To test the hypothesis that maternal glucose restriction (GR) would compromise small intestine (SI) growth and development, we used a diet induced model of IUGR. Pregnant rats and offspring were fed isoenergetic diets {0% (deficient), 12, 24% (restricted), 60% (adequate) glucose) from gestation day (gd) 0 through adolescence. SI tissue was collected at gd20, birth, 12--24h, postnatal day (pd) 7, 15, 21, 28, 35, 49 and in controls. GR affected pup weight at early timepoints, resulting in IUGR; beyond effects due to differences in body wt, GR compromised SI length at 12--24h and promoted SI growth during peak lactation (pd15; total and distal wts). Dietary glucose regulated in utero (gd20) expression of sodium-dependent glucose co-transporter (SGLT1) protein. Diet-induced precocious maturation of lactase and sucrase was observed in glucose deficient animals. In summary, there were periodic but no permanent effects of dietary glucose intake on gut growth and development.

To test the hypothesis that maternal dietary glucose restriction throughout pregnancy and lactation would perturb glucose transporter (GLUT) protein levels in offspring, isoenergetic diets containing graded levels of glucose (0, 12, 24 and 60%) were fed to pregnant rats and their offspring from gestation day (gd) 0 through postnatal day (pd) 49. Diets were defined as deficient (0%), restricted (12, 24%) or adequate (60%) in glucose. Plasma, small intestine, liver and kidney tissues were collected perinatally (gd20, birth, 12--24hrs postnatal), during lactation (pd7, 15, 21), post-weaning (pd28, 35, 49) and in adult controls. The proximal and distal regions of the small intestine responded differently to the dietary glucose restriction. Proximal small intestine GLUT2 protein levels did not change throughout postnatal development and remained unaltered with dietary glucose restriction, while distal small intestine GLUT2 protein expression changed throughout postnatal development and with dietary glucose restriction. These findings, together with information from the literature, indicate a dissociation between small intestine GLUT2 mRNA expression, GLUT2 protein levels and small intestine glycogen reserves.

Substantial evidence supports a role of diet in glucose metabolism, but only a few reports have investigated the impact of diet during pregnancy on risk of gestational diabetes (GDM). Although metabolic hormones have been detected in milk, no studies have investigated the impact of maternal metabolic status assessed during pregnancy on insulin and adiponectin concentrations in human milk. The purpose of this thesis was to investigate the association of maternal macronutrient intakes with metabolic status during pregnancy and its subsequent impact on human milk hormones. Participating women (n=216) underwent a 3-hour oral glucose tolerance test at 30 (95% confidence interval [CI] 25, 33) weeks gestation, recalled their second trimester dietary intake, and donated early (the first week) and mature (3 months postpartum) milk. Higher vegetable and fruit fiber intake was associated with reduced insulin resistance (beta±SE -0.100±0.029, p=0.0008) and increased insulin sensitivity (0.029±0.012, p=0.01) among those with a family history of type 2 diabetes. Lower % carbohydrate and higher % total fat were associated with increased GDM risk (odds ratio 0.60 [95% CI 0.40, 0.90] and 1.61 [1.06, 2.44], respectively). Prenatal metabolic abnormalities including higher pregravid body mass index (beta±SE 0.053±0.014, p=0.0003), in addition to gravid hyperglycemia (0.218±0.087, p=0.01), insulin resistance (0.255±0.047, p<0.0001), lower insulin sensitivity (-0.521±0.108, p<0.0001), and higher serum adiponectin (0.116±0.029, p<0.0001) were associated with higher insulin in mature milk. Obstetrical measures including nulliparity (0.171±0.058, p=0.004), longer duration of gestation (0.546±0.146, p=0.0002), and unscheduled caesarean section (0.387±0.162, p=0.02) were associated with higher adiponectin in early milk. Holder pasteurization, a process recommended by the Human Milk Bank Association of North America before distributing human donor milk, reduced milk adiponectin and insulin concentrations by 32.8% and 46.1%, respectively (both p<0.0001). In conclusion, the distribution of macronutrient intakes during pregnancy was associated with risk for abnormal glucose metabolism later in pregnancy. In addition, maternal prenatal metabolic abnormalities were associated with high insulin concentrations in mature milk, while only obstetrical parameters were associated adiponectin concentrations in early milk. Our findings support the need for continued work to determine optimal prenatal nutritional strategies to prevent GDM and subsequently to improve infant nutrition.

