In an effort to assess whether the craving for sweets experienced by some abstaining alcoholics is physiologically based, 48 Wistar rats were divided into 4 groups. Groups 1 and 3 were fed a liquid diet containing 35.5 percent energy as alcohol; groups 2 and 4 were fed a control diet with dextrins substituted for alcohol, all for 24 days. Group 4 was pair-fed to group 3. For the next 10 days, all rats were provided with sucrose and water ad libitum and all groups were continued on their liquid diet except that alcoholic group 3 was placed on the control diet and pair-fed group 4 was no longer pair-fed. Urine was collected at the end of the baseline, alcohol-induction, and recovery periods and analyzed for L-ascorbic acid. The mean consumption of sucrose was highest for rats still receiving alcohol and declined in all groups during the 10 days. The mean consumption of sucrose (% kcal as sucrose) for the first 4 days was 33.2, 19.5, 19.0, and 13.8% for groups 1, 2, 3, and 4 declining to 24.6, 11.2, 9.0, and 8.5 percent, respectively by the last 4 days. The sugar intake of alcoholic group 3 animals was significantly higher than pair-fed control group 4 during the first 4 days. L-ascorbic acid excretion was significantly increased in the groups receiving alcohol and declined during the recovery period. This study has raised the possibility that increased urinary excretion of ascorbic acid may suppress glycogen synthesis, leading to hypoglycemia. / Master of Science

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25187号 / 医博第5073号 / 新制||医||1072(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 万代 昌紀, 教授 川上 浩司, 教授 滝田 順子 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Exercise has a wide range of benefits for patients with type 1 diabetes, including improvements in body composition, cardiovascular risk profile and glycaemic control. Unfortunately, exercise also increases the risk of hypoglycaemia in children with type 1 diabetes, both at the time of exercise and for many hours afterwards. The availability of clear, evidence-based guidelines regarding appropriate adjustments in carbohydrate intake or insulin doses may help to prevent this exercise associated hypoglycaemia. However, current guidelines regarding exercise in children with type 1 diabetes rely heavily on adult literature or the consensus of experts. Therefore, further studies are needed in young people with diabetes to document the metabolic responses during and following exercise. In particular, the mechanisms underlying hypoglycaemia occurring many hours after exercise require further exploration. In addition, as children often exercise in the afternoon, studies performed at this time of the day are more likely to be transferrable to a real life situation. For this reason, we studied adolescents with type 1 diabetes to investigate physiological responses to exercise, focusing on afternoon activity and employing a novel variation of the euglycaemic insulin clamp technique. The core experiments involved studying diabetic adolescents on two occasions in a counterbalanced, paired design during and after afternoon exercise. Insulin was infused at a constant rate based on the subjects' usual daily insulin dose and glucose was infused to maintain euglycaemia. At 1600 hrs subjects either exercised at a moderate intensity (95% of their lactate threshold) for 45 minutes on a cycle ergometer (exercise study), or sat on the ergometer without exercising (rest study). Using this experimental design, it was found that glucose infusion rates (GIR) to maintain euglycaemia were elevated during and shortly following exercise and again from 7-11 hours after exercise compared with the rest study. Counterregulatory hormone levels were similar between the exercise and rest studies except for peaks in noradrenaline, cortisol and growth hormone levels at the end of exercise. Glucagon and adrenaline levels did not increase with exercise. The observed biphasic increase in glucose requirements paralleled the observed clinical risk of hypoglycaemia immediately during exercise and the delayed risk of hypoglycaemia which often occurs overnight.

