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Background Chagas disease is considered important and presents intense inflammatory and fibrotic processes induced by the perpetuation of the parasite in the affected tissues and organs. Therefore, it is necessary to inquire about the host defense and attack mechanisms to have a more detailed knowledge about Chagas disease. MicroRNAs are found in blood, tissues and extracellular vesicles. These small regulators of gene expression are involved in physiological and pathological processes in both mammals and parasites. Several microRNAs have deregulated expression in chagasic heart disease, although little is known about their extracellular expression. Our main objective was to evaluate the involvement of miR-21, miR-146a and miR-155 in several samples from mice infected with the TcI Ninoa strain from the acute and indeterminate phases. We also explored a potential functional association of the selected microRNAs using STRING software. This software identified 23 pathways associated with Trypanosoma cruzi infection. In addition, eleven genes were identified through bioinformatics analysis, and we found that SMAD family member 5 was downregulated in both phases. This gene serves as a mediator in the TGF-β signaling pathway. Thus, forty female mice of the CD1 strain were distributed into 4 groups and the expression levels of miR-21, miR-146a and miR-155 were measured in samples of heart tissue, total plasma and plasma extracellular vesicles by quantitative real-time polymerase chain reaction. Results Overexpression of miR-21, miR-146a and miR-155 was observed in heart and plasma in both phases. Moreover, in extracellular vesicles miR-21 and miR-146a were also overexpressed in the acute phase, whereas in the indeterminate chronic phase we found only miR-146a up-regulated. Conclusions The expression of inflammatory microRNAs miR-21, miR-146a and miR-155 were up-regulated in each of the samples from acutely and chronically infected mice. The relevant finding was that miR-146a was up-regulated in each sample in both phases; therefore, this miRNA could be a possible candidate biomarker in Chagas disease.

Sugar transport through the plasma membrane is one of the most critical events in the cellular transport of nutrients; for example, glucose has a central role in cellular metabolism and homeostasis. The way sugars enter the cell involves complex systems. Diverse protein systems participate in the membrane traffic of the sugars from the extracellular side to the cytoplasmic side. This diversity makes the phenomenon highly regulated and modulated to satisfy the different needs of each cell line. The beautiful thing about this process is how evolutionary processes have diversified a single function: to move glucose into the cell. The deregulation of these entrance systems causes some diseases. Hence, it is necessary to study them and search for a way to correct the alterations and utilize these mechanisms to promote health. This review will highlight the various mechanisms for importing the valuable sugars needed to create cellular homeostasis and survival in all kinds of cells.

Background Cold temperatures can aggravate pulmonary diseases and promote pulmonary arterial hypertension (PAH); however, the underlying mechanism has not been fully explored. Aim To explore the effect of chronic cold exposure on the production of inflammatory cytokines and microRNAs (miRNAs) in a monocrotaline (MCT)-induced PAH model. Methods Male Sprague Dawley rats were divided into a Control (23.5 ± 2 °C), Cold (5.0 ± 1 °C for ten days), MCT (60 mg/kg body weight i.p.), and MCT + Cold (ten days of cold exposure after 3 weeks of MCT injection). Hemodynamic parameters, right ventricle (RV) hypertrophy, and pulmonary arterial medial wall thickness were determined. IL-1β, IL-6, and TNF-α levels were determined using western blotting. miR-21-5p and -3p, miR-146a-5p and -3p, and miR-155-5p and -3p and plasma extracellular vesicles (EVs) and mRNA expression of Cd68, Cd163, Bmpr2, Smad5, Tgfbr2, and Smad3 were determined using RT-qPCR. Results The MCT + Cold group had aggravated RV hypertrophy hemodynamic parameters, and pulmonary arterial medial wall thickness. In lungs of the MCT + Cold, group the protein levels of TNF-α, IL-1β, and IL-6 were higher than those in the MCT group. The mRNA expression of Cd68 and Cd163 were higher in the MCT + Cold group. miR-146a-5p and miR-155-5p levels were higher in the plasma EVs and lungs of the MCT + Cold group. Cold exposure promoted a greater decrease in miR-21-5p, Bmpr2, Smad5, Tgfbr2, and Smad3 mRNA expression in lungs of the MCT + Cold group. Conclusion Cold exposure aggravates MCT-induced PAH with an increase in inflammatory marker and miRNA levels in the plasma EVs and lungs.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling. Recent evidence supports that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Recent studies have shown that garlic extract has protective effects in PAH, but the precise role of allicin, a compound derived from garlic, is unknown. Thus, we used allicin to evaluate its effects on inflammation and fibrosis in PAH. Male Wistar rats were divided into three groups: control (CON), monocrotaline (60 mg/kg) (MCT), and MCT plus allicin (16 mg/kg/oral gavage) (MCT + A). Right ventricle (RV) hypertrophy and pulmonary arterial medial wall thickness were determined. IL-1β, IL-6, TNF-α, NFκB p65, Iκβ, TGF-β, and α-SMA were determined by Western blot analysis. In addition, TNF-α and TGF-β were determined by immunohistochemistry, and miR-21-5p and mRNA expressions of Cd68, Bmpr2, and Smad5 were determined by RT-qPCR. Results: Allicin prevented increases in vessel wall thickness due to TNF-α, IL-6, IL-1β, and Cd68 in the lung. In addition, TGF-β, α-SMA, and fibrosis were lower in the MCT + A group compared with the MCT group. In the RV, allicin prevented increases in TNF-α, IL-6, and TGF-β. These observations suggest that, through the modulation of proinflammatory and profibrotic markers in the lung and heart, allicin delays the progression of PAH.

