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.

Green tea contains high concentrations of polyphenolic compounds known as catechins. Studies in animal models suggest several potential mechanisms for specific metabolic effects at rest and during exercise, including improved glycemic control, altered activity of several glucose transporter proteins and improved endurance capacity. In humans, green tea extract (GTE) supplementation has been associated with improved glycemic control under resting conditions and increased fat oxidation during exercise. This dissertation examined the potential interactive effects of GTE supplementation and exercise on metabolism in humans with a focus on glycemic control. In Study 1, we demonstrated that GTE increased lipolysis and reduced heart rate during steady-state exercise in recreationally active men. Although substrate oxidation was not affected, GTE appeared to lower postprandial glucose under resting conditions. We hypothesized that the effects of GTE on exercise metabolism and glycemic control would be more apparent in humans with reduced exercise tolerance and impaired glucose tolerance. Thus, in Study 2, we examined the effects of GTE in sedentary overweight men. There were no differences in any metabolic or physiological responses during exercise; however, following exercise, GTE supplementation reduced [glucose] and insulinemia in response to an oral glucose load. Based on the findings of Study 2, the aim of Study 3 was to elucidate potential mechanisms for the alterations in glycemic response. Through the use of a dual-glucose tracer method, we demonstrated that GTE did not affect the rate of appearance of glucose in plasma in sedentary men; however, GTE supplementation allowed for the same glucose clearance rate despite a reduced insulinemia. We also observed lower carbohydrate oxidation during exercise with GTE. These findings suggest that GTE has an insulin-sensitizing effect during recovery from exercise, possibly due to enhanced glucose transporter activity; however, this hypothesis warrants further investigation in humans. / Dissertation / Doctor of Science (PhD) / Tea is one of the most popular beverages in the world. Compared to other teas, green tea has a greater abundance of catechins, compounds that have been associated with health benefits particularly related to the metabolism of sugars and fats. This unique property of green tea could partly explain its longstanding medicinal role in some Asian cultures. Extensive research on green tea has increased its popularity over the past three decades. Studies involving both humans and other animals have shown improvements in weight control and glycemic control. In response to these findings green tea is often touted as having “anti-obesity” and anti-diabetic” properties. This dissertation examined the interaction between green tea extract supplementation and exercise on metabolism with a particular focus on blood sugar control. We observed that supplementation with green tea extract improved the response to sugar ingested after exercise. This finding has important implications for improving the control of ingested sugar in humans.

This group of experiments focused on relationships between diet, somatotropic axis, and growth. Growth hormone (GH) and insulin-like growth factor I (IGF-I) are factors in the somatotropic axis, and important to development of growth cartilage in the young animal. The entire study was divided into four main experiments. Characteristics of growth in 113 Thoroughbred foals born over a five year period were described with a series of empirical and physiological equations. Glycemic and insulinemic responses to different feed compositions were evaluated with glycemic response tests. The 24 hr pattern of plasma glucose, insulin, GH, and IGF-I was described in yearlings fed two meals a day. Finally, an association between ADG and IGF-I was described in Thoroughbreds from birth to 16 mo of age. Feeding diets to the foal that influence the somatotropic axis during growth may affect development of growth cartilage in unexpected or detrimental ways. The pattern of weight in Thoroughbred foals from birth to 16 mo of age was most closely described by multiple regression with a combination of age, girth, body length, and physeal circumference (R2 = 0.99). Glycemic and insulinemic responses were significantly higher in yearlings fed a sugar and starch supplement when compared to those fed a fat and fiber supplement (P = 0.043 and 0.031; respectively). Glucose and insulin secretion was significantly affected by the feeding of two meals in a 24 hr period (P < 0.0001). Plasma IGF-I was positively correlated with ADG from birth to 16 mo of age in foals fed either a fat and fiber or sugar and starch supplement (r = 0.34, P < 0.0001). The results from the series of experiments described here suggest a possible role of dietary mangement in reducing the risk of skeletal disorders that involve the influence of IGF-I on chondrocyte maturation. / Ph. D.

