ABSTRACT
Fibre is one of the most beneficial nutrients for health and is very frequently used in nutrition claims (NCs) to promote foods. These claims may lead consumers to believe that products bearing them are healthy and/or healthier than those without them. The main objective of this work is to address this belief. This is the first exhaustive analysis of seven processed food types with fibre-related NCs (six cereal-based and one plant-based meat analogues) comparing them with those without these claims. The Spanish Food Database, BADALI, was used for this study. Results show that as many as 88.7% of processed foods with fibre-related NCs are classified as 'less healthy' according to the Nutrient Profile Model developed by the Pan American Health Organization (PAHO-NPM). When compared to foods without these NCs, similar results were obtained in the whole sample. Most of the observed divergences when analysing individual critical nutrients by food type indicate a deterioration of the nutritional quality. Foods with fibre-related NCs contained more fibre. The more frequent use of whole grain cereals or other fibre-specific ingredients may contribute to this. Some other nutritionally relevant differences were observed and half of them reflected a deterioration of the nutritional quality. In addition, these foods presented a lower prevalence of the organic version, as well as similar rates of mineral and vitamin fortification. Therefore, processed foods with fibre-related NCs are not healthy, nor present a better nutritional profile than those without.
Subject(s)
Food Analysis , Food, Processed , Spain , Dietary Fiber , Nutritional Status , Food, Organic/analysisABSTRACT
Organic food and drink is undoubtedly a growing market. Consumers perceive organic food as healthy, and nutrition claims (NCs) and fortification may add to this perception. Whether this is true is still a matter of controversy, particularly for organic food products. We present here the first comprehensive study of large samples of six specific organic food types, analysing the nutritional quality (nutrient composition and "healthiness") as well as the use of NCs and fortification. In parallel, a comparison with conventional food is also carried out. For this purpose, the Food Database of products in the Spanish market, BADALI, was used. Four cereal-based and two dairy-substitute food types were analysed. Our results show that as many as 81% of organic foods are considered "less healthy" by the Pan American Health Organization Nutrient Profile Model (PAHO-NPM). Organic foods present a slightly improved nutrient profile compared to conventional foods. However, many of the differences, though statistically significant, are nutritionally irrelevant. Organic foods use NCs very frequently, more than conventional foods, with very little micronutrient fortification. The main conclusion of this work is that consumers' perception that organic food products are healthy is unfounded from a nutritional point of view.
Subject(s)
Food Labeling , Nutritional Status , Spain , Food Packaging , Nutritive Value , Micronutrients , Food, OrganicABSTRACT
The use of low- and no-calorie sweeteners (LNCS) in foods has increased in recent years in response to the negative effects of free sugar on health. However, the health impact of LNCS is still unclear. Studies of the prevalence of LNCS in foods have been published previously, including in Spain. However, the use of health (HCs) and nutrition claims (NCs) to promote these foods and a full nutritional characterization are largely lacking. For this purpose, we used the BADALI database with 4218 foods present in the Spanish market. Our results show that 9.3% of foods have LNCS (including both intense and polyols). Sucralose and acesulfame K were the intense sweeteners most frequently used (52.4% and 48.2%, respectively), whereas maltitol was the preferred polyol (20.3%). Of all foods with LNCS, 30% also had added sugar. Many more foods with LNCS presented HCs and NCs than those without. Sugar was the nutrient most frequently claimed in NCs for LNCS-containing foods, whereas vitamins were for those without these sweeteners. NCs compliance with regulation was similar in both conditions (60.1% for foods without and 63.9% for foods with LNCS). As expected, foods with LNCS had less total sugar content and energy. Surprisingly, the nutrient profile of yogurts with LNCS changed completely: less total and saturated fat, whereas more proteins and sodium. Biscuits with LNCS contained more fibre. The results of our study reveal that the prevalence of LNCS is becoming high in some food types in Spain and that foods containing LNCS are more frequently promoted with HCs/NCs. In addition, it confirms the general reduction in energy and sugar content expected in foods with LNCS. Furthermore, it suggests a reformulation of products beyond sugar content.
