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<p dir="ltr">In the three conducted studies, we investigated the role of serum albumin in metabolic processes, particularly in lipid metabolism and glucoregulation. The first study explored how disrupting the binding of free fatty acids (FFA) to circulating albumin affects lipid metabolism and glucose control. Male and female albumin knockout mice exhibited significantly reduced plasma FFA levels, hepatic lipid content, and blood glucose during tolerance tests compared to wild-type mice. Additionally, albumin deficiency led to changes in adipose tissue gene expression, indicating the importance of albumin and plasma FFA concentration in metabolic regulation. In the second study, the focus was on determining if impeding serum albumin's function in transporting FFAs could prevent hepatic steatosis and metabolic dysfunction in obesity. Albumin knockout mice, despite being obese due to a high-fat diet, showed lower plasma FFA levels, improved glucose tolerance, and reduced hepatic lipid accumulation compared to wild-type mice. Elevated gene expression in liver and adipose tissues suggested albumin's involvement in hepatic lipid accumulation and glucose metabolism in obesity. Lastly, in the third study, we examined the phenotype of heterozygous albumin knockout mice and compared it to wild-type and homozygous knockout mice. While homozygous knockout mice exhibited improved glucoregulation and reduced plasma FFA concentration, heterozygous knockout mice did not show significant improvements compared to wild-type mice. The findings imply that a minor suppression of albumin expression may not be adequate to enhance glucoregulation. In summary, the studies emphasize the crucial role of serum albumin in metabolic processes, illustrating how disrupting FFA binding to albumin leads to improved glucose control and reduced hepatic lipid accumulation. However, minor suppression of albumin expression may not effectively enhance metabolic health. These findings provide valuable insights into potential therapeutic interventions targeting the albumin-FFA pathway to improve metabolic outcomes.</p><p dir="ltr"><br></p>

The neonatal period in mammals is characterized by high growth rates and is dominated by skeletal muscle hypertrophy. Low birth weight (LBWT) neonates experience restricted growth and development of skeletal muscle, leading to metabolic perturbations later in life. The overall hypothesis of this dissertation was that in utero disturbances in glucose metabolism and increased energy requirements predisposes LBWT neonatal pigs to metabolic disturbances after birth. We sought to increase growth of skeletal muscle and improve glucose production through increasing dietary energy and to determine the changes in glucose catabolism and metabolic flexibility in different skeletal muscle fiber types in LBWT neonates. Piglets were considered normal birth weight (NBWT) and LBWT when birth weight was within 0.5 SD and below 2 SD of the litter average, respectively. Increasing dietary energy increased lean deposition in the longissimus dorsi (LD) in both NBWT and LBWT neonates. Although glucose rate of appearance was greater in LBWT compared to their NBWT sibling, glucose concentrations were reduced in LBWT compared to NBWT pigs, regardless of diet fed. Postprandial glucose concentrations were lower in LBWT compared to NBWT pigs, regardless of diet fed, although rate of appearance did not differ between them. This would suggest that glucose is being absorbed in the peripheral tissues to be utilized. However, expression of enzymes related to glycolysis were downregulated in both the soleus and LD of LBWT compared to NBWT neonatal pigs. In addition, expression of enzymes related to the catabolism of glucose in the serine biosynthetic pathway were decreased in both the soleus and LD muscles of LBWT compared to NBWT neonatal pigs. Expression of the pentose phosphate pathway was slightly increased in LBWT compared to NBWT siblings in both muscle types. Increased expression of pyruvate dehydrogenase 4 was exhibited in both the soleus and LD of LBWT pigs compared to NBWT siblings. This would indicate a switch in fuel utilization to more fatty acid oxidation. By contrast, CO2 production from the oxidation of palmitate was reduced in LBWT compared with NBWT pigs along with reduced oxidation