Le diabète est associé à une augmentation de risque de maladie cardiovasculaire et une dérégulation du métabolisme. Il a été suggéré que la variabilité glycémique (VG) pouvait avoir un rôle dans le développement des complications du diabète. Afin d’étudier et de caractériser les dysfonctions induites par la VG, nous avons mis au point un modèle in vitro mimant la VG sur la lignée de cardiomyocytes HL-1. Nous avons ainsi développé un traitement de 12 heures, mimant hypoglycémie, normoglycémie, hyperglycémie et VG. L’étude de la signalisation cellulaire ne nous a pas permis de montrer un rôle délétère de la VG. Nous avons toutefois mis en évidence que la VG participait à des dysfonctions mitochondriales. En effet en situation de fluctuations en glucose, les mitochondries des cellules HL-1 présentent une augmentation de leur potentiel de membrane, ainsi qu’une augmentation de la production d’anions superoxydes. Bien que nous n’ayons pas réussi à montrer de perturbation de la chaîne respiratoire après 12 heures d’exposition, nous avons pu montrer que 72 heures d’exposition provoquaient une baisse de la respiration mitochondriale. Nous avons enfin étudié l’impact des fluctuations en glucose sur la susceptibilité au développement de lésions d’hypoxie, et avons montré que les lésions sont majorées après 36 heures d’hypoxie en cas d’exposition à des fluctuations en glucose. Nos résultats montrent un rôle délétère de la VG, néanmoins des expériences complémentaires sont nécessaires afin de caractériser de manière plus précise les mécanismes impliqués. / Diabetes mellitus is associated with higher risk of cardiovascular disease and metabolism dysregulation. Glycemic variability (GV) has been suggested as a risk factor in diabetic complication. In order to characterize dysfunctions induced by GV, we developed an in vitro model that transpose GV on the cardiac cell line HL-1. We exposed our cells to a treatment of 12 hours miming hypoglycemia, normoglycemia, hyperglycemia and GV. The exploration of signaling pathways didn’t allow us to show a deleterious effect of glucose fluctuation. However we were able to point mitochondrial alteration under glucose fluctuation. HL-1 cells mitochondria exhibit a higher membrane potential and an increase of superoxide anion production. Although we didn’t show any alteration in mitochondrial respiration after 12 hours of exposition, we showed that after 72 hours of glucose fluctuation, HL-1 cells showed a decrease in mitochondrial respiration. We finally studied the impact of glucose fluctuation on the susceptibility to develop hypoxic injuries. We showed that after 36 hours of hypoxia, injuries were higher for cells exposed to glucose fluctuation. Our results indicate a deleterious effect of GV, but additional experiments are needed to better characterize the mechanisms.

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Background: The most patients in intensive care experience hyperglycemia. These may include patients with pre-existing diabetes or stress hyperglycemia as an organism's offense reaction. Our aim is not only to correct this hyperglycemia early by a reserve, but also to prevent acceleration of hyperglycemia above their commended level. In addition to insulin, the correct choice of enteral nutrition can prevent not only hyperglycemia but also glycemic variability, which seems to be a much greater risk for these patients than stable tolerable hyperglycemia. In addition to diabetic-specific formulas, whey-based enteral nutrition can support our pursuit of optimal glycemia, due to its insulinotropic effect and its ability to stimulate incretin release. Much evidence will still be needed to confirm these benefits, but we can already look at whey not only as a source of quality protein, but also as a diet with a potential to limit glycemic variability. Objective: The aim of the study was to evaluate the effect of enteral nutrition based on whey (Peptamen Intense) on parameters associated with the assessment of glycemia in intensive care patients. Assess whether there is a relationship between the variables and draw conclusions with possible application in practice. Methods: Thirty-seven patients were...