Carbohydrates and fats are the main fuel sources for energy production during exercise. Consumption of low glycemic index foods slows digestion and absorption in the small intestine. The slow digestibility of resistant starch containing foods contributes to the slow and sustained release of glucose into the bloodstream, minimizing occurrence of hyperinsulinemia-induced suppression of lipolysis. The objectives of this study were to determine the consumption of resistant starch (RS) by regular exercisers (Blacksburg and San Jose (SJ)); and to analyze the eating and exercise habits of the subjects. Subjects were recruited at gyms in SJ (n=27) and Blacksburg (n=26). Participants kept 3-day food records and completed a questionnaire on eating habits and physical activity. Mean body mass index for the subjects was similar (SJ: 23.06 Kg/m² ± 2.55; Blacksburg: 23.53 Kg/m² ± 3.09). Average exercise time was 12 hours/week, and > 50% engaged in weight training in addition to aerobic type exercise. Percentage contribution of carbohydrates to the total energy intake was significantly higher for SJ males (53.53% ± 8.06%) compared to Blacksburg males (48.39% ± 6.33%; alpha=0.10). Prominent RS food sources in both groups were pasta, potatoes, bananas, and corn. Rice and various legumes were more frequent in the SJ group. It appears that consumption of RS is higher among SJ subjects. Consumption of RS prior to prolonged exercise could cause stable glycemic and insulinemic responses that may help delay the onset of fatigue during exercise. / Master of Science

Carbohydrates are a major energy source for the human body and particularly glucose is the only energy source for the brain. Thus glucose metabolism is important to maintain normal brain function. Evidence showed insulin resistance and diabetes are associated with cognitive decline and a large amount of highly processed carbohydrate intake; in other words, a high glycemic load diet, which increases blood glucose faster and insulin demand, is associated with increased risk of insulin resistance and diabetes. Based on this premise, the hypothesis that a high glycemic load (GL) diet increases the risk of incident Alzheimer’s disease (AD) was examined among Cache County elderly people in Northern Utah. At the baseline survey, 3,831 participants 65 years of age or older completed a food frequency questionnaire (FFQ) and cognitive screening. Observation time to collect the data for incident AD was approximately 10 years. Incident AD was determined by final consensus conference after multi-steps of screening. GL was calculated as the product of carbohydrate intake and glycemic index (GI) and adjusted for energy intake. FFQs from diabetics were considered to be invalid to assess dietary carbohydrates intake and excluded. The analysis was examined separately by gender. The Cox proportional hazard regression model in survival analysis was used to relate GL to incident AD using a time variable with age of AD onset. There was no association in men but a negative association in women in the unadjusted model. Evidence of confounding by total kcal was apparent in women, particularly in the lowest GL group, which had the highest total kcal mean intake. Finally no association between GL and AD was found after adjustment for education, myocardial infarction (MI), stroke, Body Mass Index (BMI), physical activity, smoking, alcohol use, APOE ε-4 alleles, multi-vitamins use, total kcal, and controlling interaction between GL and total kcal. The low GL group had unique characteristics in lifestyle factors, macro-nutrients intake, and pattern of food use. The inverse relationship between GL and total kcal may partly be explained by lifestyle factors, particularly alcohol intake. The characteristics of low GL group, current smokers, alcohol users, and their relationship and interaction between total kcal and risk of AD should be explored further.

Advanced practice providers (APPs), consisting of nurse practitioners and physician assistants, face many challenges in the provision of evidence-based practice in their management of hospitalized adult patients with diabetes. Some of the barriers faced by APPs at a Northeast acute care facility are poor communication between disciplines, lack of confidence in initiating insulin, limited understanding of the management of insulin and the insulin pump, and insufficient treatment of the hospitalized patient with diabetes that aligns with current clinical guidelines for the management of inpatient hyperglycemia. This quality improvement project focused on the development of an evidence-based theory supported educational intervention to improve APPs' knowledge regarding glycemic management. An interdisciplinary team created the educational intervention using the analyze, design, develop, implement, and evaluate (ADDIE) instructional model. A 10-member expert panel validated the program utilizing both a formative and summative evaluation. The results from the formative evaluation was discussed with the interdisciplinary team, corrections were made, and was returned to the expert panel. Once the changes were made to the satisfaction of the expert panel, the program was then validated and submitted to the institution as a completed project to be used by the institution for APPs. This project addresses social change by increasing awareness in the management of inpatients with diabetes therefore decreasing fragmented care delivered by the APPs which will improve quality of care and patient safety.