of glucose and pyruvate. In conclusion, lipid supplementation increased growth at the expense of fat deposition in the liver of NBWT and LBWT pigs. However, supplementing with fat did not increase glucose production due to the contribution of glycerol remaining constant. Hypoglycemia cannot be attributed to greater catabolism in skeletal muscle due to decreased expression of glycolytic genes and the addition of fatty acids did not spare glucose oxidation in skeletal muscle of LBWT pigs. / PHD / During the neonatal period animals display the fastest growth rates, especially pertaining to muscle growth. Muscle development in low birth weight (LBWT) is restricted, leading not only to impaired postnatal growth but increases the risk for developing metabolic diseases later in life such as obesity and type 2 diabetes. LBWT is also characterized by decreased glucose concentrations and decreased body fat content at birth. In the present studies we sought to increase growth and improve glucose production by supplementing with a high energy diet and to compare the changes in glucose catabolism in different skeletal muscle fiber types along with analyzing the ability to switch fuel substrates in LBWT and NBWT neonatal pigs. Increasing dietary energy increased longissimus dorsi (LD) weight as a percentage of bodyweight, regardless of growth status. In addition, during fasting glucose production was higher in LBWT compared to their NBWT siblings, regardless of diet. However, glucose concentration in LBWT were lower compared to NBWT neonatal pigs. Although glucose concentrations were lower in LBWT compared to NBWT pigs after a meal, glucose production rate was unchanged among LBWT and NBWT siblings fed either a high or low energy diet. This suggests that glucose uptake is increased in peripheral tissues of LBWT pigs. However, enzymes related to glycolysis in the LD and soleus of LBWT pigs had lower expression than their NBWT sibling. In addition, the enzyme responsible for the shift in fuel selection, pyruvate dehydrogenase kinase 4 (PDK4) was highly expressed in LBWT compared to NBWT neonatal pigs in both the LD and soleus. This would suggest a switch in glucose oxidation to fatty acid oxidation in the skeletal muscle of LBWT neonatal pigs. However, oxidation of fatty acids in both the soleus and LD of LBWT was reduced compared to NBWT neonatal pigs. In conclusion, lipid supplementation increased growth at the expense of lipid deposition in the liver and did not increase glucose production. Reduced glucose concentrations are not due to greater catabolism in skeletal muscle due to decreased expression of glycolytic genes and the addition of fatty acids did not spare glucose oxidation in the skeletal muscle of LBWT pigs.

Lipedema may be considered a model for healthy expandability of subcutaneous adipose tissue (SAT). This condition is characterized by the disproportional and symmetrical SAT accumulation in the lower-body parts and extremities, avoiding the abdominal area. There are no circulating biomarkers facilitating the diagnosis of lipedema. We tested the hypothesis that women living with lipedema present a distinct pattern of circulating parameters compared to age- and BMI-matched women. In 26 women (Age 48.3 ± 13.9 years, BMI 32.6 ± 5.8 kg/m2; lipedema group: n=13; control group: n=13), we assessed circulating parameters of glucose and lipid metabolism, inflammation, oxidative stress, sex hormones and a proteomics panel. We find that women with lipedema have better glucose metabolism regulation represented by lower HbA1c (5.55 ± 0.62%) compared to controls (6.73 ± 0.85%; p<0.001); and higher adiponectin levels (lipedema: 4.69 ± 1.99 mmol/l; control: 3.28 ± 1.00 mmol/l; p=0.038). Despite normal glycemic parameters, women with lipedema have significantly higher levels of total cholesterol (5.84 ± 0.70 mmol/L vs 4.55 ± 0.77 mmol/L in control; p<0.001), LDL-C (3.38 ± 0.68 mmol/L vs 2.38 ± 0.66 mmol/L in control; p=0.002), as well as higher circulating inflammation (top 6 based on p-values: TNFSF14, CASP8, ENRAGE, EIF4EBP1 , ADA, MCP-1) and oxidative stress markers (malondialdehyde, superoxide dismutase and catalase). Our findings suggest that the expected association between activation of inflammatory and oxidative stress pathways and impaired glucose metabolism are counterbalanced by protective factors in lipedema.