Substantial evidence supports a role of diet in glucose metabolism, but only a few reports have investigated the impact of diet during pregnancy on risk of gestational diabetes (GDM). Although metabolic hormones have been detected in milk, no studies have investigated the impact of maternal metabolic status assessed during pregnancy on insulin and adiponectin concentrations in human milk. The purpose of this thesis was to investigate the association of maternal macronutrient intakes with metabolic status during pregnancy and its subsequent impact on human milk hormones. Participating women (n=216) underwent a 3-hour oral glucose tolerance test at 30 (95% confidence interval [CI] 25, 33) weeks gestation, recalled their second trimester dietary intake, and donated early (the first week) and mature (3 months postpartum) milk. Higher vegetable and fruit fiber intake was associated with reduced insulin resistance (beta±SE -0.100±0.029, p=0.0008) and increased insulin sensitivity (0.029±0.012, p=0.01) among those with a family history of type 2 diabetes. Lower % carbohydrate and higher % total fat were associated with increased GDM risk (odds ratio 0.60 [95% CI 0.40, 0.90] and 1.61 [1.06, 2.44], respectively). Prenatal metabolic abnormalities including higher pregravid body mass index (beta±SE 0.053±0.014, p=0.0003), in addition to gravid hyperglycemia (0.218±0.087, p=0.01), insulin resistance (0.255±0.047, p<0.0001), lower insulin sensitivity (-0.521±0.108, p<0.0001), and higher serum adiponectin (0.116±0.029, p<0.0001) were associated with higher insulin in mature milk. Obstetrical measures including nulliparity (0.171±0.058, p=0.004), longer duration of gestation (0.546±0.146, p=0.0002), and unscheduled caesarean section (0.387±0.162, p=0.02) were associated with higher adiponectin in early milk. Holder pasteurization, a process recommended by the Human Milk Bank Association of North America before distributing human donor milk, reduced milk adiponectin and insulin concentrations by 32.8% and 46.1%, respectively (both p<0.0001). In conclusion, the distribution of macronutrient intakes during pregnancy was associated with risk for abnormal glucose metabolism later in pregnancy. In addition, maternal prenatal metabolic abnormalities were associated with high insulin concentrations in mature milk, while only obstetrical parameters were associated adiponectin concentrations in early milk. Our findings support the need for continued work to determine optimal prenatal nutritional strategies to prevent GDM and subsequently to improve infant nutrition.

The potential effects of nutritional support with amino acids or dextrose and epidural blockade on the catabolic response to surgery were investigated in diabetic patients undergoing colorectal surgery. Protein and glucose metabolism were assessed with a stable isotope infusion technique using the two stable isotopes L-[1-13C]leucine and [6,6-2H2 ]glucose. / 1. The first intervention of a postoperative infusion of amino acids avoided pronounced hyperglycaemia in diabetic patients after colorectal surgery and achieved a positive protein balance compared to dextrose. / 2. The second intervention of a short term infusion of amino acids postoperatively blunted protein breakdown and stimulated protein synthesis. This resulted in a positive protein balance in patients with epidural blockade compared to patient controlled analgesia with intravenous morphine. With regard to glucose metabolism, amino acid supply after surgery decreased glucose clearance and endogenous glucose production independent from type of analgesia.

