Insulin sensitivity has been positively correlated with a healthy and extended lifespan, while insulin resistance, decreased insulin sensitivity, has been linked to aging and is the main indicative of type 2 diabetes. Growth Hormone Receptor/ Binding Protein Knockout mice (GHRKO), although obese, are characterized by high insulin sensitivity and a prolonged lifespan. Due to the absence of growth hormone receptors (GHR), growth hormone (GH) is unable to activate its downstream pathway. Interestingly, the secretory activity of visceral fat in GHRKO mice is altered stimulating insulin sensitivity. In this study, we transplanted normal (N) mice with GHRKO visceral fat pads to determine the role of visceral fat developed with the absence of GH signaling on the insulin-signaling pathway in animals with physiologically normal GH action. We found that the visceral fat transplant (VFT) helped the normal mice gain the beneficial effects of fat developed in the absence of GH and caused improvement of their whole body insulin sensitivity when comparing with sham-operated mice and with mice that received visceral fat from N animals. In presented study, RT-PCR was used to determine the levels of hepatic mRNA expression between three experimental groups including Normal-sham mice (N-S), normal mice transplanted with visceral fat from normal animals (N-N), and normal mice receiving visceral fat from GHRKO mice (N-KO). Additionally, Western Blot and ELISA were used to determine the level of total and phosphorylated proteins. By studying the effect of visceral fat transplant from GHRKO or N mice on the whole body insulin signaling in N male mice, and testing different genes expression and proteins quantification, we can shed light on the mechanism by which white adipose tissue (WAT) regulates whole body insulin sensitivity and longevity as well as understanding the role of WATs in development of diabetes and the process behind insulin resistance.

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Type II Diabetes Mellitus (T2D) and cardiovascular diseases (CVD) are non-communicable chronic diseases that involves impairments in glucose metabolism and vascular function. Multiple factors may increase the risk for T2D, including but not limited to genetics, obesity and lifestyle, such as physical inactivity and diet. The gut microbiota, the human's largest population of microorganisms, plays an essential role in health and disease. The physiology and function of the gastrointestinal tract can be influenced by the diet. Phosphatidylcholine (PC), a source of choline in the diet, is rich in Western-type diets. Gut microbiota metabolize choline to trimethylamine (TMA) which circulates and is oxidized in the liver to form trimethylamine N-oxide (TMAO). As a result, ingestion of PC or choline could increase levels of TMAO. Preclinical studies indicate a role of TMAO in the development of atherosclerosis. Likewise, multiple observations support a potential role of TMAO in the development of insulin resistance and T2D. Much of the research has been conducted on rodent models, while others are observational human studies. Whether acute and short-term increases in TMAO contribute to impairments in insulin sensitivity in humans remains unknown. To address this, we performed two studies utilizing a double-blind, placebo controlled, crossover design. Eligible participants consumed a 1000mg/day dose of choline bitartrate and placebo (maltodextrin) the night before each testing session (for the acute choline study) or for 4 weeks (for the short-term choline ingestion study). Oral glucose tolerance test, continuous glucose monitoring, flow-mediated dilation, and applanation tonometry was performed the day after the acute choline load and before and after the short-term choline ingestion period. We hypothesized that gut microbiota-generated increase in TMAO will impair insulin sensitivity, glucose tolerance, endothelial function and arterial stiffness in healthy sedentary humans. Following acute choline ingestion, significant increases in plasma TMAO (p = 0.013) and choline (p = 0.003) were evident. There was no statistically significant difference in insulin sensitivity, glucose tolerance or in any of the endothelial function and arterial stiffness measurements. Four weeks of 1000mg choline ingestion per day, significantly increased plasma (p = 0.042) and urine (p = 0.008) TMAO concentrations compared to the placebo. However, no significant differences were observed for any other measurements of insulin sensitivity, glucose tolerance, glycemic variability, endothelial function, and arterial stiffness. More research is needed to elucidate the mechanisms behind the mechanistic observations between elevated TMAO concentrations and T2D and CVD. / Doctor of Philosophy / Type 2 diabetes mellitus (T2D) and cardiovascular diseases (CVD) increase the risk of all-cause mortality. Choline is a nutrient that can be found in foods such as red meat, dairy, fish, and eggs. Choline is metabolized from bacteria in our gut and a metabolite called trimethylamine (TMA) is formed. TMA is then oxidized in the liver and trimethylamine-N-oxide (TMAO) is produced. A Western-type diet is rich in red meat, dairy, fish, and eggs and has been shown to increase production of the compound TMAO. Preclinical studies have suggested a causal role of TMAO in atherosclerosis and T2D and elevated plasma TMAO concentrations have been associated with an increased risk for CVD and T2D in observational studies. However, the causal nature of this relationship in humans is unknown. The studies described herein aimed to investigate the effects of increases in TMAO on insulin sensitivity and vascular function in healthy adults. The first study tested the effect of increasing TMAO on insulin sensitivity, glucose tolerance, and vascular function following an acute choline load (1000mg) and placebo (carbohydrate) the night before each testing session. In the second study, we examined the effect of increasing TMAO on insulin sensitivity, glucose tolerance, and vascular function in healthy adults, following a short-term choline load (1000mg/day) and placebo (carbohydrate) for 4 weeks. Acute and short-term choline ingestion significantly increased plasma TMAO concentrations. No significant differences were observed following acute or short-term choline ingestion for any measurement of insulin sensitivity, glucose tolerance 24-hout glycemic variability, vascular function., and arterial stiffness.