Subject(s)
Non-Nutritive Sweeteners , Sweetening Agents , Energy Intake , Food Labeling , Spain , Sugars , Sweetening Agents/analysisABSTRACT
High sodium/salt intake is a risk factor for Non-Communicable Diseases (NCDs). Excess sodium intake has been associated with high coronary heart disease, stroke and high blood pressure. The sodium daily intake is above the recommendations in the world as well as in Spain. Reducing salt content in processed foods and ready meals is one of the main strategies for reducing sodium intake. The aim of the present work is to characterise the presence of sodium in foods sold in the Spanish market. We also study a possible shift in sodium content in products over the last few years. For this purpose, 3897 products included in the BADALI food database were analysed, classified into 16 groups (G). We found that 93.3% of all foods displayed the sodium/salt content in the nutrition declaration. Meat-processed and derivatives (G8) had the highest mean and median values for sodium content, followed by snacks (G15) and sauces (G14). Only 12.7% of foods were sodium-free (≤5 mg/100 g or 100 mL), 32.4% had very low sodium (≤40 mg/100 g or 100 mL) and 48.2% were low in sodium (≤120 mg/100 g or 100 mL). On the contrary, 47.2% were high in sodium according to the Pan American Health Organisation Nutrient Profile Model (PAHO-NPM), while there were 31.9% according to the Chile-NPM. The agreement between the two NPMs was considered 'substantial' (κ = 0.67). When sodium content was compared over the years, no decrease was observed. This analysis was performed in the entire food population, by food group and in matched products. Therefore, more effort should be made by all parties involved in order to decrease the sodium/salt intake in the population.
Subject(s)
Food Analysis , Food Ingredients/analysis , Sodium, Dietary/analysis , Sodium/analysis , Fast Foods/analysis , Food Additives/analysis , Meat , Nutrients/analysis , Snacks , SpainABSTRACT
Background: Pancreatic islets are exposed to strong pro-apoptotic stimuli: inflammation and hyperglycemia, during the progression of the autoimmune diabetes (T1D). We found that the Cdk11(Cyclin Dependent Kinase 11) is downregulated by inflammation in the T1D prone NOD (non-obese diabetic) mouse model. The aim of this study is to determine the role of CDK11 in the pathogenesis of T1D and to assess the hierarchical relationship between CDK11 and Cyclin D3 in beta cell viability, since Cyclin D3, a natural ligand for CDK11, promotes beta cell viability and fitness in front of glucose. Methods: We studied T1D pathogenesis in NOD mice hemideficient for CDK11 (N-HTZ), and, in N-HTZ deficient for Cyclin D3 (K11HTZ-D3KO), in comparison to their respective controls (N-WT and K11WT-D3KO). Moreover, we exposed pancreatic islets to either pro-inflammatory cytokines in the presence of increasing glucose concentrations, or Thapsigargin, an Endoplasmic Reticulum (ER)-stress inducing agent, and assessed apoptotic events. The expression of key ER-stress markers (Chop, Atf4 and Bip) was also determined. Results: N-HTZ mice were significantly protected against T1D, and NS-HTZ pancreatic islets exhibited an impaired sensitivity to cytokine-induced apoptosis, regardless of glucose concentration. However, thapsigargin-induced apoptosis was not altered. Furthermore, CDK11 hemideficiency did not attenuate the exacerbation of T1D caused by Cyclin D3 deficiency. Conclusions: This study is the first to report that CDK11 is repressed in T1D as a protection mechanism against inflammation-induced apoptosis and suggests that CDK11 lies upstream Cyclin D3 signaling. We unveil the CDK11/Cyclin D3 tandem as a new potential intervention target in T1D.