Typ 2 Diabetes gehört zu den häufigsten Stoffwechselkrankheiten in Deutschland. Zur Basistherapie des Typ 2 Diabetes gehören eine gesunde Ernährungsweise und die Erhöhung der körperlichen Aktivität. Körperliches Training führt insbesondere bei Patienten mit Typ 2 Diabetes neben der Verbesserung der körperlichen Leistungsfähigkeit zu einer Reihe metabolischer Veränderungen, wie zur Reduktion der Fettmasse, zur Verbesserung von chronischer Hyperglykämie, des Lipidstoffwechsels und des atherogenen, pro-inflammatorischen Adipokin-Serumprofils. Chemerin ist ein erst kürzlich identifiziertes 16 kDa großes Adipokin, dessen Serumkonzentrationen bei Adipositas und Typ 2 Diabetes erhöht sind. Ziel dieser Arbeit war es deshalb, die Auswirkungen eines 12monatigen, kontrollierten, praxisnahen, kombinierten Kraft-Ausdauer-Trainingsprogramms auf die Chemerin-Serumkonzentration, das Körpergewicht, sowie Parameter des Glukosestoffwechsels (Nüchtern-Plasmaglukose, HbA1c, Nüchterninsulin, HOMA) bei Patienten mit Typ 2 Diabetes zu untersuchen. Zusätzlich wurde die Chemerin mRNA-Expression im humanen omentalen und subkutanen Fettgewebsproben von 79 Patienten charakterisiert und bei 15 Patienten der Einfluß eines Gewichtsverlustes von 45,3 ± 7,4kg ein Jahr nach bariatrischer Chirurgie auf zirkulierende Chemerin-Werte untersucht. Für die prospektive offene Interventionsstudie wurden initial 710 Patienten mit Typ 2 Diabetes untersucht, von denen 156 die Ein- und Ausschlusskriterien für die Studie erfüllten. Es wurden die Daten von 120 Patienten (77 Frauen, 43 Männer) analysiert, von denen nach Abschluss des 12monatigen Trainingsprogramms vollständige Datensätze vorlagen. Die Patienten trainierten zweimal pro Woche für jeweils 60 ± 15 Minuten bei 50-70% ihrer individuellen maximalen Leistungsfähigkeit, die zu Beginn der Studie mittels Spiroergometrie ermittelt wurde. Die Messung der Zielparameter erfolgte vor Beginn der Intervention, sowie nach 3, 6 und 12 Monaten körperlichen Trainings. Das 12monatige Trainingsprogramm führte zu einer signifikanten Reduktion der Chemerin-Serumkonzentration und zu signifikanten Verbesserungen der Nüchterninsulin-Serumkonzentrationen und des HOMA-Index´, während sich die Nüchtern-Plasmaglukose und der HbA1c-Wert kaum veränderten. Die signifikanten Veränderungen waren unabhängig von der Entwicklung des Körpergewichts, das sich im Verlauf der Studie nicht signifikant veränderte. Die Chemerinserumkonzentration war geschlechtsabhängig und bei Patienten mit T2D höher als bei gesunden Kontrollpatienten. Sie korrelierte mit dem BMI, dem Körperfettgehalt, dem HbA1c, Serum Triglyzerid- sowie hsCrP-Spiegeln und wird durch starken Gewichtsverlust nach einer bariatrischen Operation signifikant gesenkt. Außerdem konnte ein signifikanter Zusammenhang der omentalen Chemerin mRNA-Expression mit dem BMI, der Hyperinsulinämie, der Adipozytengröße, der Serum-Chemerin- und CrP-Konzentration nachgewiesen werden. Zusammengefasst zeigt die Untersuchung, dass die bei Patienten mit Typ 2 Diabetes deutlich erhöhte Chemerin-Serumkonzentration parallel zur Verbesserungen der Leistungsfähigkeit und Insulinsensitivität (Sportprogramm) auch durch eine signifikante BMI-Reduktion (Adipositas-Chirurgie) gesenkt werden kann.

