ABSTRACT Diabetes Mellitus (DM) embraces a group of metabolic diseases which main characteristic is the presence of high glucose levels in blood. It is one of the diseases with major social and health impact, both for its prevalence and also the consequences of the chronic complications that it implies. One of the research lines to improve the quality of life of people with diabetes is of technical focus. It involves several lines of research, including the development and improvement of devices to estimate "online" plasma glucose: continuous glucose monitoring systems (CGMS), both invasive and non-invasive. These devices estimate plasma glucose from sensor measurements from compartments alternative to blood. Current commercially available CGMS are minimally invasive and offer an estimation of plasma glucose from measurements in the interstitial fluid CGMS is a key component of the technical approach to build the artificial pancreas, aiming at closing the loop in combination with an insulin pump. Yet, the accuracy of current CGMS is still poor and it may partly depend on low performance of the implemented Calibration Algorithm (CA). In addition, the sensor-to-patient sensitivity is different between patients and also for the same patient in time. It is clear, then, that the development of new efficient calibration algorithms for CGMS is an interesting and challenging problem. The indirect measurement of plasma glucose through interstitial glucose is a main confounder of CGMS accuracy. Many components take part in the glucose transport dynamics. Indeed, physiology might suggest the existence of different local behaviors in the glucose transport process. For this reason, local modeling techniques may be the best option for the structure of the desired CA. Thus, similar input samples are represented by the same local model. The integration of all of them considering the input regions where they are valid is the final model of the whole data set. Clustering is t / Barceló Rico, F. (2012). Multimodel Approaches for Plasma Glucose Estimation in Continuous Glucose Monitoring. Development of New Calibration Algorithms [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/17173

Type 1 diabetes is one of the most common chronic conditions in childhood and adolescence. Despite ongoing development of more physiological insulin preparations, recent advancements in insulin pump technology and more accurate blood glucose monitoring, in clinical practice it remains challenging to achieve normoglycaemia whilst reducing the risk of hypoglycaemia, particularly in young people with type 1 diabetes. Closed-loop insulin delivery (the artificial pancreas) is an emerging technology gradually progressing from bench to clinical practice. Closed-loop systems combine glucose sensing with computer-based algorithm informed insulin delivery to provide real-time glucose-responsive insulin administration. The key objective of my thesis is to evaluate the safety, efficacy and utility of closed-loop insulin delivery in children and adolescents with type 1 diabetes outside of the research facility setting. Results of five clinical trials are presented in the main chapters of this thesis. In a mechanistic study, the impact of glucose sensor operation duration on efficacy of overnight closed-loop was investigated comparing closed-loop performance on day 1 of sensor insertion to day 3 to 4 of sensor. Twelve adolescents with type 1 diabetes attended the research facility for two overnight visits. The sequence of the interventions was random. Despite differences in sensor accuracy, overnight CL glucose control informed by sensor glucose on day 1 or day 3-4 after sensor insertion was comparable. The model predictive controller appears to mitigate against sensor inaccuracies. In home settings, overnight closed-loop application was evaluated over three months in 25 children and adolescents with type 1 diabetes aged six to 18 years. The study was conducted at three centres in the UK and adopted a randomised cross-over design. Compared to sensor-augmented pump therapy, overnight home use of closed-loop increased the proportion of time sensor glucose was in target, and reduced mean glucose and hypoglycaemia. Two randomised crossover studies evaluated the safety and efficacy of day-and-night hybrid closed-loop insulin delivery in young people with type 1 diabetes aged 10 to 18 years over seven days, and 21 days, respectively. A total of 24 subjects were enrolled in this single centre trial. Free-living home use of day-and-night closed-loop in suboptimally controlled adolescents with type 1 diabetes was safe, and improved glucose control without increasing the risk of hypoglycaemia. Finally, closed-loop technology was assessed in five very young children (aged one to seven years) with type 1 diabetes in a two-period, crossover study. Closed-loop was used during both 3-week intervention periods, either with standard strength insulin (U100), or with diluted insulin (U20). The order of intervention was random. Free-living home use of day-and-night hybrid closed-loop in very young children with type 1 diabetes was feasible and safe. Glucose control was comparable during both intervention periods. Thus, use of diluted insulin during closed-loop insulin delivery might not be of additional benefit in this population. In conclusion, studies conducted as part of my thesis demonstrate that use of hybrid closed-loop insulin delivery systems in children and adolescents aged one to 18 years in free daily living without remote monitoring or supervision is feasible, safe and effective. My work supports the progression of this technology from research to mainstream clinical practice.