Subject(s)
Apoptosis/drug effects , Blood Glucose/metabolism , Cyclin-Dependent Kinases/metabolism , Cytokines/pharmacology , Diabetes Mellitus, Type 1/enzymology , Inflammation/enzymology , Insulin-Secreting Cells/drug effects , Protein Serine-Threonine Kinases/physiology , Activating Transcription Factor 4/metabolism , Animals , Autoimmunity/drug effects , Cyclin D3/genetics , Cyclin D3/metabolism , Cyclin-Dependent Kinases/genetics , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/pathology , Disease Models, Animal , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress/drug effects , Heat-Shock Proteins/metabolism , Inflammation/blood , Inflammation/genetics , Inflammation/pathology , Insulin-Secreting Cells/enzymology , Insulin-Secreting Cells/pathology , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Protein Serine-Threonine Kinases/genetics , Thapsigargin/pharmacology , Tissue Culture Techniques , Transcription Factor CHOP/metabolismABSTRACT
Healthy eating is essential for the growth and development of children and adolescents. Eating habits established in childhood continue into adulthood. In Spain, the frequent promotion of foods with low nutritional value is already considered a threat to the health of the population, particularly to children and adolescents. In this work, we analyse 3209 foods from the Food Database, BADALI. Foods were classified as marketed to children or adolescents according to the advertising on the packaging, television or internet. We found that 17.5% of foods in the database were marketed to this population and 97% of those were considered unhealthy following the Pan American Health Organization Nutrient Profile Model (PAHO-NPM). In the total of foods for children or adolescents, 61.5% were high in fat, 58.5% in free-sugar, 45.4% in saturated fat and 45% in sodium. Foods marketed to them presented higher amounts of carbohydrates and sugar, while lower protein and fibre content than the rest. There was also considerable variability in levels of the other nutrients found in these products, which depended largely on the food group. According to our findings, there is a tendency for products marketed to children or adolescents to be unhealthy and of a poorer nutritional quality than those not targeted at them.
Subject(s)
Food , Marketing , Nutritive Value , Television , Adolescent , Adult , Child , Humans , Nutrients , SpainABSTRACT
Nutrition claims (NCs) have been shown to affect customers' perceptions and behaviour. In Europe, they are regulated by Regulation (EC) No 1924/2006. The aim of this work was to analyse the prevalence and compliance of NCs according to this regulation in Spain. For this purpose, we used the BADALI database, which included 3197 foods present in the Spanish market. Our results show that 36.1% of all foods carried NCs, at a rate of 3.3 NCs/food. The prevalence was very heterogeneous among food groups. Nuts and seeds, legumes and non-alcoholic beverages were the groups with the highest prevalence. Micronutrients, fat, fibre and sugars were the nutrients most referred to in NCs. Overall, the compliance was low, with 49.2% NCs correct. Fibre and proteins were the nutrients with most correct NCs. Vegetables and non-alcoholic beverages were the food groups with the highest proportion of correct NCs. The main reason for incorrect NCs was because the amount of the nutrient was not stated in the label. The results of our study reveal that the aim of the European Commission to ensure a high level of protection for consumers regarding NCs has not been fulfilled. Therefore, we consider it crucial that European institutions invest in guaranteeing regulation compliance.
Subject(s)
Consumer Behavior , Nutritional Status , Nutritive Value , Public Health/standards , Beverages , Food Labeling , Humans , Nutrients , Spain , VegetablesABSTRACT
AIMS: Adipose mesenchymal stem cells are a heterogeneous population. Therefore, the question posed in this study is whether the heterogenic differentiation potential exhibited by the different clones toward mesodermic lineages can be extended to nonmesodermic lineages, such as the neuroectoderm. MATERIALS & METHODS: Different single cell clones of human adipose mesenchymal stem cells from the same donor were isolated. Neuronal plasticity of the clones was assessed according to the pattern DNA methylation, gene expression and intracellular calcium responses. RESULTS: Under neurogenic culture conditions, clones presented variable expression of neuronal-specific genes, but still expressed osteogenic markers. No calcium response was exhibited in response to KCl incubation. The DNA methylation profile presented a very similar pattern in neuroectoderm gene promoters. CONCLUSIONS: Data indicate that there are no significant differences between the undifferentiated and supposedly neuronal-differentiated mesenchymal cells.