Glucose is a fundamental energy source, the utilization and regulation of which impacts exercise performance and health. These studies have used modeling techniques to evaluate glucose kinetics and dynamics in equids and developed tests to evaluate the status of glucose metabolism. In Part I, 12 exercise-trained Arabians underwent insulin-modified FSIGT (with minimal model analysis) and single-injection glucose tracer (with compartmental analysis) studies at rest and during exercise to evaluate the effects of exercise on glucose kinetics and dynamics. These geldings were maintained on pasture, but adapted for 4 months to twice-daily feeding of feeds rich in sugar and starch (SS, n=6: NSC 45%, Fat 3%, NDF 24%) or fat and fiber (FF, n=6:NSC 13%, Fat 11%, NDF 45% ). Exercise increased insulin sensitivity (P = 0.070) and glucose transport (P < 0.038). Although variables were not different between FF and SS horses at rest, during exercise SS horses tended to have lower (P = 0.085) insulin sensitivity and increased (P = 0.043) glucose utilization compared to FF horses. In Part II, satisfactory proxies for minimal model parameters were developed to facilitate the evaluation of insulin sensitivity in larger populations. These proxies were applied to a population of 163 ponies and used to characterize metabolic differences between ponies predisposed to pasture laminitis (PL) from ponies not predisposed (NL). A subset of 14 ponies (7 PL, 7 NL) also underwent the FSIGT for minimal model analysis. Ponies predisposed to laminitis were found to have lower insulin sensitivity (P < 0.007) and higher insulin secretory response (P < 0.045) by both the minimal model and proxies, and higher (P < 0.001) circulating triglycerides and body condition score. Cut-point analysis for these variables was used to define a pre-laminitic metabolic syndrome with total predictive power of 78% to identifity ponies at risk for developing pasture laminitis. Increased insulin resistance and prevalence of lamintis were associated with increased non-structural carbohydrates in spring pasture. These studies demonstrate the importance of glucose regulation for exercise and animal health. When glucose regulation is altered in the case of insulin resistance, performance could be impacted and diseases such as laminitis may occur. Insulin resistance may be moderated by exercise or by avoiding sugar and starch in feeds and pasture. / Ph. D.