Bakgrund: Omkring en tredjedel av personer med diabetessjukdom drabbas någon gång av hypoglykemi med medvetslöshet som följd. Upplevelsen av hypoglykemi var obehaglig och försökte undvikas vilket ofta resulterade i högre plasmaglukosvärden. Omvårdnaden kunde innebära att hjälpa personer att hantera obehagliga upplevelser av hypoglykemi i det dagliga livet. Syfte: Att beskriva vuxnas erfarenheter och upplevelser av hypoglykemi vid diabetes mellitus, samt vilka konsekvenser hypoglykemi leder till i det dagliga livet. Metod: Denna studie har genomförts med en kvalitativ innehållsanalys med induktiv ansats. Studien har genomförts som en sekundäranalys av semistrukturerade intervjuer. Antalet informanter var totalt 29 varav 15 med diabetes typ 1 och 14 med diabetes typ 2. Resultat: Temat som framkom var Hypoglykemi är ständigt närvarande och gestaltar sig olika med följande kategorier: Symtom av hypoglykemi kunde komma som en blixt från en klar himmel, Kunskapen kom genom livets erfarenheter, Träning och motion idag – konsekvenser i morgon, Egenvård kunde upplevas som att inte vara fri, Omgivningens stöd – en trygghet vid sjukdom. Konklusion: Förekomsten av hypoglykemi var vanligt och upplevdes som obehagligt och orsakade rädsla. Underbehandling sågs som en konsekvens. Bättre stöd, hjälp och information från specialistsjuksköterskor efterfrågades. Kunskap och information, även till anhöriga, ansågs viktigt för att minska rädsla och obehag av hypoglykemi. / Background: Approximately one third of people with diabetes suffer episodes of hypoglycaemia with a loss of consciousness as a result. The incidence of hypoglycaemia is unpleasant and patients attempt to avoid this event, which often results in higher plasmaglucose values. Dedicated nursing care involves helping people to cope with unpleasant experiences of hypoglycaemia in daily life. Aim: To describe adults' experiences of hypoglycaemia in diabetes mellitus, and the consequences hypoglycaemia leads to daily life. Method: This study was conducted with a qualitative content analysis with an inductive approach. The study was conducted as a secondary analysis of semi-structured interwievs. The number of study participants were a total of 29 of which 15 with Type 1 diabetes and 14 with Type 2 diabetes. Results: The theme that emerged was: Hypoglycaemia is an ever present risk and is shaped differently with the following categories. Symptoms of hypoglycaemia could come as a bolt from the blue. Knowledge comes from life experiences. Training and exercise today - often have consequences tomorrow for patients. Self management could be perceived as a feeling of not being free. Family support – could mean security in illness. Conclusion: The incidence of hypoglycaemia is a common event and is perceived as unpleasant and unsafe event and causing fear in people suffering from diabetes. Undertreatment was seen as a consequence. Better support, help and information from the specialist nurses were needed. Knowledge and information, even to family members, was considered important to reduce the fear and discomfort of hypoglycaemia.

Diabetes is a rapidly growing health concern in the developed world. Hypoglycaemia is a major risk factor in people with diabetes. Each year, about 7000 calls relating to hypoglycaemia are made to the Scottish Ambulance Service (SAS), including a considerable number of repeat callers. Very little is known about people’s experiences and explanations of recurrent hypoglycaemia; in particular, why some individuals manage their recurrent hypoglycaemic episodes independently, while others require more direct healthcare support. This thesis investigated participants’ experiences and individual explanations of recurrent hypoglycaemic episodes, in order to understand their health help-seeking behaviour. To do this, it compared the experiences of people who had called the emergency services within one month prior to recruitment (SAS participants), with those people who had not done so (non-SAS participants). The study employed a multiple methods longitudinal approach to prospectively capture participants’ experiences of hypoglycaemic episodes, using qualitative semi-structured interviews, hypoglycaemia and blood glucose diaries and follow-up telephone interviews over a six month period. Thirty participants were involved in the study, recruited through the Scottish Ambulance Service, Diabetes UK (Scotland), and the University of Stirling. All participants resided in the central belt of Scotland. Qualitative data was analysed using the framework method, and quantitative data was analysed using descriptive statistics. This study found that