Subject(s)
Adipose Tissue/cytology , Adult Stem Cells/physiology , Cell Differentiation/physiology , Mesenchymal Stem Cells/physiology , Neural Plate/cytology , Adult , Adult Stem Cells/cytology , Cell Culture Techniques , DNA Methylation/genetics , DNA Primers/genetics , Electrophoresis, Agar Gel , Female , Humans , Immunohistochemistry , Mesenchymal Stem Cells/cytology , Real-Time Polymerase Chain ReactionABSTRACT
The estrogen receptor ß (ERß) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ERß selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic ß-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide-induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic ß-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic ß-cell mass. We conclude that ERß agonists should be considered as new targets for the treatment of diabetes.
Subject(s)
Estrogen Receptor beta/agonists , Hypoglycemic Agents/pharmacology , Oxazoles/pharmacology , Phenols/pharmacology , Animals , Cells, Cultured , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Enzyme-Linked Immunosorbent Assay , Humans , In Vitro Techniques , Insulin/blood , Insulin-Secreting Cells/drug effects , Islets of Langerhans/drug effects , Male , Mice , Mice, Inbred C57BL , Niacinamide/pharmacology , Streptozocin/pharmacologyABSTRACT
The non-steroidal compound STX modulates the hypothalamic control of core body temperature and energy homeostasis. The aim of this work was to study the potential effects of STX on pancreatic ß-cell function. 1-10 nM STX produced an increase in glucose-induced insulin secretion in isolated islets from male mice, whereas it had no effect in islets from female mice. This insulinotropic effect of STX was abolished by the anti-estrogen ICI 182,780. STX increased intracellular calcium entry in both whole islets and isolated ß-cells, and closed the K(ATP) channel, suggesting a direct effect on ß-cells. When intraperitoneal glucose tolerance test was performed, a single dose of 100 µg/kg body weight STX improved glucose sensitivity in males, yet it had a slight effect on females. In agreement with the effect on isolated islets, 100 µg/kg dose of STX enhanced the plasma insulin increase in response to a glucose load, while it did not in females. Long-term treatment (100 µg/kg, 6 days) of male mice with STX did not alter body weight, fasting glucose, glucose sensitivity or islet insulin content. Ovariectomized females were insensitive to STX (100 µg/kg), after either an acute administration or a 6-day treatment. This long-term treatment was also ineffective in a mouse model of mild diabetes. Therefore, STX appears to have a gender-specific effect on blood glucose homeostasis, which is only manifested after an acute administration. The insulinotropic effect of STX in pancreatic ß-cells is mediated by the closure of the K(ATP) channel and the increase in intracellular calcium concentration. The in vivo improvement in glucose tolerance appears to be mostly due to the enhancement of insulin secretion from ß-cells.
Subject(s)
Acrylamides/pharmacology , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Insulin/metabolism , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Calcium/metabolism , Diabetes Mellitus/metabolism , Estrogens/pharmacology , Female , Glucose/metabolism , Glucose Tolerance Test/methods , Homeostasis/drug effects , Insulin/blood , Insulin Secretion , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , KATP Channels/metabolism , Male , Mice , Mice, Inbred C57BL , Sex FactorsABSTRACT
The endocrine pancreas has emerged as a target for estrogens. The functions of pancreatic α-, ß- and δ-cells are modulated by the endogenous hormone, 17ß-estradiol (E2). Low physiological concentrations (100pM-1nM) of E2 rapidly decrease the activity of the ATP-sensitive potassium channel (K(ATP)) and enhance glucose-induced insulin release in ß-cells in an estrogen receptor ß (ERß)-dependent manner. In addition to the insulinotropic action of ERß, the newly described estrogen receptor, GPR30, is involved in the insulinotropic effects of high doses of E2 (100nM-5µM). The specific GPR30 agonist G1 also increases insulin secretion in ß-cells. Low glucose-induced calcium oscillations and glucagon secretion are suppressed by E2. The effects on glucagon secretion may be mediated by GPR30. Somatostatin release is also decreased by E2 and G1. In this review we summarize all the data published up to date on the rapid insulinotropic effects of estrogens in the endocrine pancreas and propose a model to integrate the estrogen actions mediated through both receptors.
