increased insulin-induced glucose uptake. We studied glucose transporters in gastrocnemius muscles from food-restricted and control anesthetized rats under basal and euglycemic hyperinsulinemic conditions. Muscle membranes were prepared by subcellular fractionation in sucrose gradients. Insulin-induced glucose uptake, estimated by a 2-deoxyglucose technique, was increased 4- and 12-fold in control and food-restricted rats, respectively. Muscle insulin receptor was increased, but phosphotyrosine-associated phosphatidylinositol 3-kinase activity stimulated by insulin was lower in undernourished rats, whereas insulin receptor substrate-1 content remained unaltered. The main glucose transporter in the muscle, GLUT-4, was severely reduced albeit more efficiently translocated in response to insulin in food-deprived rats. GLUT-1, GLUT-3, and GLUT-5, minor isoforms in skeletal muscle, were found increased in food-deprived rats. The rise in these minor glucose carriers, as well as the improvement in GLUT-4 recruitment, is probably insufficient to account for the insulin-induced increase in the uptake of glucose in undernourished rats, thereby suggesting possible changes in other steps required for glucose metabolism.

Animals↗

PubMed2001

Regulation of IGF-I and -II by insulin in primary cultures of fetal rat hepatocytes.

During perinatal development, insulin and nutrients, rather than GH, regulate the IGF system. A selective primary culture of fetal rat hepatocytes has been established in our laboratory to elucidate the molecular mechanism of action of the above regulatory factors on IGF-I and -II gene expression during the late fetal period of the rat. In this model we have previously reported a regulatory role for glucose on IGF-I and -II synthesis and secretion. In the same experimental model, we now report that doses of insulin (0.1-5 microM) within the physiological range in rat fetuses during the last stages of gestation evoke an increase of IGF-I and -II mRNA abundance. Insulin regulated in a parallel manner IGF peptide secretion, and an excellent correlation was observed between IGF-I and -II mRNA and IGF-I and -II peptide levels in the conditioned media in response to the hormone. Finally, the insulin-induced rise in IGF-I and -II mRNA was not mediated by stimulation of gene transcription but by increased transcript stability. The results support the hypothesis that insulin plays a major role in IGF regulation at immature stages of development.

Animals↗

PubMed2000

Effects of experimental diabetes on renal IGF/IGFBP system during neonatal period in the rat.

Changes in the renal synthesis and concentration of insulin-like growth factors (IGFs) and their serum-binding proteins (IGFBPs) reported in insulin-deficient diabetes mellitus may be implicated in the alterations of the kidney function and morphology accompanying this disease. Most research on this subject has been carried out in adult animals, as well as in peripubertal rats, when the regulation of the IGF system is fully dependent on serum growth hormone (GH). However, relevant differences in the regulatory pathways of IGFs between adult and neonatal periods have been described. To examine the response of the IGF/IGFBP system of neonatal kidney to diabetes, renal IGF-I and -II and IGFBP-1, -2, and -3 concentration and mRNA expression were determined in streptozotocin-induced diabetic rat neonates. Diabetic neonates exhibited a kidney weight-to-body weight ratio higher than that of control rats, together with decreased IGF-I and increased IGF-II renal concentration. Because kidney mRNA expression of both IGFs decreased, the elevated renal IGF-II might result from increased uptake from circulation. Insulin treatment recovered the altered IGFs to control values, indicating the insulin-dependent regulation of IGFs in the neonatal kidney. Elevated levels of the IGFBP-1 and -2 in the kidney of diabetic neonates did not result from changes in their kidney mRNA transcript expression, suggesting also a possible uptake from circulation.

Aging↗

PubMed1999

Regulation of insulin-like growth factor-I and -II by glucose in primary cultures of fetal rat hepatocytes.

A selective primary culture of fetal rat hepatocytes was established in our laboratory in order to elucidate the molecular mechanisms of action of different factors and conditions on insulin-like growth factor (IGF)-I and -II gene expression during the perinatal period of the rat. In this model we report that, in a serum-free condition and the presence of non-stimulatory doses of insulin, 5-20 mM glucose evoked an increase of IGF-I and -II mRNA abundance. Glucose regulated in a parallel manner IGF peptide secretion, and an excellent correlation was observed between IGF-I and -II mRNA and IGF-I and -II peptide levels in the conditioned media in response to the carbohydrate. The experiment with 2-deoxyglucose suggests that glucose 6-phosphate, but not its further metabolism, is necessary for the induction of IGF transcript abundance in cultured fetal hepatocytes. Finally, the glucose-induced rise in IGF-II mRNA, the main IGF in fetal stages, was mediated by stimulation of gene transcription and increased transcript stability. The results support the idea that IGFs belong to a family of genes that are positively regulated by glucose.

Animals↗

PubMed1992

Glucose utilization and insulin action in adult rats submitted to prolonged food restriction.