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12968号 / 論医博第2101号 / 新制||医||1012(附属図書館) / 32406 / 新制||医||1012 / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 福原 俊一, 教授 川口 義弥 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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A sepse é uma patologia que desperta interesse crescente em virtude dos altos índices de morbidade e mortalidade e pelo impacto socioeconômico decorrente dos diversos cuidados dispensados ao paciente acometido pela doença. Pressupõe-se que a implementação de cuidados específicos embasados em diretrizes poderiam ser inseridos, avaliados e difundidos no campo da saúde a fim de se obter diagnóstico precoce com maior efetividade terapêutica, minimizando danos a saúde e aumentando a sobrevida dos pacientes sépticos. Dentre esses cuidados, destaca-se nesse estudo o controle da glicemia durante o quadro séptico e a relação da variabilidade glicêmica com desfecho clínico da doença. O objetivo desse estudo foi traçar o perfil sociodemográfico e clínico e verificar a variabilidade glicêmica dos pacientes com diagnóstico de sepse grave e choque séptico em uma unidade de terapia intensiva (UTI). O método do estudo teve delineamento de abordagem descritiva, exploratório, retrospectivo. Os dados foram obtidos por meio de revisão de prontuários dos pacientes internados em uma UTI para adultos, de um hospital público de cuidados terciários e diagnosticados com sepse grave ou choque séptico no ano de 2012. A variabilidade glicêmica foi avaliada por dois métodos: desvio padrão (DP) e a amplitude média das excursões glicêmicas (MAGE). Foram incluídos no estudo 116 pacientes. A caracterização sociodemográfica e clínica mostrou que a maioria dos pacientes era do sexo masculino (57,8%), com média de idade de 59 anos, 81,9% era da raça branca e 50,9% viviam em união consensual. A comorbidade prevalente foi a hipertensão arterial sistêmica (51,7%) e o tratamento cirúrgico foi a causa mais frequente de internação (55,2%). A maioria apresentou infecção de origem comunitária (66,3%), sendo os fungos leveduriformes os microrganismos mais frequentes (13,7%). A duração média da internação foi de 36,4 (DP = 27,9, mediana=31) dias. A condição dos pacientes ex-tabagistas foi associada ao óbito (p=0,004). Entre os pacientes sobreviventes a análise da glicose corporal média mostrou média de 134,6 mg/d e entre os pacientes não sobreviventes a média foi de 154,8 mg/dl. Dos pacientes não sobreviventes 39,8% apresentaram um episódio de hipoglicemia < 60 mg/dl. A ocorrência de episódios de hipoglicemia e hipoglicemia grave foi mais frequente nos pacientes não sobreviventes. Quando comparados com os pacientes não diabéticos os diabéticos apresentaram maior VG. Este estudo demonstrou características semelhantes a outros que investigaram a população crítica com diagnóstico de sepse grave e choque séptico, mostrou que apesar dos avanços no cuidado a esses pacientes, o número de óbitos continua inaceitavelmente alto. Há necessidade do controle glicêmico no paciente com sepse grave e choque séptico, a fim de evitar grande variabilidade nos valores da glicemia / Sepsis is a condition that arouses increasing interest because of the high morbidity and mortality and the socioeconomic impact of the various treatment provided to patients affected by the disease. It is assumed that the implementation of care grounded in specific guidelines could be inserted, evaluated and disseminated in the health field in order to obtain early diagnosis with greater therapeutic effectiveness while minimizing damage to health and increasing survival of septic patients. Among such care, stands out in this study glycemic control during sepsis and the relationship of glycemic variability with clinical outcome of the disease. The aim of this study was to trace the sociodemographic and clinical profile and verify glycemic variability in patients with severe sepsis and septic shock in the intensive care unit (ICU). The method of the study design was descriptive, exploratory and retrospective approach. The data were obtained through review of medical records of patients admitted to an adult ICU of a public tertiary hospital care and diagnosed with severe sepsis or septic shock in 2012 Glycemic variability was assessed by two methods. Standard deviation (SD) and the mean amplitude of glycemic excursions (MAGE). 116 patients were included in the study. The sociodemographic and clinical characterization showed that most patients were male (57.8%), mean age 59 years, 81.9% were white and 50.9% lived in a consensual union. A prevalent comorbidity was hypertension (51.7%) and surgical treatment was the most frequent cause of hospitalization (55.2%). Most patients with infection of Community origin (66.3%), and the yeast fungi the most frequent microorganisms (13.7%). The mean duration of hospitalization was 36.4 (SD = 27.9, median 31) days. The condition of former smokers was associated with death (p = 0.004). Among the surviving patients the analysis of average body glucose showed a mean 134.6 mg / from non-surviving patients, the mean was 154.8 mg / dl. Of not surviving patients 39.8% had an episode of hypoglycemia <60 mg / dl. The occurrence of hypoglycemia and severe hypoglycemia was more frequent in non-survivors. Compared with nondiabetic patients, diabetics had higher VG. This study showed similar characteristics to others who investigated the critical population with severe sepsis and septic shock, showed that despite the advances in the care of these patients, the number of deaths remains unacceptably high. There is need of glycemic control in patients with severe sepsis and septic shock, in order to avoid large variability in blood glucose values