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

Glycemic intake influences the rise in blood glucose concentration following consumption of a carbohydrate containing meal, known as the postprandial glycemic response. The glycemic response is a result of both the type and amount of carbohydrate foods consumed and is commonly measured as the glycemic index (GI) or glycemic load (GL), where the GI is a ranking in comparison to glucose and the GL is an absolute value encompassing both the GI and amount of carbohydrate consumed. Evidence from controlled trials in rat models suggests that glycemic intake has a role in development of insulin resistance, however trials and observational studies of humans have produced conflicting results. As insulin resistance is a precursor to type 2 diabetes mellitus, lifestyle factors that could prevent development of this condition have important public health implications. Previous observational studies have used food frequency questionnaires to assess usual diet, which could have resulted in a lack of precision in assessment of individual serve sizes, and have been limited to daily measures of glycemic intake. Daily measures do not take fluctuations in glycemic intake on a per meal basis into account, which may be a more relevant measure for investigation in relation to disease outcomes. This PhD research was conducted in a group of Brisbane women aged 42 to 81 years participating in the multidisciplinary Brisbane Longitudinal Assessment of Ageing in Women (LAW study). Older women may be at particular risk of insulin resistance due to age, hormonal changes, and increases in abdominal obesity associated with menopause, and the LAW study provided an ideal opportunity to study the relationship between diet and insulin resistance. Using the diet history tool, we aimed to assess the glycemic intake of the population and hypothesised that daily GI and daily GL would be significantly positively associated with increased odds of insulin resistant status. We also hypothesised that a new glycemic measure representing peaks in GL at different meals would be a stronger predictor of insulin resistant status than daily measures, and that a specially designed questionnaire would be an accurate and repeatable dietary tool for assessment of glycemic intake. To address these hypotheses, we conducted a series of studies. To assess glycemic intake, information on usual diet was obtained by detailed diet history interview and analysed using Foodworks and the Australian Food and Nutrient (AUSNUT) database, combined with a customised GI database. Mean ± SD intakes were 55.6 ± 4.4% for daily GI and 115 ± 25 for daily GL (n=470), with intake higher amoung younger participants. Bread was the largest contributor to intakes of daily GI and GL (17.1% and 20.8%, respectively), followed by fruit (15.5% and 14.2%, respectively). To determine whether daily GI and GL were significantly associated with insulin resistance, the homeostasis model assessment of insulin resistance (HOMA) was used to assess insulin resistant status. Daily GL was significantly higher in subjects who were insulin resistant compared to those who were not (134 ± 33 versus 114 ± 24 respectively, P<0.001) (n=329); the odds of subjects in the highest tertile of GL intake being insulin resistant were 12.7 times higher when compared with the lowest tertile of GL (95% CI 1.6-100.1, P=0.02). Daily GI was not significantly different in subjects who were insulin resistant compared to those who were not (56.0 ± 3.3% versus 55.7 ± 4.5%, P=0.69). To evaluate whether a new glycemic measure representing fluctuations in daily glycemic intake would be a stronger predictor of insulin resistant status than other glycemic intake measures, the GL peak score was developed to express in a single value the magnitude of GL peaks during an average day. Although a significant relationship was seen between insulin resistant status and GL peak score (Nagelkerke’s R2=0.568, P=0.039), other glycemic intake measures of daily GL (R2=0.671, P<0.001) and daily GL per megajoule (R2=0.674, P<0.001) were stronger predictors of insulin resistant status. To develop an accurate and repeatable self-administered tool for assessment of glycemic intake, two sub-samples of women (n=44 for the validation study and n=52 for the reproducibility study) completed a semi-quantitative questionnaire that contained 23 food groupings selected to include the top 100 carbohydrate foods consumed by the study population. While there were significant correlations between the glycemic intake questionnaire and the diet history for GL (r=0.54, P<0.01), carbohydrate (r=0.57, P<0.01) and GI (r=0.40, P<0.01), Bland-Altman plots showed an unacceptable difference between individual intakes in 34% of subjects for daily GL and carbohydrate, and 41% for daily GI. Reproducibility results showed significant correlations for daily GL (r=0.73, P<0.001), carbohydrate (r=0.76, P<0.001) and daily GI (r=0.64, P<0.001), but an unacceptable difference between individual intakes in 25% of subjects for daily GL and carbohydrate, and 27% for daily GI. In summary, our findings show that a significant association was observed between daily glycemic load and insulin resistant status in a group of older women, using a diet history interview to obtain precise estimation of individual carbohydrate intake. Both the type and quantity of carbohydrate are important to consider when investigating relationships between diet and insulin resistance, although our results suggest the association is more closely related to overall daily glycemic intake than individual meal intake variations. A dietary tool that permits precise estimation of carbohydrate intake is essential when evaluating possible associations between glycemic intake and individual risk of chronic diseases such as insulin resistance. Our results also suggest that studies using questionnaires to estimate glycemic intake should state degree of agreement as well as correlation coefficients when evaluating validity, as imprecise estimates of carbohydrate at an individual level may have contributed to the conflicting findings reported in previous studies.