Introduktion Diabetes Mellitus typ 1 är en autoimmun sjukdom som så småningom leder till total insulinbrist vilket är livshotande. Insulinbristsjukdomen är kronisk och är i Sverige en av de vanligaste folksjukdomarna. I världen insjuknar i dagsläget flest antal i Sverige och Finland. Vad gäller behandling vid Diabetes Mellitus typ 1 får alla patienter i dagsläget insulininjektioner antingen via insulinpenna eller via insulinpump. Glukosnivån i blodet bör mätas kontinuerligt för att kunna optimera behandlingsterapin. En annan typ av behandlingsterapi vid Diabetes Mellitus typ 1 är SAP (Sensor- augmented pump). Denna metod innebär att insulinpumpsbehandling kombineras med kontinuerlig glukosmätning (continuous glucose monitoring, CGM).Att mäta glykerat hemoglobin (HbA1c) har blivit en viktig del för att följa samt utvärdera hur behandlingen av Diabetes Mellitus fungerar. Ett lågt HbA1c ger en minskad risk för komplikationer och är ett tydligt mål i behandlingen samtidigt som risken för hypoglykemi måste tas i anspråk. Syfte Syftet med denna litteraturstudie är att undersöka om HbA1c-värden kan förbättras hos patienter med Diabetes Mellitus typ 1 vid användning av SAP-behandlingsterapi jämfört med CSII-behandlingsterapi (continuous subcutaneous insulin infusion) kombinerat med SMBG (self monitoring of blood glucose) och MDI-behandlingsterapi (multiple daily injections) kombinerat med SMBG. Syftet är även att undersöka om det finns något samband mellan användningsfrekvens av CGM-sensorer och förbättrat HbA1c-värde. Metod Denna litteraturstudie baseras på åtta stycken artiklar som hittades via databasen PubMed. Resultat och diskussion Resultatet, av de utvalda originalstudierna, visar att SAP-behandlingsterapi har en bättre effekt på optimering av HbA1c-värden, hos patienter med Diabetes Mellitus typ 1, om det jämförs med MDI-behandlingsterapi kombinerat med SMBG. Om förbättringen beror på SAP-terapibehandlingen eller om CSII och CGM separat hade gett effekten är svårt att avgöra. Däremot ses ingen signifikant skillnad, i resultatet i de originalstudier som valts ut, av denna effekt vid jämförelse av SAP-behandlingsterapi mot CSII kombinerat med SMBG. Ytterligare studier med ett större antal deltagare behövs som underlag för att kunna avläsa detta. Vad gäller relationen mellan frekvens av CGM-sensoranvändning och förändring i HbA1c-värden finns både studier som stödjer och studier som förkastar. Vid ett eventuellt byte av behandlingsterapi bör hänsyn tas till andra aspekter än surrogatmåttet HbA1c. Slutsats Resultatet av denna litteraturstudie visar att SAP-behandlingsterapi i vissa fall kan reducera HbA1c-värden i jämförelse med andra metoder. En del resultat stödjer även sambandet mellan ökad användningsfrekvens av CGM-sensorer och reducering av HbA1c-värden. Det måste tas hänsyn till andra parametrar vid eventuellt byte av behandlingsterapi. Det är av stor vikt att patienterna känner sig tillfreds med sin behandlingsterapi då det kan bibehålla motivationen till att optimera sina HbA1c-värden.