Background. The kidney is one of the major organs involved in whole-body homeostasis and it is well understood that chronic renal impairment is further complicated with deranged carbohydrate metabolism, dyslipidemia, altered abdominal fat distribution and the activation of renin-angiotensin system (RAS). Recently, RAS blockades of angiotensinconverting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) have been noticed for their potential effects on improve glucose and lipid metabolisms and lowering the risk of new-onset diabetes. However, underlying cellular and molecular mechanisms are not fully established. / Conclusions. (1) UNX induces progressive renal impairment and dysregulation of pancreatic and renal RAS in rats. (2) Pancreatic RAS activation leads to intra-islet fibrosis, insulin-secreting beta-cell deficit and insulin secretory deficiency. (3) Renal cortex RAS dysregulation induces ectopic adipocyte differentiation and lipid infiltration, in combination with lipodystrophy and lipid peroxidation, results to insulin resistance. (4) Pancreatic insulin-secretion deficit and insulin resistance contribute to the development of glucose intolerance and hyperglycemia. (5) Kidney impacting on glucose and lipid metabolism by affecting pancreatic islet and adipocyte, suggesting an essential role of the kidney in maintaining the whole-body homeostasis. (6) RAS blockade with ACEI or ARB may prevent the development of chronic renal impairment and glucose and lipid dysmetabolisms in UNX rats. (7) Common pathways modulating blood pressure, glucose and lipid metabolism warrant future studies for the better management of the global epidemic of metabolic syndrome. / Materials and methods. Chronic renal impairment and RAS disturbance were induced by unilateral nephrectomy (UNX) in adult Sprague-Dawley rats undergoing as long as 10 months of observation. Three-month old male rats were randomized into 4 groups: (1) sham operated control rats (n=10), (2) untreated UNX model rats (n=10), (3) ACEI---lisinopril treated UNX rats (n=10), and (4) ARB-olmesartan treated UNX rats (n=10). Blood glucose levels during fasting and oral glucose tolerance test (OGTT) conditions, lipids, insulin and renal function were measured at 3, 6, 8 and 10 months after operation. Histological changes of kidney, pancreas, liver, and adipose tissue were examined at 10 months post-operation. / Objectives. (1) To set up a rat model with persistent chronic renal impairment and RAS activation. (2) To examine changes of fasting blood glucose, glucose tolerance, blood lipids and insulin sensitivity. (3) To examine changes of pancreatic islets and the factors contributing to pancreatic islet damage such as RAS, transforming growth factor (TGF)-beta and alpha-smooth muscle actin (SMA). (4) To examine changes of systemic and renal adipose tissue and the factors contributing to adipopathy such as RAS, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and hydroxy-3-methylglutary coenzyme A reductase (HMGCR). (5) To investigate preventive effect of RAS blockades by the ACEI-lisinopril (4 mg/kg body weight) and ARB-olmesartan (4 mg/kg body weight) on the rat model of progressive renal deficiency. / Results. (1) UNX rats developed time-dependent progressive renal functional impairment and marked glomerulosclerosis and tubulointerstitial lesions. (2) UNX rats showed fasting hyperglycemia, progressive glucose intolerance, hyperlipidemia and insulin resistance. (3) UNX rats demonstrated insulin secretory deficiency in parallel to pancreatic islet fibrosis, beta-cell deficit, and overexpression of RAS components, TGF-beta, and alpha-SMA. (4) UNX rats displayed adipopathy evidenced by shifts the subcutaneous and visceral fats to the ectopic fat with lipid accumulation, lipofuscin pigmentation and adipocytes transformation. The adipopathy associated with down-regulation of AT1R and over-expression of angiotensin, AT2R, PPAR-gamma and HMGCR in the remnant kidney. (5) Treatment with lisinopril and olmesartan significantly attenuated the development of chronic renal impairment, RAS dysregulation and aberrant proteins expression, islet damage, adipose redistribution, and glucose and lipid dysmetabolism. / Sui, Yi. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3422. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 195-220). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Energy homeostasis is an important physiological mechanism essential for balancingenergy flow through the living systems by managing overall metabolism in the body. Thus, energy homeostasis is under a tight control by means of extremely well-regulated energy metabolism. One of the most common metabolic disorders that occur following disruption in energy homeostasis mechanisms is obesity. Obese individuals develop insulin resistance in the peripheral tissues (fat and muscle) and may also include non-alcoholic fatty liver disease. Insulin resistance is the primary factor responsible for the development of type 2 diabetes mellitus (T2D). Towards control and management of T2D condition, insulin, drugs that regulate the insulin sensitivity and drugs that regulate glucose metabolism are widely used. Repeated insulin administration is painful, expensive and requires constant glucose monitoring while other drugs have various limitations and side effects. Therefore, there is wide scope development of new anti-diabetic molecules for effective management of T2D. Studies related to energy metabolism are necessary to understand the cause of such disorders and improve existing methods to manage metabolic abnormalities. Animal models to understand such metabolic disorders have been developed by chemical treatments and genetic modifications, but diet-induced obese (DIO) animal models appear to be the better among all the models reported. DIO animal models are known to most closely mimic the physiological situation. Apart from the experimental model system studies have been conducted under physiological conditions to gain knowledge on possible mechanisms behind energy balance maintained and established during extreme situations such as pregnancy and lactation. To support fetal growth and milk synthesis several metabolic adjustments occur during pregnancy and lactation without the major disruption in the maternal energy homeostasis. In the present study, to gain knowledge on the mother’s body glucose, lipid management and insulin responses throughout the gestation and lactation periods analyses were carried out during at different stages of pregnancy and lactation in rats. It was observed that during pregnancy, the dam developed insulin resistance in peripheral tissues with decreased activation of insulin pathway and reduced glucose utilization while the liver remained unaffected. Although, as soon as the lactation began, peripheral tissue such as muscle developed increased insulin sensitivity associated with increased expression of glucose transporter gene and higher glucose metabolism. The reversal of insulin response in the muscle tissue observed during lactation appears to be a suitable model system for understanding the process by which the body undergoes a transition from insulin resistant state to sensitive state under a physiological condition. Interestingly, early lactation period is known to have much lower levels of insulin available to act upon peripheral tissues. Factors involved in this transition could be potential therapeutic agents for control of T2D, since during early stages of T2D muscle appears to be the first metabolic organ to exhibit resistance to insulin. The undercarboxylated osteocalcin (UNOC) has been reported to function as anti-diabetic molecule. UNOC is released from skeletal system during bone turnover, especially due to resorption process. Experiments were carried out to examine the role of UNOC during the transition from insulin resistant state of pregnancy to sensitive state of lactation period. It was observed that UNOC levels were lower during pregnancy, but increased during early lactation (day 3 to 6 of lactation). The increased UNOC levels seen during early lactation was higher than the levels observed in non-pregnant, non-lactating (NPNL) rats and the UNOC levels decreased following removal of pups immediately after parturition. It was noted that altering UNOC levels during early lactation altered the insulin response of the whole body and muscle transporter-4 expression (glut4) of lactating rats. A significant increase in bone turnover was also observed during lactation compared to NPNL and pregnant rats. The data suggest that increased bone turnover leads to increased UNOC levels in blood during lactation. Estrogen is known as bone protector molecule which acts via its receptors, estrogen receptor α and β (ERα and β). It was reported that ERβ is a dominant regulator of estrogen signaling when both the receptors of estrogen i.e. ERα and ERβ coexist in the target tissue and estrogen levels are relatively higher. Compared to NPNL rats estrogen levels have shown to be higher during late pregnancy and lower during early lactation. It was observed that liver and adipose tissues largely express ERα, but the muscle showed expression of both the receptors in NPNL rats indicating that muscle is the metabolic tissue that may be modulated by both the receptors. It has been reported that ERβ suppresses ERα action on glut4 transcription in the myocytes. It is possible that the altered ERs ratio modulates glut4 expression during late pregnancy and early lactation. The receptor expression ratio data indicated