Diets rich in hydrolyzable carbohydrates induce a hyperglycemic/insulinemic response and may increase the incidence of metabolic disorders associated with some types of laminitis, exertional rhabdomyolysis and osteochondrosis in horses. This study applied the minimal model of glucose and insulin dynamics to determine the effect of diet on metabolites and hormones that regulate glucose metabolism in young horses. Twelve Thoroughbred foals were raised on pasture and supplemented twice daily with a feed high in either sugar and starch (SS) or fat and fiber (FF). As weanlings (age 199 ± 19 d, weight 274 ± 18 kg), the subjects underwent a modified frequent sampling intravenous glucose tolerance test during which they remained in stalls and had access to grass hay and water ad libitum. Samples were colleted at -60, -45, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 35, 40, 50, 60 , 70 , 80, 90, 100, 120, 150, 180, 210, 240, 270, 300, 330 and 360 min with a glucose bolus of 300 mg/kg BW at 0 min and an insulin bolus of 1.5 mU/kg BW at 20 min. Plasma was analyzed for glucose, insulin, growth hormone (GH) and insulin-like growth factor-I (IGF-I) concentrations. Insulin sensitivity, glucose effectiveness, acute insulin response to glucose and disposition index were derived using Minmod Millennium and WinSAAM software. Diet groups were compared using the non-parametric Kruskal-Wallis test or the sign test. Time interactions were compared using a mixed model with repeated effects. Rank-ordered linear regression was used for correlations. Basal glucose did not differ between groups (P = 0.75). There was nearly a trend towards higher basal (P = 0.11), and median insulin was higher in the sugar and starch foals at all 36 sample points (P = 0.030). The basal glucose:basal insulin ratio for the sugar and starch supplemented foals was lower than for fat and fiber foals (P = 0.025). Insulin sensitivity (SI) was lower in foals fed sugar and starch than foals fed fat and fiber (P = 0.007). Acute insulin response to glucose was directly correlated to weight (r = 0.78; P = 0.003) and inversely correlated with SI (r = -0.55; P = 0.067). The glucose:insulin ratio was directly correlated to SI (r = 0.92; P < 0.001). Growth hormone concentrations were increased from basal from 19 to 180 min after the glucose dose (P < 0.05). Basal IGF-I was higher (P = 0.006) in the SS group compared to the FF group. Concentrations of total IGF-I increased with time (P = 0.002) in the SS group. The change in IGF-I concentration from baseline to the end of the study was positively correlated (r = 0.72; P = 0.008) to the area under the insulin curve from 0 to 80 min. Basal IGF-I was inversely correlated to SI (r = 0.71; P = 0.015). These results show that the metabolic response to a diet high in hydrolyzable carbohydrates differs from the response to a fat and fiber meal resembling forage. Weanlings adapted to meals high in glucose equivalents have higher insulin and IGF-I secretion as compared to foals adapted to a fat and fiber feed, possibly contributing to lower insulin sensitivity observed in these foals. Such deviations may contribute to metabolic dysfunction and osteochondrosis in horses fed grain diets. / Master of Science

Insulin sensitivity decreases during pregnancy, presumably an adaptation ensuring sufficient glucose supply to feto-placental tissues. Feeds high in non-structural carbohydrates are also linked to diminished insulin sensitivity in horses. Because the equine fetus is highly glucose reliant, maternal glucose and insulin dynamics during pregnancy may have implications for optimal fetal development in horses. Mismanagement of maternal nutrition during gestation could predispose the offspring to metabolic disorders (e.g. insulin resistance) later in life. In horses, insulin resistance is associated with increased risk for development of laminitis. These studies measured insulin sensitivity and glucose dynamics in pregnant and non-pregnant mares fed high sugar and starch (SS) or high fat and fiber (FF) feeds, as well as neonatal foals born from pregnant mares fed SS and FF feed. Insulin modified frequently sampled intravenous glucose tolerance tests (FSIGT) were applied to pregnant Thoroughbred mares (n = 22) at 28 ± 3 wks (Period 1) and 47 wks (Period 2) gestation, as well as non-pregnant mares (n=10) measured simultaneously. Following the first FSIGT mares were fed SS or FF feed for the remainder of the study. After 11 wks adaptation to feeding, a subset of mares were evaluated with hourly blood samples for 24 h to assess glycemic and insulinemic