Introduction: The main goal of the diabetes mellitus type 1 (DM type 1) therapy is the achievement of the best compensation of this disease. One of the tools to attain this compensation is the correctly carried out self-monitoring, from which can be the right dose of the Insulin derived. To estimate the correct dose of the Insulin is the essential knowledge of the actual dietary records, especially the amount of the carbohydrates. The thorough dietary record is in this case another tool how to significantly improve the compensation of DM type 1. Objective: The main objective of this thesis was the description of the influence of the dietary record for the compensation of DM type 1. As the evaluating parameters were set the value of HbA1c before-and-after the observation and the glycemia variability during the observation. The observation had been provided during one month where in the beginning of the observation all patients took part in the educative stay. Methods: The examined sample included in total 34 persons, but 2 of them were excluded for health reasons. The final examined sample was consist of 32 persons, out of them 18 females and 14 males, which suffer from DM type 1. The average age of these patients was 36,6 years ± 12,6, where the average lasting of DM type 1 was 14,9 years ± 9,9. In...

Ziel: In der vorliegenden Studie wurden kontinuierliche Blutzuckertagesprofile über 48 h bei Schwangeren unterschiedlicher Glukosetoleranz erhoben und mit der Ernährung zu häuslichen Bedingungen verglichen. Ergebnisse: Bei den Gestationsdiabetikerinnen wurden statistisch signifikant länger Konzentrationen über 130 mg/dl gemessen als bei den gesunden Schwangeren. Keine Unterschiede ergaben sich in Bezug auf folgende Werte: Mittelwert, Zeitdauern mit Blutzuckerwerten < 50 mg/dl, >120 mg/dl, >140 mg/dl, >150 mg/dl. Periprandial wurden bei den Gestationsdiabetikerinnen und den Schwangeren mit IGT signifikant höhere Maximalwerte im Anschluss an die Mahlzeit gemessen, als bei gesunden Schwangeren. Keine Unterschiede ergaben sich hinsichtlich der Anfangswerte und der Area under the curve. In einigen Gruppen bestanden positive Korrelationen zwischen der Zufuhr von Disacchariden und Parametern der Glukosemessung, in der Gruppe der Gestationsdiabetikerinnen bestand eine signifikante negative Korrelation zwischen dem Stärkekonsum und dem Mittelwert der Glukosemessung. Nach Mahlzeiten, deren Hauptkohlenhydratquelle mit einem höheren glykämischen Index nach Jenkins attribuiert war, fiel die Glukosereaktion größer aus, als bei Mahlzeiten mit niedrigem glykämischem Index. Zusammenfassung: In dieser prospektiven Studie konnte mit Hilfe der Technik der kontinuierlichen Glukosemessung die Verbindung zwischen Blutzuckertagesprofil und Ernährungsgewohnheiten zu häuslichen- also nicht klinisch- artifiziellen- Bedingungen hergestellt werden. / Objective: In the present study continuous glucose profiles in pregnant women with various levels of glucose tolerance were evaluated and compared with their diet in domestic conditions. Results: In women with GDM significantly longer periods with glucose levels above 130 mg/dl were measured than in healthy women. No differences were assessed as to average glucose levels and periods with glucose levels < 50 mg/dl, >120 mg/dl, >140 mg/dl, >150 mg/dl. In pregnant women with gestational diabetes or impaired glucose tolerance higher maximum glucose levels after a meal were found than in healthy women. No differences were found as to glucose levels at the beginning of the meal and area under the curve. In some groups positive correlations were calculated between intake of disaccharides and the glucose measurement, in gestational diabetic women a negative correlation between intake of starch and the average of the glucose level was found. After meals in which the main carbohydrate source was attributed with a high glycemic index change of the glucose level was higher than after meals with a low glycemic index. Conclusion: In the present prospective study we established the relation between glucose profiles measured by the method of continuous glucose monitoring and dietary habits in domestic conditions in pregnant women.