Submitted by PRISCILLA MARIA PONCE VAREDA null (priponce@hotmail.com) on 2017-12-18T18:10:02Z No. of bitstreams: 1 TESE DOUTORADO versao pos graduação.pdf: 5834333 bytes, checksum: 1f45a96cd4820a9ecccd3b40246da448 (MD5) / Approved for entry into archive by Luciana Pizzani null (luciana@btu.unesp.br) on 2017-12-19T13:27:22Z (GMT) No. of bitstreams: 1 vareda_pmp_dr_int.pdf: 5834333 bytes, checksum: 1f45a96cd4820a9ecccd3b40246da448 (MD5) / Made available in DSpace on 2017-12-19T13:27:22Z (GMT). No. of bitstreams: 1 vareda_pmp_dr_int.pdf: 5834333 bytes, checksum: 1f45a96cd4820a9ecccd3b40246da448 (MD5) Previous issue date: 2017-02-16 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O Diabetes mellitus (DM) é uma desordem metabólica caracterizada por hiperglicemia decorrente de defeitos na secreção ou ação da insulina, que acarreta distúrbios no metabolismo de carboidratos, lipídeos e proteínas. A incidência do DM aumenta de maneira alarmante em todo o mundo e os estudos com plantas que possuam efeitos antidiabéticos despertam cada vez mais o interesse por parte de pesquisadores. Em resultados anteriores, observamos que camundongos induzidos por estreptozotocina exibiram melhora no quadro diabético após serem submetidos ao tratamento com extrato bruto das folhas de Myrcia bella. Neste trabalho, decidimos avaliar os mecanismos moleculares envolvidos nos processos de captação e armazenamento de glicose em tecidos periféricos como fígado, músculo esquelético e tecido adiposo neste modelo experimental. No mais, procuramos avaliar a atividade inibitória in vitro e in vivo do extrato de M. bella sobre as enzimas alfa glicosidase e alfa amilase, bem como o conteúdo de insulina no pâncreas. Camundongos diabéticos (STZ SAL e STZ EXT) e controles normoglicêmicos (CTL SAL e CTL EXT) foram tratados durante 21 dias com salina ou extrato bruto de M. bella na dose de 600 mg/kg. Foram coletados porções de fígado para avaliação da expressão de genes e proteínas envolvidos nos processos de glicogênese, glicogenólise e neoglicogênese. Ainda, amostras de músculo gastrocnêmio foram obtidas para avaliação de genes e proteínas envolvidas na via de sinalização de insulina e captação de glicose. Da mesma forma, a expressão das principais proteínas envolvidas na sinalização de insulina em tecido adiposo branco retroperitoneal também foi observada. O pâncreas foi coletado para avaliação do conteúdo de insulina. O tratamento com extrato bruto parece modular os processos de estoque e liberação de glicose no fígado de camundongos diabéticos (STZ EXT) através do aumento na expressão das proteínas glicogênio sintase e diminuição da expressão de PEPCK e glicose -6-fosfatase e dos respectivos genes responsáveis pela tradução das duas últimas. O tratamento com extrato de M. bella também promoveu aumento da expressão da proteína GLUT4 em tecido adiposo retroperitoneal de camundongos diabéticos (STZ EXT). Os ensaios in vitro e in vivo mostraram que o extrato é eficiente tanto na inibição das enzimas alfa glicosidase e alfa amilase assim como na diminuição da glicemia pós prandial, após ingestão de amido e maltose. Através dos resultados obtidos pudemos concluir, pelo menos em parte, que o extrato age na redução da glicemia de camundongos diabéticos através da modulação dos processos que regulam a captação, estoque e liberação de glicose pelo fígado. Ainda, sua ação também pode ser associada em parte pela captação de glicose pelo tecido adiposo, assim como pela inibição das enzimas alfa glicosidase e alfa amilase intestinais. / Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion or action, which results in carbohydrates, proteins and lipids metabolism disturbances. DM incidence increases alarmingly worldwide and studies with plants, which exhibit anti-diabetic effects, arouse researcher’s interests. In previous results we observed that streptozotocin-induced diabetic mice showed an improvement in diabetic condition after the treatment with Myrcia bella leaves crude extract. In this work, we have decided to evaluate the molecular mechanisms involved in glucose uptake and storage process in peripheral tissues such as liver, gastrocnemius muscle and adipose tissue. Furthermore, to evaluate the extract in vivo and in vitro inhibitory activity of alpha glycosidase and alpha amylase enzymes and insulin content in pancreas. Diabetic mice (STZ SAL and STZ EXT) and normoglicemic control mice (CTL SAL and CTL