Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 3 uppsatser.

Thesis (M.S.)--University of Michigan, 1983.

Thesis (M.S.)--University of Michigan, 1993.

Thesis (M.S.)--Wake Forest University. Dept. of Health and Exercise Science, 2002. / Vita. Includes bibliographical references (leaves 98-106).

Thesis (Ph. D.)--Duke University, 2008. / Includes bibliographical references.

Thesis (M.S.)--University of Michigan, 1983.

Thesis (M.S.)--University of Michigan, 1983.

Thesis (Ph. D.)--University of Lund, 1998. / Originally issued as the author's doctoral thesis. Includes bibliographical references.

Cardiovascular disease (CVD) and type two diabetes mellitus (T2D) are among the leading causes of death worldwide. Insulin resistance (IR) and hyperglycaemia are risk factors for CVD and T2D and are known to be prevalent in youth. Physical activity (PA) is known to improve IR and glucose tolerance in youth, but current levels of PA are low meaning alternative PA recommendations are needed. The purpose of this thesis is to investigate the effect of low volume high-intensity interval exercise (HIIE) on insulin and glucose health outcomes in male children and adolescents. Additionally, the thesis will explore the potential for HIIE to improve glycaemic control in paediatric patients with type one diabetes mellitus (T1D). Chapter 4 examines the relationship between estimates of insulin sensitivity (IS) based on oral glucose tolerance test (OGTT) and fasted assessment methods, in addition to the day-to-day reliability of these measures in children and adolescents. Results from this chapter advocated the Cederholm index to measure IS in this sample due to the low day to day reliability (coefficient of variation (%CV) of 6.4%). Chapter 5 demonstrates comparable results, reporting moderate improvements to IS and glucose tolerance measured via an OGTT 10 minutes after a single bout of HIIE and work-matched moderate-intensity exercise (MIE) in adolescent boys (13-15 y old). The findings from Chapter 5 are extended in Chapter 6, where changes to OGTT derived IS and glucose tolerance were measured up to 24 h post exercise and fasting measures of IS up to 48 h after exercise. Improvements to IS and glucose tolerance after the OGTT persisted for up to 24 h after HIIE and MIE, but no changes to fasting outcomes were observed over the 48 h period. In contrast to Chapter 5, Chapter 7 reports that a single bout of HIIE but not work-matched MIE resulted in only a small improvement in IS in 8-10 year old boys. Chapter 8 assesses the efficacy of 6 sessions of HIIE performed over 2 weeks to alter fasting and postprandial (mixed-meal tolerance test) insulin and glucose outcomes in adolescent boys. In contrast to acute exercise (Chapters 5 and 6), HIIE training over 2 weeks did not improve insulin and glucose outcomes in this population. Finally, Chapter 9 presents a case study on three adolescents with T1D to examine the effect of acute HIIE and MIE on glycaemic control. This study indicates that both MIE and HIIE have the potential to improve short-term (24 h) glycaemic control within this clinical population. Taken collectively, the studies from this thesis demonstrate that HIIE offers an effectual and feasible alternative to MIE to improve insulin and glucose health outcomes in healthy children and adolescents, and short-term glycaemic control in adolescents with T1D.