Der Gestationsdiabetes ist eine der häufigsten Erkrankungen in der Schwangerschaft. Obwohl der Zusammenhang zwischen den Blutzuckerwerten und der Morbidität der Schwangeren und des Kindes hinreichend belegt ist, gibt es bemerkenswert viele klinisch relevante Fragen, die bisher nur unzureichend untersucht wurden. Die vorliegende Arbeit beschäftigt sich mit einigen Fragestellungen aus diesem Themenbereich, unter Einbeziehung einer neuen Methode der Glukosemessung, der kontinuierlichen Glukosemessung. In Deutschland wird in der Schwangerschaft lediglich ein Urin-Stix als Screening-Methode auf Gestationsdiabetes durchgeführt. Die wenigen Publikationen, die sich mit der Sensitivität des Urin-Stix zur Detektion des Gestationsdiabetes beschäftigen, zeigen eine nur geringe Sensitivität. Die in unserem Hause durchgeführte Untersuchung an 1001 Schwangeren bestätigt die bisherigen Ergebnisse an einer großen Fallzahl und weist zudem noch eine deutliche Abhängigkeit der Glukosurie-Rate von den diastolischen Blutdruckwerten nach. Eine weitere Untersuchung wurde zu dem 50-g-Glukose-Screeningtests durchgeführt, den wir seit 1993 routinemäßig bei allen Schwangeren durchführen, die sich in unserer Klinik vorstellen. Mit einer Sensitivität und Spezifität von ca. 90% - bezogen auf den oralen Glukosetoleranztest - zeigte dieser Test ein gutes Ergebnis, allerdings fanden wir heraus, dass die Rate positiver Ergebnisse von dem Zeitpunkt der vorangegangenen Mahlzeit abhängig ist und zwischen 11%-40% liegt. Bisher konnte kein Nachweis erbracht werden, dass die einem oralen Glukosetoleranztest (oGTT) vorangehende Kohlenhydratzufuhr bei Schwangeren einen Einfluss auf die Ergebnisse hat, wie es die Empfehlungen der Fachgesellschaften vermuten. In der von uns durchgeführten Studie, bei der wir - im Gegensatz zu den anderen Studien - detallierte Ernährungsprotokolle verwendeten, konnte diese Vermutung bestätigt werden. Aufgrund erhöhter Konzentrationen an Gestagen, Östrogenen und dem humanen Plazentalaktogen wurde häufig vermutet, dass Schwangere mit Gemini eher einen Gestationsdiabetes haben müssten. Wir konnten dies in einer Matched-Pair-Studie widerlegen. Die kontinuierliche Glukosemessung erlaubte neue Einblicke in die Physiologie und Pathophysiologie der Schwangerschaft. Nachdem wir zunächst ein Auswertungsverfahren etabliert hatten, wurden Schwangere mit und ohne Glukosetoleranzstörung mit Hilfe des kontinuierlichen Glukosemonitors der Fa. MedtronicMinimed (CGMS) untersucht. Es zeigte sich, dass das CGMS eine deutlich bessere Differenzierung zwischen den Gesunden und den Schwangeren mit eingeschränkter Glukosetoleranz ermöglichte, dies im Gegensatz zum konventionellen Blutzuckertagesprofil. In einer weiteren Auswertung untersuchten wir den Zusammenhang zwischen der mütterlichen sowie der neonatalen Morbidität und den einzelnen postprandialen Messzeitpunkten. Es zeigten sich signifikante Unterschiede der Glukosewerte für die Schwangerschaftsausgangsparameter Entbindungsmodus, Makrosomie und fetale Verlegungsrate im postprandialen Zeitintervall von 45-105 Minuten. Erstmalig konnten wir so die Assoziation zwischen neonatalen Morbiditäten und den postprandialen Glukosekonzentrationen zu verschiedenen Messzeitpunkten nachweisen. / Gestational diabetes is the most common complication during pregnancies. Although the correlation has been clearly established between blood glucose levels and morbidity rates for both mothers and babies, there are surprisingly many clinically relevant questions that still have not been adequately addressed. The study presented here investigates some aspects of this topic, using a new method for measuring blood sugar levels, continuous glucose measurement. In Germany, the only screening method normally used to test pregnant women for gestational diabetes is a urine test strip. The few publications that deal with the sensitivity of urine test strips for detecting gestational diabetes show only minimal sensitivity. The study carried out in our clinic with a large number of test cases (1001 pregnant women) confirmed previous findings and demonstrates that the glucosuria rate directly corresponds to diastolic blood pressure values. An additional appraisal was made of the 50-gram glucose screening tests which we have routinely carried out on all pregnant women visiting our clinic since 1993. With a sensitivity and specificity of approx. 