The cellular damage caused by redox imbalance is involved in the pathogenesis of many cardiovascular diseases. Besides, redox imbalance is related to the alteration of protein acetylation processes, causing not only chromatin remodeling but also disturbances in so many processes where protein acetylation is involved, such as metabolism and signal transduction. The modulation of acetylases and deacetylases enzymes aids in maintaining the redox homeostasis, avoiding the deleterious cellular effects associated with the dysregulation of protein acetylation. Of note, regulation of protein acetylation has shown protective effects to ameliorate cardiovascular diseases. For instance, HDAC inhibition has been related to inducing cardiac protective effects and it is an interesting approach to the management of cardiovascular diseases. On the other hand, the upregulation of SIRT protein activity has also been implicated in the relief of cardiovascular diseases. This review focuses on the major protein acetylation modulators described, involving pharmacological and bioactive compounds targeting deacetylase and acetylase enzymes contributing to heart protection through redox homeostasis.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by the loss and obstructive remodeling of the pulmonary arterial wall, causing a rise in pulmonary arterial pressure and pulmonary vascular resistance, which is responsible for right heart failure, functional decline, and death. Although many drugs are available for the treatment of this condition, it continues to be life-threatening, and its long-term treatment is expensive. On the other hand, many natural compounds present in food have beneficial effects on several cardiovascular conditions. Several studies have explored many of the potential beneficial effects of natural plant products on PAH. However, the mechanisms by which natural products, such as nutraceuticals, exert protective and therapeutic effects on PAH are not fully understood. In this review, we analyze the current knowledge on nutraceuticals and their potential use in the protection and treatment of PAH, as well as whether nutraceuticals could enhance the effects of drugs used in PAH through similar mechanisms.

In modern societies, high fructose intake from sugar-sweetened beverages has contributed to obesity development. In the diet, sucrose and high fructose corn syrup are the main sources of fructose and can be metabolized in the intestine and transported into the systemic circulation. The liver can metabolize around 70% of fructose intake, while the remaining is metabolized by other tissues. Several tissues including adipose tissue express the main fructose transporter GLUT5. In vivo, chronic fructose intake promotes white adipose tissue accumulation through activating adipogenesis. In vitro experiments have also demonstrated that fructose alone induces adipogenesis by several mechanisms, including (1) triglycerides and very-low-density lipoprotein (VLDL) production by fructose metabolism, (2) the stimulation of glucocorticoid activation by increasing 11β-HSD1 activity, and (3) the promotion of reactive oxygen species (ROS) production through uric acid, NOX and XOR expression, mTORC1 signaling and Ang II induction. Moreover, it has been observed that fructose induces adipogenesis through increased ACE2 expression, which promotes high Ang-(1-7) levels, and through the inhibition of the thermogenic program by regulating Sirt1 and UCP1. Finally, microRNAs may also be involved in regulating adipogenesis in high fructose intake conditions. In this paper, we propose further directions for research in fructose participation in adipogenesis.

The omentin is an adipokine, which role is due to the capacity of regulate metabolic (insulin sensitivity) and anti-inflammatory activities, thus conferring vascular protection during obesity and diabetes mellitus type 2. By this, it is important to know the mechanisms by which omentin confers cardiovascular protection, with the purpose of establish omentin a possible therapeutic target or molecule on this scenario.