hypoglycaemic episodes had a wide ranging impact on people’s everyday life. It was not only the actual hypoglycaemic episode that affected participants’ everyday life, but also fears and worries about future hypoglycaemic episodes, the preparations that participants engaged in, and the process of recovery. Hypoglycaemia unawareness was found to be a major problem for many people living with diabetes. It appeared to be associated with the likelihood of needing external help. There were differences between participant groups with regard to management of hypoglycaemia unawareness. Non-SAS participants adopted strategies to prepare for future hypoglycaemic episodes, and appeared to be more knowledgeable about their diabetes and its management, resulting in needing less external help. SAS participants experienced more severe hypoglycaemic episodes. Consequently, they relied more on external help. Findings of this study call for a re-conceptualisation of the previously recognised ‘balancing act’ of managing diabetes and hypoglycaemic episodes. This study introduces the concept of a hypoglycaemic episode balancing continuum (HEBC) which enables a deeper understanding of the factors involved in this balancing act: it demonstrates that people balance the various risks differently, depending on whether they prioritised their fear of hypoglycaemia over fears of long-term complications. People’s position on the continuum directly affected their management strategies for hypoglycaemic episodes. Most hypoglycaemic episodes were managed by the individual without requiring any external help. However, participants’ ability to self-care differed and deficits occurred, resulting in participants being more likely to need involvement of others (family/friends). When the capacity of others to help broke down, participants’ were more likely to need SAS emergency care. In order to explain how hypoglycaemic episodes are managed, this thesis has developed a hypoglycaemic episode help-seeking network (HEHS network), which helps to identify the various agents involved in helping to manage hypoglycaemic episodes. Findings from this study have implications for clinical practice. For example, looking at hypoglycaemia unawareness, this study has shown that current understanding may fail to take account of participants’ real experiences, which show hypoglycaemia unawareness to be a fluid phenomenon that can affect people at various times. If blood glucose levels can fail to predict onset of hypoglycaemic episodes, healthcare professionals may need to broaden the range of blood glucose readings that might indicate a hypoglycaemic episode and tailor specific advice to individual patients. To reduce the use of emergency services, more attention must be paid to hypoglycaemia unawareness and better advice provided about this condition. Also, more education should be provided for family members/carers, given the crucial role they play in the management of diabetes and hypoglycaemic episodes, and being a link in the process leading to increased use of emergency services. The HEBC could be developed into a useful ‘screening tool’ to help healthcare professionals identify those at greater risk of hypoglycaemic episodes and those at greater risk of long-term complications, and to target advice more specifically to these patient groups. Further research could explore family member/carer knowledge in more detail to better understand their role in helping to manage hypoglycaemic episodes.

Os valores de glicemia considerados fisiológicos em recém-nascidos, assim como os valores considerados patológicos, levando a danos no sistema neurológico, são bastante debatidos na literatura e há pouco consenso. O objetivo deste trabalho foi analisar a glicemia de 172 recém-nascidos adequados para a idade gestacional, a termo e em aleitamento materno exclusivo, no primeiro dia de vida, através de monitor contínuo de glicemia intersticial, que registra a glicemia a cada 5 minutos. O aparelho foi retirado após 24 horas e os resultados foram analisados em programa de computador. A amostra apresentou glicemia média de 66,6 mg/dl logo após o nascimento, com redução até a sexta hora de vida, com o valor de 53,7 mg/dl. Apenas na decima quarta hora de vida, a glicemia voltou a atingir valores entre 60 e 70 mg/dl. A média da glicemia dos recém-nascidos, durante o primeiro dia de vida, foi de 60,1 mg/dl (+/- 8,3). Da amostra, 63,9% apresentou uma ou mais medidas iguais ou menores que 50 mg/dl, 16,3% apresentou uma ou mais medidas iguais ou menores que 40 mg/dl; 4,6% apresentou uma ou mais medidas iguais ou menores que 30 mg/dl e 1,2% apresentou uma ou mais