EXT) were treated during 21 days with saline or M. bella crude extract at 600 mg/kg. Liver was collected to gene and protein expression involved in glycogenesis, glycogenolysis and gluconeogenesis process. Gastrocnemius muscle to gene and protein expression involved in insulin signaling pathway and glucose uptake and white adipose tissue to the expression of the mainly proteins involved in insulin signaling pathway. Pancreas was collected to evaluate the insulin content. The treatment with M. bella crude extract seems to modulate the process of glucose storage and release in liver of diabetic mice (STZ EXT) thought the increase of glycogen synthase expression and decrease of the of PEPCK and glucose – 6- phosphatase expression as well as the respectively genes involved in the translation of PEPCK and glucose – 6- phosphatase . The treatment with M. bella extract also increased the GLUT4 protein expression in adipose tissue of diabetic mice (STZ EXT). The in vitro and in vivo analysis showed the extract is efficient in alpha glycosidase and amylase enzymes inhibition as well as in decreasing the postprandial glycemia after starch and maltose ingestion. Finally, we conclude that, at least in part, the extract acts in glycemia reduction through modulation of processes that regulates glucose uptake, storage and release from liver. Moreover, the extract action may be associated with the glucose uptake in adipose tissue as well as through the inhibition of alpha glycosidase and alpha amylase enzymes. / 2012/23605-2

Submitted by LEVY MALMONGE (l.malmonge@hotmail.com) on 2016-05-11T13:53:42Z No. of bitstreams: 1 Dissertação Mestrado Levy Malmonge.pdf: 1689039 bytes, checksum: 8283104d3ab314c8cf56c74d68981798 (MD5) / Approved for entry into archive by Felipe Augusto Arakaki (arakaki@reitoria.unesp.br) on 2016-05-13T14:41:52Z (GMT) No. of bitstreams: 1 martinneto_lm_me_bot.pdf: 1689039 bytes, checksum: 8283104d3ab314c8cf56c74d68981798 (MD5) / Made available in DSpace on 2016-05-13T14:41:52Z (GMT). No. of bitstreams: 1 martinneto_lm_me_bot.pdf: 1689039 bytes, checksum: 8283104d3ab314c8cf56c74d68981798 (MD5) Previous issue date: 2016-02-25 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A insulina é o hormônio produzido pelas células beta das ilhotas pancreáticas, responsável pela captação da glicose pelos tecidos periféricos. A glicose é o principal estimulante para a secreção deste hormônio e é também o substrato energético mais utilizado pelas células para produção de energia ou armazenamento na forma de glicogênio. A insulina atinge os tecidos-alvo e se liga a um receptor de superfície da membrana plasmática, ativando uma cascata de fosforilação envolvendo as proteínas IRS1, PI-3 cinase, AKT e GLUT4. Qualquer defeito nesta sequência resulta em uma menor captação da glicose e uma maior secreção de insulina, estabelecendo um quadro chamado resistência periférica à insulina, frequente em pacientes portadores de malignidades que apresentam também uma síndrome conhecida como caquexia, caracterizada pela perda de peso, de tecido adiposo, atrofia muscular e anorexia. Esse conjunto de fatores é resultado da tentativa do organismo de produzir energia em grande escala para suprir o hospedeiro e seu tumor. Trabalhos anteriores em nosso laboratório já haviam descrito que a secreção de insulina por ilhotas de camundongos portadores de tumor solido de Ehrlich, apóes 14 dias de inoculação, apresentava-se diminuída, enquanto a sensibilidade periférica tanto à insulina quanto à glicose se mostraram aumentadas, portanto, o presente trabalho teve como objetivo avaliar a via de sinalização de insulina em tecido muscular, hepático e adiposo de camundongos caquéticos portadores do tumor sólido de Ehrlich 14 dias após inoculação. Foram analisadas as expressões gênicas por RT-qPCR e expressão protéica por Western Blotting das proteínas da via de sinalização da insulina, como IR, IRS1, PI3-K e AKT. Em uma análise geral do quadro sistêmico dos camundongos, estes apresentaram alterações metabólicas condizentes com o quadro de caquexia já estabelecido, como perda de peso, esplenomegalia, diminuição de colesterol, de glicogênios hepático e muscular e aumento de triglicerídeos plasmáticos. No tecido hepático, proteínas-chave na regulação da via - IR e AKT – apresentaram niveis proteicos aumentadas, enquanto no tecido muscular a proteína IRS1 em sua forma inativa, juntamente com AKT, estavam