Circulating microRNAs (miRNAs) and the functional implications of miRNAs contained in extracellular vesicles (EVs) have gained attention in the last decade. Little is known about the regulation of the abundance of plasma miRNAs in response to chronic ingestion of carbohydrates. Therefore, we explored the circulating levels of miR-21, miR-146a, miR-155, and miR-223 in rats consuming sucrose in drinking water. Weanling Wistar rats were 25 weeks with 30% sucrose in drinking water, and miRNAs expression was determined in total plasma and in microvesicles, by RT-qPCR with TaqMan probe based assays for miR-21, miR-146a, miR-155, and miR-223, using cel-miR-39 (as spike in control and reference). Endotoxemia was also measured. Sucrose-fed animals showed higher body weight and retroperitoneal adipose tissue as well as higher glucose and triglyceride plasma levels than controls. Plasma endotoxin levels were low and not different among groups. Plasma miR-21 and miR-223 were higher in the sucrose group (p<0.05), whereas miR-155 tended to be lower (p=0.0661), and miR-146a did not show significant differences. In the plasma EVs the same trend was found except for miR-146a that showed significantly higher levels (p<0.05). Overall, our results show that high carbohydrate ingestion modulates circulating miRNAs levels related to an inflammatory response.

Maitotoxin (MTX) is the most potent marine toxin known to date. It is responsible for a particular human intoxication syndrome called ciguatera fish poisoning (CFP). Several reports indicate that MTX is an activator of non-selective cation channels (NSCC) in different cell types. The molecular identity of these channels is still an unresolved topic, and it has been proposed that the transient receptor potential (TRP) channels are involved in this effect. In Xenopus laevis oocytes, MTX at picomolar (pM) concentrations induces the activation of NSCC with functional and pharmacological properties that resemble the activity of TRP channels. The purpose of this study was to characterize the molecular identity of the TRP channel involved in the MTX response, using the small interference RNA (siRNA) approach and the two-electrode voltage-clamp technique (TEVC). The injection of a specifically designed siRNA to silence the transient receptor potential canonical type 1 (TRPC1) protein expression abolished the MTX response. MTX had no effect on oocytes, even at doses 20-fold higher compared to cells without injection. Total mRNA and protein levels of TRPC1 were notably diminished. The TRPC4 siRNA did not change the MTX effect, even though it was important to note that the protein level was reduced by the silencing of TRPC4. Our results suggest that MTX could be a selective activator of TRPC1 channels in X. laevis oocytes and a useful pharmacological tool for further studies on these TRP channels.

Obesity is considered to significantly increase the risk of the development of a vast range of metabolic diseases. However, adipogenesis is a complex physiological process, necessary to sequester lipids effectively to avoid lipotoxicity in other tissues, like the liver, heart, muscle, essential for maintaining metabolic homeostasis and has a crucial role as a component of the innate immune system, far beyond than only being an inert mass of energy storage. In pathophysiological conditions, adipogenesis promotes a pro-inflammatory state, angiogenesis and the release of adipokines, which become dangerous to health. It results in a hypoxic state, causing oxidative stress and the synthesis and release of harmful free fatty acids. In this review, we try to explain the mechanisms occurring at the breaking point, at which adipogenesis leads to an uncontrolled lipotoxicity. This review highlights the types of adipose tissue and their functions, their way of storing lipids until a critical point, which is associated with hypoxia, inflammation, insulin resistance as well as lipodystrophy and adipogenesis modulation by Krüppel-like factors and miRNAs.