90% - as compared to the oral glucose test – this screening method yielded good results; however, we did notice that the interval since the most recent meal influences the positive outcome rate, which ranges from 11 % - 40 %. Up to the present, no one has been able to prove that eating carbohydrates before an oral glucose tolerance test (oGTT) influences the results, a belief often found in experts’ recommendations for pregnant women. However, our study, in which the pregnant women – unlike other studies – kept detailed food journals, did indeed confirm this hypothesis. Based on the higher concentrations of gestagen, estrogen and the human placenta lactogen, researchers often presume that mothers carrying twins are more likely than other expectant mothers to have gestational diabetes. Using a matched-pair-study, we refuted this idea. Continuous glucose testing allows new insights into the physiology and pathophysiology of pregnancy. After establishing an analytical procedure, we examined pregnant women both with and without glucose tolerance dysfunction using the continuous glucose monitors (CGMS) made by MedtronicMinimed. We demonstrated that the CGMS - as opposed to a conventional daily log of blood glucose values - provided markedly better differentiation between healthy women and those with impaired glucose tolerance. In a further analytical step, we studied the correlation between postprandial testing intervals and maternal and infant morbidity rates. Corresponding to the pregnancy parameters birth method, macrosomia and fetal transferral rate, significant differences were seen when glucose levels monitored 45 - 105 minutes after a meal were compared. For the first time, it was possible to demonstrate a clear correlation between postprandial glucose concentrations checked at various intervals and neonatal morbidity.

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...

Title: Mountain tourism for diabetics with an insulin pump Objectives: The aim of this study is to find out whether it is suitable for patients with type 1 diabetes mellitus treated with an insulin pump to undergo physical activity in the form of mountain tourism, as the more intense physical aktivity affects blood glucose levels and whether patients are able to work with advanced insulin pump functions. Methods: The work is conceived as an observational study of the Medtronic educational project. One day mountain hike trip of a distance about 30 km was attended by 40 patients (men and women) with diabetes aged 15-25 years. Non-invasive methods were used. The data was obtained by monitoring insulin pump probes, glucometers and continuous monitoring, which were further evaluated using the CareLink Pro software. Results: Physical activity in the form of mountain tourism is suitable for patients with DM1 treated on an insulin pump. 80% of the probands did not have a risk status of hypoglycaemia, and even though the determined normoglycemia for research was performed by a larger number of adults as opposed to children, this FA has a demonstrable effect on blood glucose levels. It also brings positive benefits for patients because they learn how to work better with advanced insulin pump functions....

The aim of this thesis is to contribute to the clarification of the pathogenesis of chronic complications of diabetes mellitus. The main goal of the research was glycaemic variability, its contribution to the activation of oxidative stress and its possible role in the process of advanced glycation, all beyond the scope of persistent hyperglycaemia itself. Another aim of the work is to contribute to the clarification of a possible relationship between glycaemic variability and vascular complications of diabetes. We were the first to describe the association between the concentrations of reactive aldehydes formed during lipid peroxidation and disorders of skin microvascular reactivity in patients with type 1 diabetes (DM1). Elevated markers of oxidative stress were found in this group, furthermore during the 3 years of follow-up higher plasma antioxidant activity was observed. These findings were not dependent of the method of glucose monitoring and glucose variability, which was lower in a subgroup of patients using real-time continuous glucose monitoring (rt-CGM), compared to a subgroup using conventional glucometers. However, it is clear, that hyperglycaemia alone induces increased oxidative stress in patients with diabetes. Simultaneously we observed the opposite process of oxidative stress...