Hyperglycemia is prevalent in critical care, as patients experience stress-induced hyperglycemia, even with no history of diabetes. Hyperglycemia has a significant impact on patient mortality and other negative clinical outcomes such as severe infection, sepsis and septic shock. Tight glycemic control can significantly reduce these negative outcomes by reducing hyperglycemic episode, but achieving it remains clinically elusive, particularly with regard to what constitutes tight control and what protocols are optimal in terms of results and clinical effort. The model used in this thesis is validated using an independent data and readily be used for different clinical interventions. Moreover, this model also able to accurately predict clinical intervention outcomes given that the model prediction error is very small, which is better than any other reported model. In particular, model-based glycemic control methods is used to capture patient-specific physiological dynamics, such as insulin sensitivity, SI. To date, sepsis diagnosis has been a great challenge despite advancement in technologies and medical research. Critically, septic patients are often classified by practitioners according to their experience before standard test results can be assessed, as to avoid delay in treatment. Moreover, several scoring systems have also been widely used to represent sepsis condition and better standardization of sepsis definition across different centers. In this thesis, insulin sensitivity, SI, a model-based metric is used to identify sepsis condition based on the finding that SI represents metabolic condition of a patient. Additionally, several clinical and physiological variables obtained during patient’s stay in critical care are also investigated using mathematical computation and statistical analysis to identify relevant metric which can be accurately use for sepsis interventions. Even though information on SI, clinical and physiological variables of a patient are insufficient to determine the sepsis status, these informations have brought to a different perspective of diagnosing sepsis. Microcirculation dysfunction is very common in sepsis. Tracking of microcirculation state among septic patient enable better tracking of patient state particularly sepsis status. The tracking can potentially be done by using a pulse oximeter that can extract additional information related to oxygen extraction level. The processed signals are therefore represent relative absorption of oxyhemoglobin and reduced hemoglobin that can be used to assess microcirculation status. In addition, this thesis focus on the real challenge of early treatment of sepsis and sepsis diagnosis where several potential metabolic markers are investigated. Microcirculation conditions are assessed using a non-invasive method that is generally used in typical ICU settings. In particular, the concept and method used to assess microcirculation and metabolic conditions are developed in this thesis. Finally, the work presented in this thesis can act as a starting point for many other glycemic control problems in other environments. These areas include cardiac critical care and neonatal critical care that share most similarities to the environment studied in this thesis, to general diabetes where the population is growing exponentially world wide. Eventually, this added knowledge can lead clinical developments from protocol simulations to better clinical decision making.

Class of 2010 Abstract / OBJECTIVES: To evaluate glycemic control, therapy associated weight loss/gain, and hypoglycemic events for the newer type 2 diabetic agents pramlintide, exenatide, and sitagliptin. METHODS: The meta-analysis examined the efficacy of three currently FDA approved peptide analogues in nonpregnant adults with type 2 diabetes mellitus. All randomized, placebo controlled trials of exenatide, pramlintide, and sitagliptin that were indexed in MEDLINE or and the Cochrane Database of Systematic Reviews that fit the inclusion criteria were included. The drug treatment efficacy was analyzed in terms of HbA1c (glycosylated hemoglobin) change from baseline compared to placebo in trials lasting at least 12 weeks. Weight change from baseline per treatment group was also a primary measure. The safety of the treatments was assessed in terms of number of hypoglycemic events noted in the clinical trials. Each of these dependent variables was assessed separately for the three products. RESULTS: The meta-analysis of the six exenatide articles included in the analysis found statistically significant reductions in both HbA1c and weight when compared to placebo. However, patients were three times as likely to experience hypoglycemia with exenatide than placebo (RR= 3.01 95%CI[0.427 to 3.865]). Meta-analysis of pramlintide studies showed statistically significant lowering of HbA1c and weight. Overall pramlintide resulted in a rate of hypoglycemia nearly equal to that of placebo (RR= 0.94 95%CI[0.699 to 1.265]). Meta-analysis of sitagliptin found statistically significant reductions in HbA1c compared to placebo. However, sitagliptin use was not associated with a reduction in weight in the random effects meta-analysis model. In terms of hypoglycemic events, sitagliptin use was associated with 2.89 times greater risk of causing hypoglycemic episodes compared to placebo (RR=2.89 95%CI[0.704 to 5.877]). CONCLUSIONS: All three newer products were associated with improved glycemic control compared to placebo. Improvement in weight was associated with exenatide and pramlintide treatment. Pramlintide was not associated with an increase in hypoglycemic episodes.