Obesity is a major public health problem worldwide. The quantity and site of accumulation of adipose tissue is of great importance for the physiopathology of this disease.The aim of this study was to assess the effect of a high carbohydrate diet on adipose tissue distribution.Male Wistar rats, control (CONT) and high sucrose diet (HSD; 30% sucrose in their drinking water), were monitored during 24 weeks and total energy and macronutrient intake were estimated by measuring daily average consumption. A bioelectrical impedance procedure was performed at 22 weeks of treatment to assess body compartments and systolic arterial blood pressure was measured. Serum was obtained and retroperitoneal adipose tissue was collected and weighed.HSD ingested less pellets and beverage, consuming less lipids and proteins than CONT, but the same amount of carbohydrates. Retroperitoneal adipose tissue was more abundant in HSD. Both groups were normoglycemic; triglycerides, adiponectin and leptin levels were higher, while total cholesterol and HDL-cholesterol were lower in HSD; insulin, HOMA index and systolic blood pressure had a tendency of being higher in HSD.This model presents dyslipidemia and a strong tendency for insulin resistance and hypertension. Even though there was no difference in body compartments between groups, retroperitoneal adipose tissue was significantly increased in HSD. This suggests that a rearrangement of adipose tissue distribution towards the abdominal cavity takes place as a result of chronic high sucrose consumption, which contributes to a higher risk of suffering from metabolic and chronic degenerative diseases.Introducción: la obesidad es uno de los mayores problemas de salud pública en todo el mundo. El momento en que se establecee, la distribución y cantidad de tejido adiposo son de gran importancia para comprender su fisiopatología. Objetivos: observar la distribución de tejido adiposo en una dieta alta en sacarosa desde una edad temprana en un modelo animal. Métodos: se utilizaron ratas Wistar recién destetadas, animales control (CONT; agua ad libitum) y animales con dieta alta en sacarosa (HSD; 30% de sacarosa en el agua) durante 24 semanas. Se calcularon las kilocalorías y macronutrientes ingeridos diariamente; se evaluaron por impedancia bioeléctrica los compartimientos corporales, se midió la presión sistólica, se obtuvo el tejido adiposo retroperitoneal y el suero para medir parámetros bioquímicos. Resultados: los animales HSD comieron y bebieron menos, obteniendo menos proteínas y lípidos, sin diferencia en los hidratos de carbono. El tejido adiposo fue más abundante en HSD. Ambos grupos CONT Y HSD fueron normoglucémicos; HSD tuvieron triglicéridos, adiponectina y leptina altos, y el colesterol y las HDL más bajos; la insulina, el HOMA y la presión sistólica tuvieron tendencia a ser mayores en HSD. Discusión: este modelo presenta dislipidemia y una tendencia a tener resistencia a la insulina e hipertensión. A pesar de no haber una diferencia en los compartimentos corporales entre grupos, el tejido adiposo tuvo una localización específica en la espalda y fue más abundante en HSD. En conclusión, la distribución de grasa en el abdomen es consecuencia de una ingestión crónica alta en sacarosa, lo que predispone a padecer enfermedades crónico-degenerativas.

The omentin is an adipokine, which role is due to the capacity of regulate metabolic (insulin sensitivity) and anti-inflammatory activities, thus conferring vascular protection during obesity and diabetes mellitus type 2. By this, it is important to know the mechanisms by which omentin confers cardiovascular protection, with the purpose of establish omentin a possible therapeutic target or molecule on this scenario.

The pathogenic mechanisms leading to cardiovascular disorders in patients with chronic kidney disease have not been clearly established, although increased oxidative stress has been pointed out as a potential cause. Therefore, as cardiovascular events are still the first cause of death in patients with chronic kidney disease and traditional drugs or therapies rarely have effects on cardiac complications, we sought to determine the effect of curcumin in treating cardiac dysfunction in rats with established chronic renal disease. Treatment consisted in daily administration of curcumin (120 mg/kg/day) dissolved in 0.05 % carboxymethylcellulose via oral gavages during 30 days, beginning from day 30 after 5/6 nephrectomy (5/6Nx). Cardiac function, markers of oxidative stress, activation of PI3K/Akt/GSK3β and MEK1/2-ERK1/2 pathway, metalloproteinase-II (MMP-2) content, overall gelatinolytic activity, ROS production and mitochondrial integrity were evaluated after 1-month treatment. Curcumin restored systolic blood pressure, diminished interventricular and rear wall thickening, decreased left ventricle dimension at end-systole (LVSd) and restored ejection fraction in nephrectomized rats. Also, it diminished metalloproteinase-II levels and overall gelatinase activity, decreased oxidative stress and inhibited the mitochondrial permeability transition pore opening. Our findings suggest that curcumin might have therapeutic potential in treatment of heart disease in patients with established CKD by attenuating oxidative stress-related events as cardiac remodeling, mitochondrial dysfunction and cell death.