Orientadores: Antonio Carlos Boschiero, Alex Rafacho / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-24T03:03:43Z (GMT). No. of bitstreams: 1 Protzek_AndreOtavioPeres_D.pdf: 8312725 bytes, checksum: 2126056342598338000e5d9925e59082 (MD5) Previous issue date: 2013 / Resumo: Os glicocorticoides (GC) são amplamente utilizados devido aos seus efeitos anti-inflamatórios. Porém, o tratamento com GC pode induzir efeitos deletérios sobre a homeostase glicêmica como a resistência à insulina (RI), intolerância à glicose e, dependendo do tempo e dose, pode levar a instalação do Diabetes mellitus tipo 2 (DM2). Neste sentido, ratos têm sido vastamente utilizados como modelo animal para elucidar as compensações pancreáticas envolvidas na hiperinsulinemia induzida por GC e, poucos estudos enfocando os efeitos do tratamento com GC foram realizados em camundongos. Além disso, não é completamente elucidado se a hiperinsulinemia compensatória induzida pelo tratamento com GC esta associada com alteração do clearance de insulina. Assim, nossos objetivos foram avaliar se: as compensações do pâncreas endócrino em resposta ao tratamento com GC são similares entre camundongos e ratos e, identificar possíveis mecanismos que as expliquem; e se a hiperinsulinemia compensatória induzida pelo tratamento com GC em camundongos e ratos esta associada com alterações do clearance de insulina e a expressão da proteína insuling degrading enzyme (IDE) no fígado. Para isto, camundongos Swiss e ratos Wistar machos foram tratados com o glicocorticoide sintético dexametasona (1 mg/kg p.c.; 5 dias consecutivos). O tratamento com GC induziu RI, hiperinsulinemia e dislipidemia em ambas as espécies, embora mais pronunciado em ratos, que também apresentaram intolerância à glicose e hiperglicemia no jejum. Ambas as espécies tratadas com GC apresentaram incremento da secreção de insulina ex vivo estimulada com glicose, massa e proliferação de células ?, que foram associados com aumento da sinalização da via Ir-?/AKT/mTOR e redução da via AMPK/ACC/AS160 em ilhotas isoladas. O clearance de insulina reduziu em camundongos e ratos tratados com GC, o que foi associado com redução da expressão de IDE no fígado. Desta forma, nossos resultados indicam que camundongos são menos sensíveis aos efeitos deletérios do tratamento com GC sobre a homeostase glicêmica, quando comparado com ratos. Ainda, camundongos e ratos apresentam compensações pancreáticas semelhantes (incremento da função e massa de células ?) em resposta ao tratamento com GC, que foi associado com aumento da sinalização da via canônica de insulina e redução da via não canônica em ilhotas isoladas. Além disso, a redução do clearance de insulina foi, ao menos em parte, devido a redução da expressão de IDE no fígado, o que contribuiu para a hiperinsulinemia compensatória em ambas as espécies tratadas com GC. Em conclusão, estes resultados corroboram a hipótese de que fármacos que inibam a expressão ou atividade da IDE no fígado podem ser uma intervenção anti-diabetogênica que auxilie na manutenção da homeostase glicêmica sem sobrecarregar as células ? / Abstract: Glucocorticoids (GCs) are widely used as anti-inflammatory agent, but they may induce adverse metabolic effects such as insulin resistance (IR), glucose intolerance, and occasionally, diabetes mellitus type 2. Healthy rats have been used as animal models to elucidate the islet compensatory mechanisms involved in these metabolic disturbances, and only a few studies, which have focused on the in vivo effects of GCs, have been conducted in mice models. Yet, whether the reduced insulin clearance also contributes to the compensatory hyperinsulinemia in GC-treated rodents is not fully understood. Here, we aimed to elucidate whether mice and rats share the pancreatic compensations that result in response to dexamethasone (DEX) treatment and also to identify the possible mechanisms that can explain its effects. Yet, we investigated whether the hyperinsulinemia induced by GC treatment in mice and rats is associated with altered hepatic insulin degrading enzyme (IDE) expression and insulin clearance. For this, male Swiss mice and Wistar rats were treated with the synthetic GC dexamethasone (1 mg/kg b.w.; 5 days). DEX treatment induced IR, hyperinsulinemia and dyslipidemia in both species (there was a higher magnitude in rats), but treatment had a greater effect in rats that had glucose intolerance and increased basal blood glucose compared to the control group. Ex vivo insulin secretion at different glucose concentrations was higher in both groups of DEX-treated rodents compared to their controls. Mice and rats showed a significant increase in ?-cell mass due to increased ?-cell proliferation, which was associated with upregulation of the Ir-?/AKT/mTOR and downregulation of AMPK/ACC/AS160 signaling. Insulin clearance reduced in GC-treated mice and rats, which were associated with reduced hepatic IDE expression. Thus, mice are less vulnerable than rats to the deleterious effect of GCs on glucose homeostasis. In addition, rats and mice share common islet compensations (increased ?-cell function and mass) in response to GC treatment, which were associated with increased canonical and decreased non-canonical insulin signaling. Farther, the reduced insulin clearance in GC-treated rodents was, at least in part, due to reduced hepatic IDE expression, which contributed to the compensatory hyperinsulinemia. These findings corroborate the idea that pharmacological interventions that inhibit hepatic IDE may be an alternative anti-diabetic agent that helps to maintain glucose homeostasis due to hyperinsulinemia instead of hypoglycemic agent, which increase the overload in the ?-cells and may lead to ?-cell failure and DM2 / Doutorado / Fisiologia / Doutor em Biologia Funcional e Molecular