Glucose tolerance and insulin effects on glucose production and utilization by various tissues were studied in 70-day-old anesthetized rats submitted to food restriction from the fetal stage. Basal and glucose-induced plasma insulin levels were reduced in food-restricted rats without alterations in glucose tolerance. Insulin action was quantified by using the euglycemic-hyperinsulinemic clamp technique. Glucose turnover rates were measured by using D-[6-3H]glucose. Exogenous insulin failed to decrease glucose production in food-restricted rats. Weight-related whole body glucose utilization was higher in restricted rats than in controls both in the basal (21.9 +/- 0.7 vs. 9.4 +/- 0.6 mg.min-1.kg-1) and hyperinsulinemic states (37.5 +/- 1.1 vs. 14.0 +/- 1.2 mg.min-1.kg-1). Local glucose utilization by peripheral tissues was estimated by a 2-deoxy-D-[1-3H]glucose technique. In both basal and hyperinsulinemic conditions glucose utilization was increased in various adipose and muscle tissues of the food-restricted rats as compared with the controls. Thus we conclude that food restriction leads to an increase in the insulin-mediated glucose uptake by various peripheral tissues and to insulin resistance in the liver.

Adipose Tissue↗

PubMed1992

Effect of growth hormone on liver glycogen accumulation in suckling rats.

The regulation of liver glycogen turnover in the neonatal period differs from that of the adult state. Little is also known about the regulation exerted by GH in the first period of life. To shed light on the regulation of glycogen production and in particular to study the role of GH on liver glycogen accumulation, we investigated the effect of GH administration in control or GH-deficient neonatal rats. A slow-release GH preparation was injected subcutaneously on days 9 and 12 of life, in normal and neonatally treated rats with thyroxine or cortisol. Seventy-two hours after the last GH administration, liver glycogen was increased without concomitant elevation of plasma insulin and corticosterone levels and in addition without sequential inactivation of glycogen synthase. These data strongly suggest that the current concepts on the regulation of the hepatic synthesis of glycogen should be revised.

Animals↗

PubMed1987

Effect of feeding pattern on the sensitivity of hepatic carnitine palmitoyl-transferase to inhibition by malonyl-CoA in the rat.

1. The feeding pattern influences the inhibitory effects of malonyl-CoA on carnitine palmitoyltransferase-I. 2. The sensitivity of liver carnitine palmitoyltransferase-I to malonyl-CoA is increased in rats meal-fed when compared to rats fed ad libitum. 3. Moreover, liver carnitine palmitoyltransferase-I of meal-fed rats remains more sensitive to inhibition by malonyl-CoA during a 24 hour fast than liver carnitine palmitoyltransferase-I of rats previously fed ad libitum.

Acyl Coenzyme A↗

PubMed1985

Glycemia, ketonemia, and brain enzymes of ketone body utilization in suckling and adult rats undernourished from intrauterine life.

The effect of undernutrition from the 16th day of pregnancy up to 70th day of life on blood glucose and ketone bodies and on several brain mitochondrial enzymes related to energy metabolism or biosynthetic function was investigated. Undernutrition in perinatal period was established by means of a food restriction to pregnant rats and, later, to the lactating mother; undernourished postweaned rats received half the diet consumed by the controls. Body and brain weight from undernourished rats was less than controls throughout the entire period studied. Glycemia and ketonemia were also always lower than controls. Cytochrome c oxidase, citrate synthase, 3-hydroxybutyrate dehydrogenase, 3-oxoacid coenzyme A transferase, and acetoacetyl-coenzyme A thiolase activities during the suckling period were in most stages lower than controls; subsequently, activities in undernourished rats reached or surpassed the control values. These results could explain the "catch up" phenomenon in several ultrastructural parameters found by other authors in undernourished postweaned rats.

Animals↗

PubMed1985

Influence of hormones and undernutrition on brain development in newborn rats.

High L-thyroxine (T4) and cortisol doses given to rats during the first 8 days of life and on the first day only respectively, produce decrease of body and brain weight and perturbances to brain energy substrates, i.e. glucose and ketone bodies. The same alterations are found in the undernourished rats from the prenatal period. The pituitary GH and TSH is decreased in the T4- and cortisol-injected animals. The plasma ACTH is decreased in the treated cortisol animals at 8, 12 and 22 days of life. The pituitary TSH content is reduced with respect to controls in the undernourished animals from 14 to 70 days of life. From the exposed experiments we suggest an alteration in the hypothalamic-pituitary complex in T4- and cortisol-treated rats, and describe the similarities between the three experimental models.

Aging↗

PubMed1984

Glucose homeostasis in fasted neonatal rats treated with high doses of L-thyroxine.

A neo-T4 syndrome was induced by subcutaneous administration of high doses of L-thyroxine (T4) to neonatal rats. These doses produced important alterations in carbohydrate metabolism: hypoglycemia, hypoinsulinemia and increased levels of blood lactate, pyruvate and ketone bodies. T4-treated and control rats were subjected to fasting. In contrast to controls where glycemia decreased to 60% of basal values, in 11-day-old neo-T4 rats blood glucose levels decreased to only 90% of basal values. These different adaptations to fasting area discussed with regard to endocrine equilibrium in neo-T4 rats.

Animals↗