medidas iguais ou menores que 20 mg/dl. Os resultados mostraram um padrão de glicemia para essa casuística, com glicemia que cai rapidamente do nascimento até a sexta hora de vida e volta a subir até a decima quinta hora, ao atingir um valor que permanece estável até o final do dia. Este estudo permitiu elaborar uma curva de evolução dos valores de glicemia intersticial, com média e dois desvios padrões acima e abaixo. A porcentagem de recém-nascidos com a glicemia igual ou abaixo de 40 mg/dl, nesse estudo, comparada a outros estudos utilizando dosagem intermitente, mostrou que a monitorização contínua é capaz de detectar maior ocorrência de valores abaixo de 40 mg/dl. Recém-nascidos com valores de glicemia igual ou abaixo de 30 mg/dl estão abaixo da curva de normalidade traçada nesse estudo e devem, posteriormente, serem estudados em estudo prospectivo. A curva de evolução dos valores de glicemia pode contribuir para o estabelecimento de padrão de valoresglicêmicos durante as primeiras 24 horas de vida em recém-nascidos nascidos a termo, adequados a idade gestacional e sem agravos no período neonatal. / The values of glycemia that are considered physiological in neonates, as well as those considered pathological (that is, leading to damages in the neurological system) are widely debated in literature, and there is little consensus. The objective of this study was to analyze the glycemia of 172 appropriate for gestational age term newborns, who were exclusively breastfed, on the first day of life, through a continuous glucose monitoring device, which calculates interstitial glycemia every 5 minutes. The device was removed after 24 hours, and the results were analyzed in a computer program. The sample had a mean glycemia of 66.6 mg/dl shortly after birth, with a reduction until 6 hours of life, reaching a value of 53.7 mg/dl. At only 14 hours of life, the blood glucose returned to values between 60 and 70 mg/dl. The mean blood glucose of the newborns during the first day of life was 60.1 mg/dl (+/- 8.3). 63.9% of the sample had one or more values of glycemia equal to or lower than 50 mg/dl, 16.3% had one or more values equal to or lower than 40 mg/dl. 4.6% had one or more values equal to or lower than 30 mg/dl and 1.2% had one or more values equal to or lower than 20 mg/dl. The results present the glycemia pattern considered physiological for this sample, with glycemia that falls rapidly from birth up to 6 hours of life and goes back up to 15 hours, reaching a value that remains stable until the end of the first day. This study allowed the development of an evolution curve of interstitial glycemia values, with mean and two standard deviations above and below it. The percentage of newborns with glycemia at or below 40mg/dl in this study, compared to other studies using intermittent dosing, showed that continuous monitoring is able to detect a higher occurrence of values below 40 mg/dl. Newborns with blood glucose values equal to or lower than 30 mg/dl are below the normality curve plotted in this study and should be further studied in a prospective study. The evolution curve of the glycemia values may contribute to the establishment of glycemic values during the first 24 hours of life in term newborns who are appropriate for gestational age and didn\'t present any conditions in the neonatal period.

Introdução: a glicose é um importante substrato para o metabolismo celular em especial, do cérebro. A hipoglicemia neonatal está associada ao risco do desenvolvimento de sequelas neurológicas. A hipoglicemia neonatal afeta de 3% a 43% dos neonatos e sua prevalência em neonatos a termo em aleitamento materno exclusivo tem sido pouco explorada em nosso meio. Objetivo: analisar a ocorrência de hipoglicemia transitória em recém-nascidos internados em Hospital Amigo da Criança. Método: estudo transversal com coleta de dados dos prontuários médicos de neonatos com controle de glicemia capilar nas primeiras 24 horas de vida. Foram analisados 381 prontuários de neonatos internados na unidade Alojamento Conjunto de um hospital-escola da cidade de São Paulo entre 1º de julho a 31 de dezembro de 2006. Os dados foram armazenados, processados e analisados nos programas estatísticos SPSS 13.0 for Windows e NCSS/PASS 2000 Dawson Edition. Para o tratamento estatístico, foram adotados os testes Qui-Quadrado para verificar a associação entre variáveis qualitativas e o Exato de Fischer. O nível de significância descritivo adotado foi = 0,05 e as diferenças estatísticas com valor de p < 0,05 foram consideradas significativas. Resultados: a prevalência de hipoglicemia foi de 1,1%; as variáveis: hipertensão arterial na