Subject(s)
Estradiol/physiology , Estrogen Receptor beta/physiology , Estrogens/physiology , Islets of Langerhans/metabolism , Receptors, Estrogen/physiology , Receptors, G-Protein-Coupled/physiology , Animals , Estradiol/pharmacology , Estrogen Receptor alpha/metabolism , Estrogen Receptor alpha/physiology , Estrogen Receptor beta/metabolism , Estrogens/pharmacology , Glucose/metabolism , Humans , Insulin/metabolism , Insulin Secretion , Islets of Langerhans/cytology , Receptors, Estrogen/metabolism , Receptors, G-Protein-Coupled/metabolismABSTRACT
We have successfully been able to synthesise a specific estrogen receptor-directed biolabel based on a fluorescent water-soluble perylenebisimide, thus offering great potential for determining the presence of estrogen receptors in any kind of cell. Moreover, this synthetic strategy allows the preparation of other conjugates involved in the study of any kind of receptor, simply by selecting the appropriate agonist or antagonist.
Subject(s)
Estradiol/chemistry , Fluorescent Dyes/chemistry , Imides/chemistry , Perylene/analogs & derivatives , Steroids/chemistry , Cell Line, Tumor , Humans , Microscopy, Confocal , Perylene/chemistry , Receptors, Estrogen/chemistry , Water/chemistryABSTRACT
ATP-sensitive potassium channels (K(ATP)) regulate electrical activity and insulin secretion in pancreatic ß-cells. When glucose concentration increases, the [ATP]/[ADP] ratio rises closing K(ATP) channels, and the membrane potential depolarizes, triggering insulin secretion. This pivotal role of K(ATP) channels is used not only by glucose but also by neurotransmitters, hormones and other physiological agents to modulate electrical and secretory ß-cell response. In recent years, it has been demonstrated that estrogens and estrogen receptors are involved in glucose homeostasis, and that they can modulate the electrical activity and insulin secretion of pancreatic ß-cells. The hormone 17ß-estradiol (E2), at physiological levels, is implicated in maintaining normal insulin sensitivity for ß-cell function. Long term exposure to E2 increases insulin content, insulin gene expression and insulin release via the estrogen receptor α (ERα), while rapid responses to E2 can regulate K(ATP) channels increasing cGMP levels through the estrogen receptor ß (ERß) and type A guanylate cyclase receptor (GC-A). This review summarizes the main actions of 17ß-estradiol on K(ATP) channels and the subsequent insulin release in pancreatic ß-cells.
Subject(s)
Estradiol/metabolism , Estrogens/metabolism , Insulin-Secreting Cells/metabolism , KATP Channels/metabolism , ATP-Binding Cassette Transporters/metabolism , Animals , Humans , Insulin/metabolism , Insulin Secretion , Potassium Channels, Inwardly Rectifying/metabolism , Receptors, Drug/metabolism , Receptors, Estrogen/metabolism , Receptors, Guanylate Cyclase-Coupled/metabolism , Sulfonylurea ReceptorsABSTRACT
Atrial natriuretic peptide (ANP) and its guanylyl cyclase-A (GC-A) receptor are being involved in metabolism, although their role in the endocrine pancreas is still greatly unknown. The aim of this work is to study a possible role for the ANP/GC-A system in modulating pancreatic beta-cell function. The results presented here show a direct effect of the GC-A receptor in regulating glucose-stimulated insulin secretion (GSIS) and beta-cell mass. GC-A activation by its natural ligand, ANP, rapidly blocked ATP-dependent potassium (K(ATP)) channel activity, increased glucose-elicited Ca(2+) signals, and enhanced GSIS in islets of Langerhans. The effect in GSIS was inhibited in islets from GC-A knockout (KO) mice. Pancreatic islets from GC-A KO mice responded to increasing glucose concentrations with enhanced insulin secretion compared with wild type (WT). Remarkably, islets from GC-A KO mice were smaller, presented lower beta-cell mass and decreased insulin content. However, glucose-induced Ca(2+) response was more vigorous in GC-A KO islets, and basal K(ATP) channel activity in GC-A KO beta-cells was greatly diminished compared with WT. When protein levels of the two K(ATP) channel constitutive subunits sulfonylurea receptor 1 and Inward rectifier potassium channel 6.2 were measured, both were diminished in GC-A KO islets. These alterations on beta-cell function were not associated with disruption of glucose tolerance or insulin sensitivity in vivo. Glucose and insulin tolerance tests were similar in WT and GC-A KO mice. Our data suggest that the ANP/GC-A system may have a modulating effect on beta-cell function.