A sepse é uma patologia que desperta interesse crescente em virtude dos altos índices de morbidade e mortalidade e pelo impacto socioeconômico decorrente dos diversos cuidados dispensados ao paciente acometido pela doença. Pressupõe-se que a implementação de cuidados específicos embasados em diretrizes poderiam ser inseridos, avaliados e difundidos no campo da saúde a fim de se obter diagnóstico precoce com maior efetividade terapêutica, minimizando danos a saúde e aumentando a sobrevida dos pacientes sépticos. Dentre esses cuidados, destaca-se nesse estudo o controle da glicemia durante o quadro séptico e a relação da variabilidade glicêmica com desfecho clínico da doença. O objetivo desse estudo foi traçar o perfil sociodemográfico e clínico e verificar a variabilidade glicêmica dos pacientes com diagnóstico de sepse grave e choque séptico em uma unidade de terapia intensiva (UTI). O método do estudo teve delineamento de abordagem descritiva, exploratório, retrospectivo. Os dados foram obtidos por meio de revisão de prontuários dos pacientes internados em uma UTI para adultos, de um hospital público de cuidados terciários e diagnosticados com sepse grave ou choque séptico no ano de 2012. A variabilidade glicêmica foi avaliada por dois métodos: desvio padrão (DP) e a amplitude média das excursões glicêmicas (MAGE). Foram incluídos no estudo 116 pacientes. A caracterização sociodemográfica e clínica mostrou que a maioria dos pacientes era do sexo masculino (57,8%), com média de idade de 59 anos, 81,9% era da raça branca e 50,9% viviam em união consensual. A comorbidade prevalente foi a hipertensão arterial sistêmica (51,7%) e o tratamento cirúrgico foi a causa mais frequente de internação (55,2%). A maioria apresentou infecção de origem comunitária (66,3%), sendo os fungos leveduriformes os microrganismos mais frequentes (13,7%). A duração média da internação foi de 36,4 (DP = 27,9, mediana=31) dias. A condição dos pacientes ex-tabagistas foi associada ao óbito (p=0,004). Entre os pacientes sobreviventes a análise da glicose corporal média mostrou média de 134,6 mg/d e entre os pacientes não sobreviventes a média foi de 154,8 mg/dl. Dos pacientes não sobreviventes 39,8% apresentaram um episódio de hipoglicemia < 60 mg/dl. A ocorrência de episódios de hipoglicemia e hipoglicemia grave foi mais frequente nos pacientes não sobreviventes. Quando comparados com os pacientes não diabéticos os diabéticos apresentaram maior VG. Este estudo demonstrou características semelhantes a outros que investigaram a população crítica com diagnóstico de sepse grave e choque séptico, mostrou que apesar dos avanços no cuidado a esses pacientes, o número de óbitos continua inaceitavelmente alto. Há necessidade do controle glicêmico no paciente com sepse grave e choque séptico, a fim de evitar grande variabilidade nos valores da glicemia / Sepsis is a condition that arouses increasing interest because of the high morbidity and mortality and the socioeconomic impact of the various treatment provided to patients affected by the disease. It is assumed that the implementation of care grounded in specific guidelines could be inserted, evaluated and disseminated in the health field in order to obtain early diagnosis with greater therapeutic effectiveness while minimizing damage to health and increasing survival of septic patients. Among such care, stands out in this study glycemic control during sepsis and the relationship of glycemic variability with clinical outcome of the disease. The aim of this study was to trace the sociodemographic and clinical profile and verify glycemic variability in patients with severe sepsis and septic shock in the intensive care unit (ICU). The method of the study design was descriptive, exploratory and retrospective approach. The data were obtained through review of medical records of patients admitted to an adult ICU of a public tertiary hospital care and diagnosed with severe sepsis or septic shock in 2012 Glycemic variability was assessed by two methods. Standard deviation (SD) and the mean amplitude of glycemic excursions (MAGE). 116 patients were included in the study. The sociodemographic and clinical characterization showed that most patients were male (57.8%), mean age 59 years, 81.9% were white and 50.9% lived in a consensual union. A prevalent comorbidity was hypertension (51.7%) and surgical treatment was the most frequent cause of hospitalization (55.2%). Most patients with infection of Community origin (66.3%), and the yeast fungi the most frequent microorganisms (13.7%). The mean duration of hospitalization was 36.4 (SD = 27.9, median 31) days. The condition of former smokers was associated with death (p = 0.004). Among the surviving patients the analysis of average body glucose showed a mean 134.6 mg / from non-surviving patients, the mean was 154.8 mg / dl. Of not surviving patients 39.8% had an episode of hypoglycemia <60 mg / dl. The occurrence of hypoglycemia and severe hypoglycemia was more frequent in non-survivors. Compared with nondiabetic patients, diabetics had higher VG. This study showed similar characteristics to others who investigated the critical population with severe sepsis and septic shock, showed that despite the advances in the care of these patients, the number of deaths remains unacceptably high. There is need of glycemic control in patients with severe sepsis and septic shock, in order to avoid large variability in blood glucose values

The main objective of this study was research on biomarkers used in both diagnosis and therapy of diabetic complications. The main focus of our work came to be on one of these biomarkers - glycemic variability (GV). High GV is linked with more frequent occurance of hypoglycemia. There are even indications it might contribute to development of diabetic complications. With modern technology - continuous glucose monitoring (CGM), we are now able to reliably describe, calculate and reduce GV. So far it is unclear whether increased GV can contribute to the development of microvascular complications (MVC) in type 1 diabetes (T1D). Studies published so far have assessed GV primarily from routine self-monitoring of blood glucose (SMBG) using glucometers. In the light of this uncertaity, the first part of this work compares GV calculated from CGM with the presence of MVC in T1D patients. GV calculated from CGM, but not from SMBG, proved to be significantly higher in T1D patients with MVC, even though there was no significant difference in glycated hemoglobin (HbA1c). This finding supports the hypothesis that higher GV is related to higher risk of MVC and that HbA1c does not describe diabetes control completely. Moreover, it was shown that GV calculated from SMBG is insufficient. There is still no fully...