response to three times daily feeding while on pasture. Neonatal foal FSIGTs (n=20) were conducted at 5 ± 1 d of age. The minimal model of glucose and insulin dynamics was used to determine insulin sensitivity (SI), glucose effectiveness (Sg), acute insulin response to glucose (AIRg) and disposition index (DI). Pregnant mares during Period 1 exhibited lowered SI, Sg and elevated AIRg relative to non-pregnant mares. Pregnant mares demonstrated greater glycemic and insulinemic responses to feeding of both SS and FF meals than non-pregnant mares consuming the same feeds. Also, SS feed elicited greater glycemic and insulinemic areas under the curve following feeding than FF feed in pregnant mares. These data support that pregnancy in mares in associated with lowered SI by 28 wks gestation and that altered SI, Sg and AIRg are associated with different responses to consuming SS and FF feeds. Foals exhibited high basal glucose, basal insulin, SI and Sg relative to mature horses, indicating a large capacity for glucose uptake with or without insulin. Basal glucose concentrations were higher and basal insulin concentrations tended to be higher in SS than FF foals (P = 0.016 and P = 0.071, respectively). Glucose and insulin dynamics in late gestation mares and neonatal foals exemplify the adaptive nature of energy metabolism in horses. Furthermore, dietary energy composition affects glucose and insulin responses to feeding in late gestation mares, which in turn was associated with different basal blood concentrations of these variables in the resulting neonatal foals. / Master of Science

Obesity and associated metabolic disorders, called as "metabolic syndrome", currently represent a major social and economical problem of public health. From the energy balance point of view, long-lasting energy surplus leads eventually to massive accumulation of energy stores resulting in various adverse effects on metabolism and health. General goal of the thesis was to examine these metabolic disorders at cellular and whole-body level using suitable mouse models. The main focus was on the most metabolically active tissue, namely skeletal muscle, liver and adipose tissue and on the regulatory roles of AMP-activated protein kinase (AMPK) and leptin in the energy metabolism. The whole thesis is based on four published studies. Two studies were focused on skeletal muscle. In the first study, we proved the involvement of leptin and AMPK in the metabolic response to high-fat diet-feeding. We described a mechanism of muscle non- shivering thermogenesis based on enhanced lipid catabolism, which contributes to the genetically-determined resistance of inbred A/J mice to obesity. Such mechanism was not operating in obesity-prone C57BL/6 mice. In the second study, performed using C57BL/6 mice, we have described beneficial effect of combination treatment using n-3 polyunsaturated fatty acids (n-3 PUFA) of...

Introdução: Os glicocorticoides (GCs) estão envolvidos na regulação e adaptação da resposta ao estresse, exercendo seus efeitos através de seus receptores. Variações polimórficas no gene do receptor de glicocorticoide (GR) têm sido caracterizadas funcionalmente. O polimorfismo A3669G do gene do GR está relacionado a modificações na sensibilidade aos GCs e mudanças no perfil metabólico. Concentrações fisiológicas de GCs estimulam a ingestão calórica e, na presença de insulina, modificam a preferência alimentar. A variante A3669G do gene do GR parece levar a um menor risco para diabetes, em pacientes com Síndrome de Cushing, e para o tabagismo, quando associado a um polimorfismo do gene do receptor de mineralocorticoide, sugerindo uma modulação na via de recompensa. O objetivo deste trabalho é avaliar a associação de variantes do polimorfismo A3669G do gene do GR com o comportamento alimentar e parâmetros metabólicos em uma amostra de estudantes, correlacionando com dados de neuroimagem funcional. Métodos: A amostra provém de alunos de 6 escolas de Porto Alegre, avaliados em 2008 e em 2013. Em 2008, 131 indivíduos apresentavam o protocolo completo de avaliação e, destes, 74 retornaram em 2013. A avaliação incluiu genotipagem, antropometria, exames laboratoriais, comportamento alimentar e um paradigma avaliando a ativação cerebral em resposta a visualização de imagens de alimentos palatáveis, não palatáveis e de objetos neutros. A análise da associação com os fenótipos foi realizada através do teste t de Student e Chi quadrado; os dados do estudo longitudinal foram analisados por meio de Equações de Estimatição Generalizada. Resultados: A variante G do polimorfismo