Subject(s)
Atrial Natriuretic Factor/physiology , Insulin-Secreting Cells/physiology , Receptors, Atrial Natriuretic Factor/physiology , Animals , Atrial Natriuretic Factor/pharmacology , Calcium Signaling/drug effects , Calcium Signaling/genetics , Cells, Cultured , Dose-Response Relationship, Drug , Female , Glucose/metabolism , Glucose/pharmacology , Insulin/analysis , Insulin/metabolism , Insulin Secretion , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , KATP Channels/drug effects , KATP Channels/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Atrial Natriuretic Factor/genetics , Receptors, Atrial Natriuretic Factor/metabolismABSTRACT
The ATP-sensitive potassium (K(ATP)) channel is a key molecule involved in glucose-stimulated insulin secretion. The activity of this channel regulates beta-cell membrane potential, glucose- induced [Ca(2+)](i) signals, and insulin release. In this study, the rapid effect of physiological concentrations of 17beta-estradiol (E2) on K(ATP) channel activity was studied in intact beta-cells by use of the patch-clamp technique. When cells from wild-type (WT) mice were used, 1 nm E2 rapidly reduced K(ATP) channel activity by 60%. The action of E2 on K(ATP) channel was not modified in beta-cells from ERalpha-/- mice, yet it was significantly reduced in cells from ERbeta-/- mice. The effect of E2 was mimicked by the ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN). Activation of ERbeta by DPN enhanced glucose-induced Ca(2+) signals and insulin release. Previous evidence indicated that the acute inhibitory effects of E2 on K(ATP) channel activity involve cyclic GMP and cyclic GMP-dependent protein kinase. In this study, we used beta-cells from mice with genetic ablation of the membrane guanylate cyclase A receptor for atrial natriuretic peptide (also called the atrial natriuretic peptide receptor) (GC-A KO mice) to demonstrate the involvement of this membrane receptor in the rapid E2 actions triggered in beta-cells. E2 rapidly inhibited K(ATP) channel activity and enhanced insulin release in islets from WT mice but not in islets from GC-A KO mice. In addition, DPN reduced K(ATP) channel activity in beta-cells from WT mice, but not in beta-cells from GC-A KO mice. This work unveils a new role for ERbeta as an insulinotropic molecule that may have important physiological and pharmacological implications.