that muscle is an ERβ dominant during late pregnancy, while it is ERα dominant during early lactation. Further, alteration in UNOC levels during early lactation changed ERs ratio but not sufficient enough to alter the ER dominance, indicating lack of effect of UNOC on ER dominance during early lactation. Experiments were conducted to alter insulin sensitivity during early lactation to extrapolate physiological findings to a pathological condition of the DIO model by feeding rats with high-fat diet (HFD). During early lactation, HFD dams had lower insulin response, lower circulatory UNOC level and lower UNOC receptor (GPRC6A) expression in the muscle. Gene expression of muscle glut4 was lower in HFD rats and the tissue remained ERα dominant indicating no role of HFD on ERs ratio in muscle during early lactation. UNOC has been found to have negative effect on lipid accumulation. During pregnancy, lipid accumulation is one of the first events essential for proper fetal development. Since UNOC levels were suppressed during pregnancy, experiments were carried out to examine relevance of UNOC suppression on lipid accumulation during early pregnancy. For this purpose, pharmacological approaches were utilized to alter UNOC levels during early pregnancy. It was observed that the transient elevation of UNOC levels caused decrease in maternal fat depots without changing circulatory triacylglyceride (TAG) levels. In experiments that decreased UNOC levels in NPNL state to mimic lower levels of UNOC present during early pregnancy, it was found fat storage was higher and TG was found to be lowered in the circulation. These results indicate that UNOC can cause a reduction in fat accumulation and TG levels but UNOC effects on TG levels, was not observed during pregnancy. The data taken together suggest that suppression of UNOC is required for better fat deposition in the mother’s body. Although, some studies have indicated an insulin response transition occurring during pregnancy to lactation, but the factors involved in this transition have not been reported. This report discusses about the factors such as UNOC and ERs and their involvement in the transition process. UNOC role has been studied in genetically modified models and in metabolic disorders such as obesity model system and evidence for physiological role of UNOC would further support its candidature as anti-diabetic molecule. The present research work is the first report to detail relevance of UNOC in physiological conditions such as pregnancy and lactation for glucose and lipid management.

Les nucléotides et nucléosides sont des molécules essentielles à la vie. Outre leurs fonctions intracellulaires, ils jouent un rôle dans la communication intercellulaire. Les nucléotides et nucléosides sont libérés dans l’espace extracellulaire par différents mécanismes et ensuite rapidement métabolisés par des ecto-nucléotidases. Ils exercent leurs effets paracrines et/ou autocrines en activant des récepteurs présents à la surface membranaire des cellules. Les récepteurs P1, au nombre de quatre (A1, A2A, A2B et A3), sont activés par l’adénosine. Les récepteurs P2X1-7 ont une activité intrinsèque de canal ionique et sont essentiellement activés par l’ATP. Les récepteurs P2Y possèdent sept domaines transmembranaires et sont couplés à des protéines G. A ce jour huit sous-types ont été identifiés : P2Y1,2,4,6,11,12,13,14. Ces récepteurs sont activés par des nucléotides adényliques (ATP et ADP) et/ou uridyliques (UTP, UDP et UDP-glucose). Les récepteurs P1 et P2 modulent l’activité de multiples processus biologiques : système immunitaire (A2A, P2X7, P2Y11,…), agrégation plaquettaire (P2Y1, P2Y12, P2X1), tonus vasculaire, angiogenèse,… Notre laboratoire a identifié et caractérisé plusieurs récepteurs P2Y : P2Y4, P2Y6, P2Y11 et P2Y13. Ce dernier est activé par l’ADP et est couplé à une protéine Gi. L’abondance du transcrit P2Y13 murin est caractérisée par l’ordre suivant : rate >> pancréas > foie = cerveau. Afin de déterminer son rôle physiologique, nous avons généré une lignée de souris invalidées pour le récepteur P2Y13. Après avoir validé l’inactivation du gène P2Y13 dans ces souris, nous avons analysé leur phénotype. Les souris P2Y13-/- ne présentent pas d’anomalie évidente : elles sont viables, fertiles et se développent normalement. Etant donné le profil d’expression de ce récepteur, nous avons analysé leur système immunitaire, en particulier les cellules dendritiques (DC). In vivo, l’invalidation du récepteur P2Y13 ne semble pas avoir d’impact sur les réponses inflammatoires (choc septique, infiltration de neutrophiles, test à la formaline) et auto-immunes (uvéorétinite expérimentale). In vitro, nous avons montré que l’ADPβS induit une mobilisation de calcium cytoplasmique dans les DC