A3669G do gene do GR foi encontrado em 17,6% em 2008 e em 14,9% da amostra em 2013. Não houve diferença entre os grupos de carreadores do alelo G e não carreadores quanto a diferentes confundidores; a comparação entre as médias dos dois grupos sobre o consumo calórico proveniente de proteínas, carboidratos e gorduras em 2008 não revelou diferenças significativas; nesta etapa, as análises evidenciaram maior consumo de açúcares e de calorias totais no grupo não carreador do alelo G. Em 2013, estes indivíduos não carreadores do alelo G do polimorfismo A3669G apresentaram maior insulinemia e além de aumento no índice de resistência à insulina, sem diferenças no consumo alimentar. Os dados de neuroimagem funcional indicaram que a visualização de imagens de alimentos palatáveis pelo grupo não carreador do alelo G ativou o giro occipital médio, uma região implicada no processamento visual, mostrando menor ativação em giro pré central e nas áreas de Brodmann 4 e 6, relacionadas ao planejamento motor e sensibilidade ao sabor. Conclusão: Os resultados mostram que os indivíduos não carreadores da variante G do polimorfismo A3669G do gene do GR apresentaram menor sensibilidade à insulina, precedidos pela modulação na preferência alimentar. Os achados em neuroimagem funcional indicam maior saliência de incentivo aos alimentos palatáveis e predisposição à impulsividade no grupo não carreador do alelo G. Sugere-se que a redução na sensibilidade em nível celular aos GCs relacionada à presença do alelo G, afete a ingestão alimentar, reduzindo o consumo de alimentos palatáveis, diminuindo o risco para doenças metabólicas. / Introduction: Glucocorticoids are involved in regulation and adaptation of the stress response, exerting effects through its receptors. Variations on the glucocorticoid receptors genes have been characterized functionally. The A3669G polymorphism of the glucocorticoid receptor gene is related to a change in the tissue sensitivity to glucocorticoids and altered metabolic profile. Physiological concentrations of glucocorticoids stimulate food intake and in the presence of insulin affect food preferences. The G variant of the A3669G polymorphism appears to lead to a lower risk for diabetes, in patients with Cushing's syndrome, and smoking, when associated with a polymorphism of the mineralocorticoid receptor gene, suggesting a modulation in reward pathways. The objective of this study is to evaluate the association of A3669G polymorphism variants with feeding behavior and metabolic parameters in a sample of students correlating with functional neuroimaging data. Methods: The sample includes students of 6 schools in Porto Alegre, evaluated at two occasions 2008 and in 2013. In 2008, 131 individuals had complete protocol assessment and, from these, 74 returned in for re- evaluation in 2013. The evaluation included genotyping, anthropometry, laboratory tests, feeding behavior and a functional MRI paradigm to verify brain activation in response to the visualization of palatable, non- palatable foods and neutral items. The association with phenotypes was performed using Student's t test and Chi-square; longitudinal study data were evaluated using Generalized Estimating Equations. Results: The variant of the A3669G polymorphism was found in 17.6% of the students in 2008 and 14.9% of the sample in 2013. There was no difference between groups in the sample composition; the comparison between groups of the mean caloric intake originating from proteins, carbohydrates and fats in 2008 revealed no significant differences; at this time, analysis showed lower consumption of sugars and total calories in the G carrier group. In 2013, these individuals showed a reduction in insulin level and resistance, with no differences in food intake. The fMRI data indicated that viewing a food palatable image by the wild-type allele carrier group activated a region involved in visual processing (middle occipital gyrus) and deactivated an area related to motor planning and sensitivity to taste (pre central gyrus). Conclusion: The results showed that G carriers of the A3669G polymorphism of glucocorticoid receptor gene had lower insulin resistance levels, preceded by modulation of their food preference. The findings in functional neuroimaging showed increased incentive salience on viewing palatable food images and a predisposition for impulsivity in noncarriers. Data suggest that reduction in glucocorticoids sensitivity at a cellular level affects food intake, by reducing consumption of palatable foods, possibly decreasing the risk for metabolic diseases.