diminuídas. O tecido adiposo apresentou aumento na expressão gênica de algumas proteínas, mas não apresentou alteração na expressão proteica das mesmas. Portanto, o mesmo organismo apresenta orgãos com maior sensibilidade à insulina, como o tecido hepático e outros com resistencia à insulina, como o tecido muscular, mostrando uma resposta tecido-especifica à ação da insulina. / Insulin is the hormone produced by the β cells of the pancreatic islets, responsible for the absorption of glucose by peripheral tissues. Glucose is the major stimulant for the secretion of this hormone and is also the main substrate used by the cells for energy production or storage as glycogen. After the stimulus, insulin arrives at the target tissues and binds to its receptor at the surface of the cell membrane, activating a cascade of proteins phosphorylation such as IRS1, PI-3 kinase, AKT and GLUT4. Any defect in this sequence results in a lower glucose uptake and increased insulin secretion, resulting in a situation called insulin resistance, often seen in patients with malignancies and intimately linked with a syndrome called cachexia characterized by loss of weight and fat mass, muscle wasting and anorexia. These factors are the result of an attempt of the body to produce energy on a large scale to supply the host and his tumor because tumor cells absorb nutrients faster than normal cells. This study aimed to investigate the insulin signaling pathway in muscle, liver and fat tissue of solid Ehrlich carcinoma-bearing mice after 14 days of inoculation. At this time, previous studies of our laboratory had already described that the secretion of insulin showed significant decrease, while the peripheral sensitivity, for both insulin and glucose was increased. From this, we analyzed the gene expression by RT-PCR and protein expression by Western Blotting of the insulin signaling pathway proteins such as IR, IRS1, PI3-K and AKT. In a general analysis, the animals showed metabolic abnormalities consistent with cachexia already established, such as weight loss, splenomegaly, decreased cholesterol, liver and muscle glycogen and increased plasma triglycerides. In liver, IR and AKT, key proteins in the pathway regulation, were increased, while in muscle IRS1 protein in its inactive form, along with AKT were decreased. The fat tissue showed no alterations in protein expression, but showed a increased expression of genes for some proteins of the pathway. These data allow us to conclude that the sensitivity shown in ipITT it is a tissue-specific response, that is, while there is greater sensitivity to insulin in the liver, muscle appears to be resistant to the hormone.

Orientador: José Roberto Bosqueiro / Resumo: O Diabetes mellitus (DM) é uma desordem metabólica caracterizada por hiperglicemia decorrente de defeitos na secreção ou ação da insulina, que acarreta distúrbios no metabolismo de carboidratos, lipídeos e proteínas. A incidência do DM aumenta de maneira alarmante em todo o mundo e os estudos com plantas que possuam efeitos antidiabéticos despertam cada vez mais o interesse por parte de pesquisadores. Em resultados anteriores, observamos que camundongos induzidos por estreptozotocina exibiram melhora no quadro diabético após serem submetidos ao tratamento com extrato bruto das folhas de Myrcia bella. Neste trabalho, decidimos avaliar os mecanismos moleculares envolvidos nos processos de captação e armazenamento de glicose em tecidos periféricos como fígado, músculo esquelético e tecido adiposo neste modelo experimental. No mais, procuramos avaliar a atividade inibitória in vitro e in vivo do extrato de M. bella sobre as enzimas alfa glicosidase e alfa amilase, bem como o conteúdo de insulina no pâncreas. Camundongos diabéticos (STZ SAL e STZ EXT) e controles normoglicêmicos (CTL SAL e CTL EXT) foram tratados durante 21 dias com salina ou extrato bruto de M. bella na dose de 600 mg/kg. Foram coletados porções de fígado para avaliação da expressão de genes e proteínas envolvidos nos processos de glicogênese, glicogenólise e neoglicogênese. Ainda, amostras de músculo gastrocnêmio foram obtidas para avaliação de genes e proteínas envolvidas na via de sinalização de insulina e cap... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion or action, which results in carbohydrates, proteins and lipids metabolism disturbances. DM incidence increases alarmingly worldwide and studies with plants, which exhibit anti-diabetic effects, arouse researcher’s interests. In previous results we observed that streptozotocin-induced diabetic mice showed an improvement in diabetic condition after the treatment with Myrcia bella leaves crude extract. In this work, we have decided to evaluate the molecular mechanisms involved in glucose uptake and storage process in peripheral tissues such as liver, gastrocnemius muscle and adipose tissue. Furthermore, to evaluate the extract in vivo and in vitro inhibitory activity of alpha glycosidase and alpha amylase enzymes and insulin content in pancreas. Diabetic mice (STZ SAL and STZ EXT) and normoglicemic control mice (CTL SAL and CTL EXT) were treated during 21 days with saline or M. bella crude extract at 600 mg/kg. Liver was collected to gene and protein expression involved in glycogenesis, glycogenolysis and gluconeogenesis process. Gastrocnemius muscle to gene and protein expression involved in insulin signaling pathway and glucose uptake and white adipose tissue to the expression of the mainly proteins involved in insulin signaling pathway. Pancreas was collected to evaluate the insulin content. The treatment with M. bella crude extract seems to modulate the pr... (Complete abstract click electronic access below) / Doutor

Orientador: José Roberto Bosqueiro / Resumo: A insulina é o hormônio produzido pelas células beta das ilhotas pancreáticas, responsável pela captação da glicose pelos tecidos periféricos. A glicose é o principal estimulante para a secreção deste hormônio e é também o substrato energético mais utilizado pelas células para produção de energia ou armazenamento na forma de glicogênio. A insulina atinge os tecidos-alvo e se liga a um receptor de superfície da membrana plasmática, ativando uma cascata de fosforilação envolvendo as proteínas IRS1, PI-3 cinase, AKT e GLUT4. Qualquer defeito nesta sequência resulta em uma menor captação da glicose e uma maior secreção de insulina, estabelecendo um quadro chamado resistência periférica à insulina, frequente em pacientes portadores de malignidades que apresentam também uma síndrome conhecida como caquexia, caracterizada pela perda de peso, de tecido adiposo, atrofia muscular e anorexia. Esse conjunto de fatores é resultado da tentativa do organismo de produzir energia em grande escala para suprir o hospedeiro e seu tumor. Trabalhos anteriores em nosso laboratório já haviam descrito que a secreção de insulina por ilhotas de camundongos portadores de tumor solido de Ehrlich, apóes 14 dias de inoculação, apresentava-se diminuída, enquanto a sensibilidade periférica tanto à insulina quanto à glicose se mostraram aumentadas, portanto, o presente trabalho teve como objetivo avaliar a via de sinalização de insulina em tecido muscular, hepático e adiposo de camundongos caquéticos portador... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Insulin is the hormone produced by the β cells of the pancreatic islets, responsible for the absorption of glucose by peripheral tissues. Glucose is the major stimulant for the secretion of this hormone and is also the main substrate used by the cells for energy production or storage as glycogen. After the stimulus, insulin arrives at the target tissues and binds to its receptor at the surface of the cell membrane, activating a cascade of proteins phosphorylation such as IRS1, PI-3 kinase, AKT and GLUT4. Any defect in this sequence results in a lower glucose uptake and increased insulin secretion, resulting in a situation called insulin resistance, often seen in patients with malignancies and intimately linked with a syndrome called cachexia characterized by loss of weight and fat mass, muscle wasting and anorexia. These factors are the result of an attempt of the body to produce energy on a large scale to supply the host and his tumor because tumor cells absorb nutrients faster than normal cells. This study aimed to investigate the insulin signaling pathway in muscle, liver and fat tissue of solid Ehrlich carcinoma-bearing mice after 14 days of inoculation. At this time, previous studies of our laboratory had already described that the secretion of insulin showed significant decrease, while the peripheral sensitivity, for both insulin and glucose was increased. From this, we analyzed the gene expression by RT-PCR and protein expression by Western Blotting of the insulin sign... (Complete abstract click electronic access below) / Mestre