Summary 1. Although adult cardiac metabolism depends on fatty acids rather than on carbohydrates, hypoxic hearts consume glucose and infusion with a glucose–insulin–potassium solution (GIK) helps in the recovery of the pressure register, the heart rate and electrocardiogram of rat hypoxic whole hearts. 2. Rat myocytes obtained by enzymatic disaggregation captured significant amounts of glucose in Tyrode's solution (9.8 ± 2.05% during oxygenation and 16.26 ± 2.76% during hypoxia) after 60 min incubation. Cells incubated with GIK showed a significantly increased glucose uptake (to 30.04 ± 1.99% during oxygenation and to 37.06 ± 1.97% during hypoxia). 3. Glucose was the component of the Tyrode's solution that most enhanced its own entry, increasing glucose entry to 45.42 ± 2.64% with oxygen and 41.42 ± 2.69% under hypoxia. 4. Antibodies against glucose transporters 1 and 4 (GLUT-1 and -4, respectively) decreased glucose transport during GIK treatment under hypoxia. 5. We conclude that GIK has beneficial effects mediated by GLUT-1 and -4 during hypoxia, inducing recovery of the damaged tissue.

Changes in contractility of newborn and adult hearts with different substrates were studied under oxygenation and hypoxia. Under oxygenation, insulin (50 mU/l) and low doses of fatty acids (sodium palmitate 0.12 mM) increased the differential ventricular pressure (DVP), while higher doses of fatty acids (from 0.3 to 1.5 mM) decreased it. However, when both low doses of fatty acids and insulin were added simultaneously, tension development decreased. Hypoxia reduced DVP, and low doses of fatty acids restored cardiac force. The contractile response to extracellular glucose concentrations changed during development, and sensitivity to high doses of fatty acids increased with age. In adult cardiomyocytes, glucose uptake was also inhibited by sodium palmitate under oxygenation when cardiac metabolism is fatty acid dependent, but not under hypoxia, when it consumes carbohydrates. Newborn cardiomyocytes consumed more glucose than adult cells, they did not respond to insulin, and palmitate did not completely inhibit glucose uptake neither under oxygenation nor under hypoxia. Substrate availability modified glucose uptake and contractility by independent mechanisms.

The pattern of association between neurotensin (NT)-immunoreactive (NTIR) preganglionic nerve terminals and cardiac and noncardiac neurons in the stellate ganglion of the cat is analyzed, based on the finding of an excitatory modulation effect of exogenous NT on cardiac functions. For this purpose, NT-containing terminals were labeled by immunohistochemistry, and ganglion cells were detected by retrograde labeling of cardiac and vertebral nerves to identify cardiac and noncardiac neurons. To determine a possible regional localization of NTIR terminals and ganglion cells, the ganglia were divided into four areas: caudal, dorsomedial, cranial, and ventromedial, related to the two major afferent nerves (thoracic white rami 3 [T3WR] and 2 [T2WR]) and the two efferent nerves (vertebral and cardiac). NTIR terminals were widespread in the complete ganglion tissue; they covered practically all the regions explored, although two clusters of high concentration of NTIR terminals were detected in the cranial and caudal areas. By retrograde labelling it was found that cardiac cells were arranged around the exit of the cardiac nerve and that the vertebral neurons were extended from the exit of the vertebral nerve to the entrance of T3WR. The finding of association of NTIR terminals with cardiac neurons may account for the cardioregulatory effect of NT; however, since the presence of NTIR terminals close to the noncardiac neurons is notorious, other regulatory functions of NT must be considered.

Natriuretic peptides, beside their endocrine actions, have paracrine functions which include regulating glucose uptake and metabolism. Atrial natriuretic peptide (ANP) actions are mediated by cGMP which is implicated in the metabolic adaptation of glucose metabolism to oxygen deprivation in the heart. Although, it has been reported that ANP increases glucose uptake, cGMP decreases it. The aim of the present paper was to evaluate the role of the glucose transporters 1 and 4 (GLUTS), in glucose uptake produced by ANP in fatty acid-dependent adult cardiomyocytes and glucose-dependent neonatal cardiomyocytes under oxygenation and hypoxia, which reverts adult metabolism to glucose-dependent. We also explored if the calcium-calmodulin complex participates in ANP-induced increase in glucose uptake. Neonatal cells had a higher glucose uptake than adult cells and GLUT 1 participated in basal uptake in both cell types. Hypoxia increased glucose uptake in adult cardiomyocytes but not in neonatal cells and this increase in glucose uptake was mediated by GLUT4. ANP increased glucose uptake in both adult and neonatal myocytes, under oxygenation and hypoxia, and GLUT4 favored this increase. Neonatal cells were less sensitive to ANP. Trifluoperazine, a calcium-calmodulin blocker, inhibited the ANP-induced increase in glucose uptake. This suggests that ANP promotes GLUT 4 calcium-mediated recruitment to the cell membrane. In conclusion, glucose uptake regulation is one of the paracrine metabolic effects of ANP in adult and neonatal cardiomyocytes under oxygenation and hypoxia. This effect of this peptide could explain the beneficial effects found in the internal medicine and surgical fields.