spléniques et qu’il stimule l’endocytose d’antigènes par celles-ci. L’utilisation de DC transgéniques a permis d’exclure l’implication du récepteur P2Y13 et a montré que ces effets sont médiés par le récepteur P2Y12 qui est également activé par l’ADPβS. Ces observations suggèrent qu’il serait intéressant d’analyser le système immunitaire des souris P2Y12-/-, en particulier les réponses immunes dépendantes des DC. D’autre part, ce travail a débouché sur la mise en évidence d’un effet anti-inflammatoire médié par le récepteur de l’adénosine A2B dans les DC dérivées de la moelle osseuse. Enfin, nous avons récemment mis en évidence un rôle potentiel du récepteur P2Y13 dans le métabolisme des glucides et des lipides. Nous avons observé que les souris P2Y13-/- produisent plus d’insuline en réponse à une injection de glucose que les souris contrôles tandis que leur glycémie ne semble pas altérée. De plus, les souris P2Y13-/- sous régime riche en graisses reproduisent 3 caractéristiques du syndrome métabolique chez l'homme : surpoids, dyslipidémie (augmentation des triglycérides et du non HDL-cholestérol) et hyperinsulinémie. Notre travail de thèse débouche donc sur deux conclusions et une perspective : • l’adénosine exerce une action anti-inflammatoire sur les cellules dendritiques dérivées de moelle osseuse via l’activation du récepteur A2B ; • le récepteur P2Y12 est exprimé fonctionnellement dans les cellules dendritiques murines et stimule l’endocytose ; • le récepteur P2Y13 pourrait jouer un rôle important dans le contrôle du métabolisme des lipides et des glucides ainsi que du poids corporel, suggérant que des agonistes spécifiques de ce récepteur pourraient permettre de contrecarrer l’obésité et ses conséquences métaboliques néfastes.

Mes travaux de thèse se sont portés sur les cellules pyramidales du néocortex de rongeur, en condition normale et pathologique. L'altération précoce du métabolisme du glucose est une caractéristique fonctionnelle invariante de la maladie d'Alzheimer (MA) qui pourrait être à l'origine des dysfonctionnements synaptiques et de la neurodégénerescence tardive associés à la maladie. Pour mieux comprendre la pathogenèse de la MA, j'ai cherché à clarifier les mécanismes responsables de l'hypométabolisme précoce du glucose observé dans la maladie. Mes travaux ont mis à jour des altérations des flux métaboliques du glucose chez un modèle murin de la MA à un stade asymptomatique juvénile. Les données d'imagerie cellulaire révèlent une augmentation du flux glycolytique associée à une diminution de l'activité de la voie des Pentoses Phosphates dans les cellules pyramidales néocorticales des souris 3xTg-AD sans altération du transport du glucose. Le système noradrénergique exerce une profonde influence sur les processus cognitifs. Une partie de ma thèse a été consacrée à éclaircir les effets de la NA sur la modulation de l'excitabilité des cellules pyramidales dans le cortex somatosensoriel de souris. Mes résultats montrent que les agonistes α1 et β noradrénergiques inhibent les courants responsables de l'hyperpolarisation lente qui suit les potentiels d'actions et suggèrent un effet coopératif des récepteurs α1 et β noradrénergiques. L'implication des récepteurs α1 dans la genèse d'une dépolarisation lente post PA reste à déterminer. Ces deux phénomènes convergeraient vers une dépolarisation accrue de la membrane du neurone, facilitant une nouvelle décharge de PA. / During my thesis, I focused on the neocortical pyramidal cells in normal and pathological condition. The early alteration of glucose metabolism is an invariant feature of Alzheimer's disease ( AD) which might lead to the late synaptic dysfunctions and neuronal loss related to the pathology. To better understand the AD pathogenesis, I sought to clarify the mechanisms responsible for the early glucose hypometabolism observed in the pathology. This work has highlighted alterations in glucose fluxes at a juvenile presymptomatic stage in a mouse model of AD. The cellular imaging data revealed an increase of the glycolytic pathway associated with a reduction in the PPP in pyramidal neurons of 3xTg-AD mice without any alteration of glucose transport. The noradrenergic system has a significant influence on cognitive processes. A part of my thesis has been devoted to highlight the effect of noradrenaline on pyramidal cells' excitability in the mouse somatosensory cortex. My results show that α1 and β noradrenergic agonists inhibit the currents responsible for sAHP and suggest a cooperative effect of α1 and β noradrenergic receptors. The RA-α1 involvement in the genesis of a slow After Depolarization has yet to be determined. Those two phenomena will lead to an increased depolarization of neuronal membrane, facilitating a novel action potential discharge.