Objectif : Déterminer la fiabilité et la précision d’un prototype d’appareil non invasif de mesure de glucose dans le tissu interstitiel, le PGS (Photonic Glucose Sensor), en utilisant des clamps glycémiques multi-étagés. Méthodes : Le PGS a été évalué chez 13 sujets avec diabète de type 1. Deux PGS étaient testés par sujet, un sur chacun des triceps, pour évaluer la sensibilité, la spécificité, la reproductibilité et la précision comparativement à la technique de référence (le Beckman®). Chaque sujet était soumis à un clamp de glucose multi-étagé de 8 heures aux concentrations de 3, 5, 8 et 12 mmol/L, de 2 heures chacun. Résultats : La corrélation entre le PGS et le Beckman® était de 0,70. Pour la détection des hypoglycémies, la sensibilité était de 63,4%, la spécificité de 91,6%, la valeur prédictive positive (VPP) 71,8% et la valeur prédictive négative (VPN) 88,2%. Pour la détection de l’hyperglycémie, la sensibilité était de 64,7% et la spécificité de 92%, la VPP 70,8% et la VPN : 89,7%. La courbe ROC (Receiver Operating Characteristics) démontrait une précision de 0,86 pour l’hypoglycémie et de 0,87 pour l’hyperglycémie. La reproductibilité selon la « Clark Error Grid » était de 88% (A+B). Conclusion : La performance du PGS était comparable, sinon meilleure que les autres appareils sur le marché(Freestyle® Navigator, Medtronic Guardian® RT, Dexcom® STS-7) avec l’avantage qu’il n’y a pas d’aiguille. Il s’agit donc d’un appareil avec beaucoup de potentiel comme outil pour faciliter le monitoring au cours du traitement intensif du diabète. Mot clés : Diabète, diabète de type 1, PGS (Photonic Glucose Sensor), mesure continue de glucose, courbe ROC, « Clark Error Grid». / Objective: To determine the reliability and precision of a prototype of a non-invasive device for continuous measurement of interstitial glucose, the PGS (Photonic Glucose Sensor), using multi-level glycaemic clamp. Methods: The PGS was evaluated in 13 subjects with type 1 diabetes. Two PGS were tested with each subject, one on each triceps, to evaluate the sensitivity, specificity, reproducibility and accuracy compared to the reference technique, the glucose analyzer Beckman®. Each subject was submitted to a multi-level 8 hour glucose clamp at 3, 5, 8 and 12 mmol / L, 2 hours each. Results: The correlation between the PGS and the Beckman® was 0.70. For the detection of hypoglycaemia, the sensitivity was 63.4%, the specificity 91.6%, the positive predictive value (PPV) 71.8% and the negative predictive value (NPV) 88.2%. For the detection of hyperglycaemia, the sensitivity was 64.7% the specificity 92%, the PPV 70.8% and the NPV: 89.7%. The ROC (Receiver Operating Characteristics) curve showed an accuracy of 0.86 and 0.87 for hypoglycaemia and hyperglycaemia respectively. Reproducibility according to the Clark Error Grid was 88% in the A and B zone. Conclusion: The performance of the PGS was comparable or better than other continuous glucose monitoring devices on the market (Freestyle® Navigator, Medtronic Guardian® RT, Dexcom® STS-7) with the advantage that it has no needle. It is therefore an interesting device and hopefully, which could facilitate the monitoring in the intensive treatment of diabetes. Key words: Diabetes, type 1 diabetes, PGS (Photonic Glucose Sensor), ROC curve, Clark Error Grid, continuous glucose monitoring, CGMS.