Based on the cardiac metabolic changes during hypoxia, in this second part of our review we propose, the polarizing solution as an alternative for the maintenance of the cardiac cells during an infarction, in conjunction with other alternative therapies.

The protective role of estrogens against peripheral vascular and coronary disease in women is well documented; however, it is not present in diabetic women. Estrogens reduce tension development through non-genomic mechanisms that include changes in calcium concentrations in endothelial and smooth muscle cells, and regulation of nitric oxide synthase (NOS) in endothelial cells. Insulin increases endothelin-1 (ET-1) release from endothelial cells modulating smooth muscle calcium levels and elevating force generated by femoral and coronary arteries. This paper examines whether 17 beta-estradiol (E2 beta) modulates changes in femoral and coronary artery contractility induced by insulin. Femoral and coronary arteries were obtained from male Wistar rats, placed in isolated tissue baths for in vitro studies, perfused with different solutions, and the contractile response to KCl 40 mmol/L was measured. Insulin increased arterial contraction induced by KCl. This increase was not present when the endothelium was removed. In the presence of E2 beta, we observed a dose dependent reduction in the tension developed and this effect disappeared when the endothelium was removed. The insulin-induced contraction was significantly reduced in presence of E2 beta. These data indicate that the effect of insulin on femoral and coronary vascular contractility is modulated by E2 beta.

We describe different metabolic states of the heart, during developmental stages, hypoxia and illness, to understand and use them to try to reestablish the normal conditions.

We studied whether the contractile responses to potassium chloride (KCI) of rat coronary and femoral arteries differ when perfused with solutions containing varying concentrations of metabolic substrates (glucose, oxygen, insulin) and whether these differences might explain some of the beneficial effects of glucose-insulin-potassium (GIK or polarizing) solution. We also studied the mediation of the endothelium on these effects. Contraction of femoral arteries decreased with low and high glucose while in coronary arteries it increased as the glucose concentrations rose. Endothelin receptor antagonists blocked this increase. The tension increase induced by insulin in both vessels was smaller in the coronary arteries. The ETA receptor antagonist PD51242 blocked most of the insulin effect in the coronary arteries, whereas in the femoral arteries this was blocked by the ET(B) receptor antagonist BQ788. Hypoxia blocked the constrictive responses to glucose and insulin of the coronary but not of the femoral arteries. GIK increased contractile force in hypoxic femoral arteries but reduced that in coronary arteries. The contractile response decreased by GIK in hypoxic coronary arteries was restored by N(G)-nitro-L-arginine methyl ester, suggesting mediation by nitric oxide. We conclude that in the presence of high glucose and/or insulin levels, coronary arteries respond to KCl differently from femoral arteries, their behavior during hypoxia might explain some of the beneficial effects of GIK.

Metabolic syndrome (MS) may comprise several clinical conditions such as obesity, diabetes and inflammatory disorders, which are characterized by metabolic imbalances. The study of glucose transport and regulation by insulin in lymphocytes is important, since the way they increase inflammation and susceptibility to infections are common in MS. We studied glucose internalization in isolated thymocytes and splenocytes, its regulation by insulin, and the role of three glucose transporters (Gluts) in control and in MS rats. Control glucose internalization and insulin responses were lower in splenocytes than in thymocytes. Control and insulin-induced glucose internalization in thymocytes declined with age, while transport by splenocyte continued to respond to insulin. Control thymocyte glucose internalization was blocked by antibodies against Glut 1 and 4, while the insulin response also was blocked by an anti-Glut 3 antibody. On four month old control and insulin-induced response, splenocyte transport was only blocked by Glut 1 and 4 antibodies. At six months splenocyte glucose internalization depended on Glut 1 and was less sensitive to the effects of an anti-Glut 4 antibody. In MS splenocytes the capacity of anti-Glut 1 antibodies to inhibit control and insulin-dependent glucose transport was less significant, and we found that in MS rats, glucose internalization was dependent on Glut 3 and Glut 4. In summary, the altered metabolic state present in MS rats shows signs of modulation of glucose internalization by the Glut1, Glut 3 and Glut 4 transporters, compared with its own age control.