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-06-14T17:35:19Z No. of bitstreams: 1 DanyloMelo.pdf: 745489 bytes, checksum: c5ad51adb0decdb7d8050bcf5074660b (MD5) / Made available in DSpace on 2017-06-14T17:35:19Z (GMT). No. of bitstreams: 1 DanyloMelo.pdf: 745489 bytes, checksum: c5ad51adb0decdb7d8050bcf5074660b (MD5) Previous issue date: 2016-09-29 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ) / Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA) / Synthetic glucocorticoids (GCs) induce several adverse effects when administered in high doses and/or prolonged, as peripheral insulin resistance, glucose intolerance, and alterations in lipid metabolism, especially hypertriglyceridemia. There are few studies on the metabolic impact caused by long-term treatments with different synthetic GCs, especially with prednisone, GC of intermediate action and first choice in its pharmacologic class. Therefore, we seek to verify the metabolic alterations caused by sub chronic treatment with prednisone in rats and compare them with existing and in acute model of insulin resistance induced by dexamethasone effects. For this, Wistar rats with of 90 days were treated with dexamethasone (D5) (1 mg/kg, i.p.) for 5 consecutive days and, its controls (C5) with saline, and Wistar rats of 60 days old were treated with prednisone (80 mg/kg, orally) for 15 days (P15) and 30 days (P30) consecutive and their respective controls (C15 and C30), received vehicle solution. The D5 results a decreased body weight (12.3%) and lower weight of retroperitoneal fat (38%), increased serum fasting glucose (12%) and fed (30%), insulin (80%) and triglycerides (339%) (p <0.05). Total fat and triglycerides liver were 29% and 52% higher in rats D5, compared to the C5 rats (p <0.05). The P15 rats had increased weight 61% less, reduction of retroperitoneal fat (29%) and increased plasma triglyceride concentrations (60%) compared to the C15 rats (p <0.05). As long as P30 rats had increased weight 44% less, reduction of retroperitoneal fat (25%) and increased serum triglycerides (78%) and liver total fat (26%) compared to the C30 rats (p <0,05). In vivo tests revealed the presence of impaired glucose tolerance (oGTT) in rats D5 and P30, and reduced insulin sensitivity (ipITT, HOMA, TYG) in D5 animals (p <0.05). Ex vivo test showed greater sensitivity in the pancreatic islets front glucose only in D5 rats. In conclusion, the sub chronic administration of prednisone promoted finer metabolic changes in glucose homeostasis, compared to acute administration of dexamethasone, suggesting the preferential use of prednisone when it is intended to minimize the adverse metabolic effects associated with the use of GCs. / Os glicocorticoides (GCs) sintéticos podem induzir diversos efeitos adversos, quando administrados em doses elevadas e/ou por tempo prolongado, como resistência insulínica periférica, intolerância à glicose, e alterações no metabolismo lipídico, especialmente hipertrigliceridemia. Porém existem poucos estudos sobre o impacto metabólico promovido por tratamentos prolongados com diferentes GCs sintéticos, especialmente com a prednisona, GC de ação intermediária e de primeira escolha em sua classe farmacológica. Diante disso, buscou-se verificar as alterações metabólicas ocasionadas pelo tratamento subcrônico com prednisona em ratos e compará-las aos efeitos presentes e conhecidos em modelo agudo de indução de resistência insulínica pela dexametasona. Para tal, ratos Wistar com noventa dias de vida foram tratados com dexametasona (D5) (1 mg/Kg, i.p.) durante 5 dias consecutivos e, os seus controles (C5) com salina, e ratos Wistar com 60 dias de vida foram tratados com prednisona (80 mg/Kg, v.o.) durante 15 dias (P15) e 30 dias (P30) consecutivos e, os seus respectivos controles (C15 e C30), receberam veículo. Os ratos D5 apresentaram redução do peso corpóreo (12,3%) e menor peso da gordura retroperitoneal (38%), aumento das concentrações séricas de glicose em jejum (12%) e alimentado (30%), insulina (80%) e triglicerídeos (339%) (p<0,05). O conteúdo de gordura total hepático, bem como triglicerídeos foram 29% e 52% maiores nos ratos D5, em relação aos ratos C5 (p<0,05). Os ratos P15 apresentaram um ganho de peso 61% menor, redução da gordura retroperitoneal (29%) e aumento nas concentrações plasmáticas de triglicerídeos (60%), em relação aos ratos C15 (p<0,05). Enquanto os ratos P30 apresentaram um ganho de peso 44% menor, redução da gordura retroperitoneal (25%) e aumento nas concentrações séricas de triglicerídeos (78%) e gordura total hepática (26%), em relação aos ratos C30 (p<0,05). Os testes in vivo revelaram a presença de intolerância à glicose (GTT) nos ratos D5 e P30 e redução da sensibilidade à insulina (ITT, HOMA, TyG) nos animais D5 (p<0,05). O teste ex vivo revelou maior sensibilidade nas ilhotas pancreáticas frente à glicose somente nos ratos D5. Em conclusão, a administração subcrônica de prednisona promoveu alterações metabólicas mais sutis na homeostasia da glicose, quando comparada à administração aguda de dexametasona, sugerindo assim, o uso preferencial da prednisona quando se pretende minimização dos efeitos adversos metabólicos associados ao uso de GCs.