O efeito de alterações no estado de óxido-redução (redox), tanto pelo aumento no estado oxidativo quanto pelo aumento no estado redutor, foi avaliado sobre a funcionalidade de ilhotas pancreáticas, através da análise da secreção de insulina estimulada pela glicose (GSIS), metabolismo da glicose e oscilações intracelulares de cálcio. O aumento no estado oxidativo inibiu a funcionalidade da célula pancreática. Entretanto, diminuição no estado oxidativo pela adição de antioxidantes exerceu efeito dual sobre a funcionalidade da célula <font face=\"Symbol\">&#946 pancreática, na qual pequenas alterações no estado redox estimularam a GSIS, enquanto alterações maiores suprimiram este efeito positivo. Adicionalmente, o conteúdo das espécies reativas de oxigênio (EROs) foi modulado por mudanças na concentração de glicose. Agudamente, o aumento na concentração de glicose suprimiu o conteúdo de EROs, que pôde ser correlacionada com o aumento na atividade da via de formação de NADPH, a via das pentoses-fosfato. Sob estes aspectos, alterações no estado redox podem ser parte do processo da GSIS. / The effect of changes in the oxidation/reduction (redox) state over pancreatic islet function was analyzed by shifts toward oxidative or reducing environments. Pancreatic cell function was analyzed by glucose-stimulated insulin secretion (GSIS), glucose metabolism and intracellular calcium oscillations. Redox modulation favoring the oxidative state inhibited pancreatic cell function. However, the suppression of the oxidative state by antioxidant treatment exerted a dual effect on pancreatic <font face=\"Symbol\">&#946 cell function, where small changes were positively correlated with an increase in insulin secretion, while higher changes suppressed GSIS. Additionally, the reactive oxygen species (ROS) content was modulated by changes in glucose concentration. Increasing concentrations of glucose acutely suppressed ROS content, what was correlated with the activation of the NADPH source, the pentose-phosphate pathway. Thus, the intracellular adjustment of ROS content may be part of the insulin secretion mechanism in response to glucose.

A forte associação entre obesidade e resistência à insulina denota a participação do tecido adiposo na patogênese das anormalidades metabólicas encontradas no Diabetes Mellitus (DM). Entretanto, a falta de tecido adiposo também pode desencadear sérias complicações metabólicas. O objetivo deste trabalho foi verificar o papel do tecido adiposo sobre as anormalidades metabólicas apresentadas pelo modelo experimental de DM induzido por estreptozotocina no período neonatal em ratos, caracterizado pela reduzida massa adiposa e presença de resistência à insulina na idade adulta. Cinco grupos de animais foram experimentados: controle não diabético (C); diabéticos tratados com: insulina (I); pioglitazona (P); ou metformina (M) e; grupo diabético não tratado (D). Verificamos que apenas os grupos I e P recuperaram o peso corporal e a massa adiposa, concomitante à uma melhora na responsividade à insulina. A normalização da massa adiposa observada nos grupos I e P está relacionada a aumento na expressão gênica de fatores de transcrição diretamente relacionados à adipogênese, assim como a um aumento na incorporação de glicose em lípides. Assim, a manutenção da massa adiposa exerce um papel-chave no controle metabólico apresentado por este modelo experimental. / A strong relationship between obesity and insulin resistance denotes the participation of adipose tissue in the pathogenesis of metabolic abnormalities seen in Diabetes Mellitus (DM). However, not only the excess, but the lack of adipose tissue can also trigger serious metabolic complications. The present study aimed to verify the role of adipose tissue on metabolic abnormalities seen in a DM experimental model induced by streptozotocin during neonatal period in rats, characterized by reduced adipose mass and presence of insulin resistance during adulthood. Five experimental groups were performed: non-diabetic control (C); treated diabetic with: insulin (I); pioglitazone (P); or metformin (M) and; non-treated diabetic (D). We verified that only I and P groups recovered body weight and adipose mass, concomitant to an improvement of insulin responsiveness The normalization of adipose mass in groups I and P is related to increased gene expression of transcription factors directly related to adipogenesis as well as increase in glucose incorporation into lipids. Therefore the maintenance of adipose mass exerts a key role in the metabolic control presented by this experimental model.