Subject(s)
Estradiol/pharmacology , Estrogen Receptor beta/physiology , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , KATP Channels/drug effects , KATP Channels/metabolism , Receptors, Atrial Natriuretic Factor/physiology , Animals , Calcium/metabolism , Cells, Cultured , Estrogen Receptor alpha/agonists , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/physiology , Estrogen Receptor beta/agonists , Estrogen Receptor beta/genetics , Female , Immunohistochemistry , Mice , Mice, Knockout , Nitriles/pharmacology , Patch-Clamp Techniques , Phenols , Pyrazoles/pharmacology , Receptors, Atrial Natriuretic Factor/geneticsABSTRACT
Pregnancy is characterized by peripheral insulin resistance, which is developed in parallel with a plasma increase of maternal hormones; these include prolactin, placental lactogens, progesterone and oestradiol among others. Maternal insulin resistance is counteracted by the adaptation of the islets of Langerhans to the higher insulin demand. If this adjustment is not produced, gestational diabetes may be developed. The adaptation process of islets is characterized by an increase of insulin biosynthesis, an enhanced glucose-stimulated insulin secretion (GSIS) and an increase of beta-cell mass. It is not completely understood why, in some individuals, beta-cell mass and function fail to adapt to the metabolic demands of pregnancy, yet a disruption of the beta-cell response to maternal hormones may play a key part. The role of the maternal hormone 17beta-oestradiol (E2) in this adaptation process has been largely unknown. However, in recent years, it has been demonstrated that E2 acts directly on beta-cells to increase insulin biosynthesis and to enhance GSIS through different molecular mechanisms. E2 does not increase beta-cell proliferation but it is involved in beta-cell survival. Classical oestrogen receptors ERalpha and ERbeta, as well as the G protein-coupled oestrogen receptor (GPER) seem to be involved in these adaptation changes. In addition, as the main production of E2 in post-menopausal women comes from the adipose tissue, E2 may act as a messenger between adipocytes and islets in obesity.
Subject(s)
Estrogens/metabolism , Insulin Resistance/physiology , Islets of Langerhans/cytology , Islets of Langerhans/physiology , Pregnancy/metabolism , Signal Transduction/physiology , Animals , Female , HumansABSTRACT
The estrogen receptor ERalpha is emerging as a key molecule involved in glucose and lipid metabolism. The main functions of pancreatic beta-cells are the biosynthesis and release of insulin, the only hormone that can directly decrease blood glucose levels. Estrogen receptors ERalpha and ERbeta exist in beta-cells. The role of ERbeta is still unknown, yet ERalpha plays an important role in the regulation of insulin biosynthesis, insulin secretion and beta-cell survival. Activation of ERalpha by 17beta-estradiol (E2) and the environmental estrogen bisphenol-A (BPA) promotes an increase of insulin biosynthesis through a non-classical estrogen-activated pathway that involves phosphorylation of ERK1/2. The activation of ERalpha by physiological concentrations of E2 may play an important role in the adaptation of the endocrine pancreas to pregnancy. However, if ERalpha is over stimulated by an excess of E2 or the action of an environmental estrogen such as BPA, it will produce an excessive insulin signaling. This may provoke insulin resistance in the liver and muscle, as well as beta-cell exhaustion and therefore, it may contribute to the development of type II diabetes.
Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/metabolism , Estrogen Receptor alpha/metabolism , Estrogens/metabolism , Homeostasis , Insulin-Secreting Cells/physiology , Animals , Benzhydryl Compounds , Estradiol/metabolism , Estrogen Receptor beta/metabolism , Estrogens, Non-Steroidal/pharmacology , Female , Humans , Insulin/metabolism , Insulin-Secreting Cells/drug effects , Phenols/pharmacology , Pregnancy , Signal Transduction/physiologyABSTRACT
OBJECTIVE: Leptin released from adipocytes plays a key role in the control of food intake, energy balance, and glucose homeostasis. In addition to its central action, leptin directly affects pancreatic beta-cells, inhibiting insulin secretion, and, thus, modulating glucose homeostasis. However, despite the importance of glucagon secretion in glucose homeostasis, the role of leptin in alpha-cell function has not been studied in detail. In the present study, we have investigated this functional interaction. RESEARCH DESIGN AND METHODS: The presence of leptin receptors (ObR) was demonstrated by RT-PCR analysis, Western blot, and immunocytochemistry. Electrical activity was analyzed by patch-clamp and Ca(2+) signals by confocal microscopy. Exocytosis and glucagon secretion were assessed using fluorescence methods and radioimmunoassay, respectively. RESULTS: The expression of several ObR isoforms (a-e) was detected in glucagon-secreting alphaTC1-9 cells. ObRb, the main isoform involved in leptin signaling, was identified at the protein level in alphaTC1-9 cells as well as in mouse and human alpha-cells. The application of leptin (6.25 nmol/l) hyperpolarized the alpha-cell membrane potential, suppressing the electrical activity induced by 0.5 mmol/l glucose. Additionally, leptin inhibited Ca(2+) signaling in alphaTC1-9 cells and in mouse and human alpha-cells within intact islets. A similar result occurred with 0.625 nmol/l leptin. These effects were accompanied by a decrease in glucagon secretion from mouse islets and were counteracted by the phosphatidylinositol 3-kinase inhibitor, wortmannin, suggesting the involvement of this pathway in leptin action. CONCLUSIONS: These results demonstrate that leptin inhibits alpha-cell function, and, thus, these cells are involved in the adipoinsular communication.