gestação, infusão endovenosa de soro glicosado no trabalho de parto, presença de escoriação mamilar nas primeiras 24 horas pós-parto apresentaram significância estatística com a ocorrência de hipoglicemia neonatal, respectivamente, com valores de p = 0,0283; p < 0,0001 e p = 0,0058. A frequência de neonatos que desenvolveram hipoglicemia foi menor no grupo de neonatos amamentados entre as 2ª e 6ª horas de vida (p = 0,0013). A ocorrência de diagnóstico de hipoglicemia neonatal foi bem maior entre os neonatos que apresentaram valores de glicemia capilar 40 mg/dl nas primeiras 24 horas de vida, 15 (83,3%), com p < 0,0001. Neonatos com sinais relacionados à hipoglicemia, 210 (55,1%) foram os que mais apresentaram diagnóstico de hipoglicemia (p = 0,0137). Conclusão: a hipoglicemia neonatal é um distúrbio metabólico raro que acomete os recém-nascidos a termo e saudáveis, sobretudo nas primeiras 6 horas de vida. Alguns fatores obstétricos e os relacionados à amamentação e lactação, bem como os neonatos sintomáticos, em especial, quando apresentam tremores, devem ser considerados como preditores da ocorrência de diagnóstico de hipoglicemia no recém-nascido. Estudos devem ser realizados para analisar a relação entre o diabetes gestacional e a ocorrência de hipoglicemia neonatal / Introduction: the glucose is a major substrate for brain cellular metabolism. The neonatal hypoglycaemia is associated with a risk of developing neurological sequelae. The neonatal hypoglycaemia affecting 3% to 43% infant newborns and their prevalence in full-term newborns admitted in the Baby-Friendly Initiative Hospital, on exclusive breastfeeding, has been little explored in Brazil. Objective: to analyze the occurrence of transient hypoglycaemia in newborns admitted to a maternity ward that adopts The Baby-Friendly initiative Hospital Model. Method: a cross-sectional study whose data were extracted from 381 newborn hospital records undergoing capillary blood glucose control in the first 24 hours of life and from their mothers hospital records, admitted in the room-in ward at School Hospital of University of São Paulo, SP, Brazil, from July to December, 2006. Data were collected after the research project was approved by the Local Research Ethics Committee. Data were collected, stored and analyzed using SPSS 13.0 for Windows and NCSS / PASS 2000 Dawson Edition. Chi-square and Fishers tests to determine the association between qualitative variables were applied, = 0,05 (p value < 0.05) were adopted to consider statistical differences. Results: the prevalence of hypoglycemia was 1.1%. The variables hypertension during the pregnancy; intravenous continuous infusion of glucose during the labor; nipple excoriation in the first 24 hours after delivery showed statistical significance with the occurrence of neonatal hypoglycemia, respectively, p = 0.0283, p <0.0001 and p = 0.0058. The frequency of neonates who developed hypoglycemia was lower in the group of infants breastfed between the second and sixth hour of life (p = 0.0013), the occurrence of diagnosis of neonatal hypoglycemia was higher among newborns who had capillary blood glucose values 40 mg/dL in the first 24 hours of life, 15 (83.3%), with p < 0.0001. The group of neonates with symptomatic hypoglycemia, 210 (55.1%), had more babies with diagnosis of hypoglycemia, (p = 0.0137). Conclusion: the neonatal hypoglycemia is a rare metabolic disorder that affects the healthy full-term newborns especially in the first six hours of life. Some obstetric factors, breastfeeding patterns, lactation conditions and symptomatic neonates, particularly when the baby shows signs of tremor should be regarded as predictors of developing neonatal hypoglycemia. Studies should be conducted to examine the relationship between gestational diabetes and the occurrence of neonatal hypoglycemia in full term neonates who exclusively breastfed

Os insulinomas são os mais comuns neoplasmas endócrinos pancreáticos, constituindo cerca de 17% de todos os tumores neuroendócrinos do trato digestivo. São tumores raros, que tem, como principal manifestação clínica, a hipoglicemia, a qual é ocasionada por secreção exagerada de insulina pelo tumor. Devido ao fato de serem tumores raros, o conhecimento das mudanças genéticas associadas à iniciação e progressão desses tumores é muito limitado. Em função disto, o objetivo deste trabalho é a identificação de genes diferencialmente expressos em insulinomas benignos humanos, visando o melhor entendimento dos mecanismos moleculares do processo tumorigênico dos insulinomas e a descoberta de novos alvos moleculares para terapia. Utilizando-se a plataforma de \"bioarrays\" CodeLink foram identificados 354 genes mais expressos nos insulinomas benignos, sendo que 16% estavam envolvidos em proliferação. Dentre estes genes foram escolhidos 6 genes para validação por \"Real-Time PCR\", onde os genes SPARCL1, PRSS11 STAT4, ECRG4, ASCL1 confirmaram sua expressão diferencial nos tumores, porém a diferença do gene IGFALS não foi estatisticamente significativa. Através da técnica \"Representational Difference Analysis\", isolou-se o clone FLJ13072, como super-expresso nos insulinomas benignos quando comparado à ilhotas normais, sendo que a seqüência protéica putativa deste gene apresenta um domínio conservado de helicase, podendo estar envolvido em eventos de transcrição, tradução, reparo de DNA e remodelamento de cromatina. Uma das dificuldades encontradas no estudo dos insulinomas é a falta de linhagens celulares humanas. Por esta razão, iniciou-se o estabelecimento de culturas primárias e precoces de insulinomas humanos visando sua utilização como modelos celulares para futuros estudos funcionais dos genes identificados. / Insulinomas are the most common pancreatic endocrine neoplasms, comprising around 17% of all neuroendocrine tumors of the digestive tract. These rare tumors have hypoglycemia as the main clinical manifestation, caused by over secretion of insulin by the tumor. Based on that, the objective of this work is the identification of differentially expressed genes in human benign insulinomas, aiming at the better understanding of the molecular mechanisms of their tumorigenic process and the discovery of new molecular targets for therapeutics. Using the CodeLink bioarrays platform (GE Healthcare) 354 genes upregulated in human benign insulinomas were identified, among which, 16% are involved in cell proliferation. From these genes, 6 were chosen for validation by Real Time PCR, where SPARCL1, PRSS11, STAT4, ECRG4 and ASCL1 were shown to be upregulated in all benign tumors, however the expression difference of IGFALS gene were not statistically significant. Using the RDA (Representational Difference Analysis) methodology, the unknown gene FLJ13072 was shown to be upregulated in benign isulinomas when compared to normal pancreatic islets. The putative protein product from this gene has an helicase domain, being possibly involved in processes like transcription, translation, DNA repair and chromatin remodeling. An important drawback for the study of insulinomas is the lack of human cell lines. Because of that, the establishment of early primary cultures of human insulinomas was initiated, aiming at its use as a cell model for future functional studies of the genes identified.

Physical activity (PA) provides many benefits to adolescents with Type 1 Diabetes (T1D); however, adolescents with T1D tend to have lower fitness and PA levels. One reason adolescents with T1D engage in less PA is due to a fear of hypoglycemia. Most studies examining PA in relation to glycemic control measure PA through self-report, thus introducing bias. The purpose of this study was to objectively monitor PA and glucose in adolescents with T1D to examine the temporal associations between moderate and vigorous intensity physical activity (MVPA) and hypoglycemia. Twenty participants (14 to 19 yr, n=10 females and 10 males) with a T1D diagnosis for at least 1 year were recruited. Participant fitness was evaluated via indirect calorimetry during a maximal treadmill exercise test, and body composition was measured using air displacement plethysmography. An accelerometer (GENEActiv, Activinsights Ltd, Kimbolton, UK) was worn on the wrist continuously for 7 days and the waveform data used to estimate MVPA in min/d. Blood glucose values were simultaneously tracked using continuous glucose monitoring (DexCom SEVEN PLUS, San Diego, CA). After controlling for gender, % body fat (%BF), and fitness, the likelihood of hypoglycemia (¡Ü 70 mg/dl) at nighttime or the next day due to MVPA was examined using logistic regression. Participants were of avg fitness (females: 43.9 ml/kg/min; males: 49.8 ml/kg/min) and fatness (females: 26.2%; males: 19.2%), and 63.2% of participants met the US federal guidelines of accumulating 60 min/d of MVPA. Hypoglycemia was 22% more likely in those who had 30 min/d more MVPA than those with less (95% CI: 1.03, 1.45; p =0.022). The results indicate that participating in MVPA increases the risk of hypoglycemia during the night time and the following day. The relationship is independent of gender, %BF and fitness. While promoting PA as a healthy behavior, it is important to educate adolescents with T1D on prevention of hypoglycemia following PA.

Abstract not available