Subject(s)
Glucagon-Secreting Cells/physiology , Leptin/pharmacology , Animals , Calcium/physiology , Cells, Cultured , Exocytosis , Glucagon/metabolism , Glucagon-Secreting Cells/cytology , Glucagon-Secreting Cells/drug effects , Glucagon-Secreting Cells/metabolism , Immunohistochemistry , Mice , Mice, Inbred Strains , Microscopy, Confocal , RNA/genetics , RNA/isolation & purification , Receptors, Leptin/genetics , Receptors, Leptin/physiology , Reverse Transcriptase Polymerase Chain Reaction , Signal TransductionABSTRACT
PPAR alpha is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. PPAR alpha is involved in the regulation of in vivo triglyceride levels, presumably through its effects on fatty acid and lipoprotein metabolism. Some nuclear receptors have been involved in rapid effects mediated by non-genomic mechanisms. In this paper, we report the rapid non-genomic effects of PPAR alpha ligands on the intracellular calcium concentration ([Ca2+]i), mitochondrial function, reactive oxygen species (ROS) generation, and secretion of insulin in freshly isolated mouse islets of Langerhans. The hypolipidemic fibrate PPAR alpha agonist WY-14 643 decreased the glucose-induced calcium oscillations in intact islets. This effect was mimicked by the synthetic agonist GW7647 and the endogenous agonist oleylethanolamide. The WY-14 643 action was rapid in onset (5 min) and was still produced in the presence of protein and mRNA synthesis inhibitors, cycloheximide, and actinomycin-d. This suggests that it is independent of gene transcription. In addition, WY-14 623 impaired mitochondrial function, increased ROS formation and decreased insulin release. PPAR alpha is present in beta-cells, mainly in the cytosol and nucleus, with a small subpopulation localized in the plasma membrane. However, the presence of the PPAR alpha ligand effects in mice bearing a disrupted Ppar alpha gene raises the possibility that the rapid effects of the agonists in pancreatic beta-cells are independent of the receptor. We conclude that PPAR alpha agonists produce a decrease in glucose-induced [Ca2+]i signals and insulin secretion in beta-cells through a rapid, non-genomic mechanism.
Subject(s)
Anticholesteremic Agents/pharmacology , Calcium/metabolism , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Insulin/metabolism , Transcription Factors/metabolism , Animals , Butyrates/pharmacology , Insulin Secretion , Male , Mediator Complex Subunit 1 , Mice , Mitochondria/drug effects , Oleic Acids/metabolism , Phenylurea Compounds/pharmacology , Pyrimidines/pharmacology , Reactive Oxygen Species/metabolismABSTRACT
The function of pancreatic beta-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ER alpha and ER beta, are important molecules involved in glucose metabolism, yet their role in pancreatic beta-cell physiology is still greatly unknown. In this report we show that both ER alpha and ER beta are present in pancreatic beta-cells. Long term exposure to physiological concentrations of 17beta-estradiol (E2) increased beta-cell insulin content, insulin gene expression and insulin release, yet pancreatic beta-cell mass was unaltered. The up-regulation of pancreatic beta-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA). The use of ER alpha and ER beta agonists as well as ER alphaKO and ER betaKO mice suggests that the estrogen receptor involved is ER alpha. The up-regulation of pancreatic insulin content by ER alpha activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis.