O diabetes mellitus (DM) é uma doença que está associada com aumento da morbidade, mortalidade e custos econômicos. O DM tipo 2 é a forma de diabetes mais comum, acometendo 85%-90% de todos os casos. O mau controle glicêmico é um fator determinante do desenvolvimento e progressão das complicações do DM. A hemoglobina glicada (A1C) se tornou a medida de referência para o controle de DM por mais de duas décadas. Existe um grande incentivo, tanto da perspectiva de saúde pública quanto da clínica, em detectar pessoas com risco futuro de desenvolver DM2, pois este é um forte fator de risco para doença cardiovascular. Também existem evidências que é possível prevenir ou retardar o DM nas pessoas com tolerância a glicose diminuída, desde que estes casos sejam identificados e tratados adequadamente. Os testes disponíveis hoje para o diagnóstico do DM, glicemia de jejum (GJ) e teste oral de tolerância à glicose (TOTG), carecem de sensibilidade e/ou especificidade. Recentes estudos têm evidenciado que a A1C pode ser uma nova ferramenta para diagnóstico do DM, sendo que diversos pontos de corte tem sido estudados. Maiores investigações para a validação do desempenho diagnóstico deste teste na predição do DM são necessárias para podermos utilizar esta ferramenta com segurança na triagem e diagnóstico do DM. / Diabetes mellitus (DM) is a disease associated with greater mortality and economical costs. Type 2 DM is the commonest form of DM, accounting for 85-90 % of its cases. Glycemic levels are a determinant factor for the development and progression of DM complications. Glycated hemoglobin (A1C) became the reference measure of glycemic control for more than two decades. There is a great incentive in detecting persons with future risk of developing DM, because this is a strong risk factor for cardiovascular disease. Also there are evidences that it is possible to prevent or to delay DM in persons with prediabetes, since identified and treated appropriately. Available tests for DM diagnosis, fasting glycemia (FG) and oral glucose tolerance test (OGTT), lack sensibility and/or specificity. Recent studies have shown that A1C can be a new tool for DM diagnosis and several cutoff points have been analyzed. However, the validation of this test as diagnostic modality to detect DM might be necessary in order to provide a useful tool for DM diagnosis.

A prevalência de diabetes mellitus (DM) está aumentando constantemente em todo o mundo a uma taxa alarmante. Devido às suas complicações que causam uma maior morbidade, invalidez e mortalidade, o DM representa um enorme problema para a saúde pública. Com isso, ações, tanto em diagnóstico como em tratamento, são necessárias para desacelerar a tendência atual e prevenir o desenvolvimento das complicações do DM. Recentemente, a hemoglobina glicada (HbA1c) foi introduzida nos critérios diagnósticos de DM. Os resultados de HbA1c são igualmente apropriados para o diagnóstico, apesar de não necessariamente detectarem DM nos mesmos indivíduos detectados pelos critérios de glicemia. No entanto, os níveis de HbA1c podem ser influenciados por qualquer condição que altere a vida útil dos eritrócitos e metabolismo da hemoglobina, independentemente da glicemia, resultando em erro diagnóstico neste grupo da população com estas condições. Além disso, estudos epidemiológicos revelaram que a glicemia pós-prandial tem um maior risco de causar complicações cardiovasculares em relação à hiperglicemia persistente e pode ser acessada com precisão usando a albumina glicada (AG) e não a HbA1c. Nesse contexto, estudos recentes têm evidenciado que a AG pode ser um marcador para diagnóstico do DM e também ser utilizado como um marcador alternativo à HbA1c para o controle glicêmico. No entanto, esses estudos, foram realizados apenas na população asiática e podem não ser aplicáveis a outros grupos étnicos. Por isso, mais investigações para a validação do desempenho diagnóstico da AG na predição do DM em diferentes grupos etnicos são necessárias. Neste estudo avaliamos o desempenho da AG no diagnóstico do DM em 242 indivíduos brasileiros com idade média de 54,4 anos (+ 13,0). Baseando-se nos valores de glicose plasmática durante o teste oral de tolerância à glicose (TOTG), o DM foi detectado em 31,8%. AG ≥16,8% apresentou acurácia similar para a detecção de DM conforme definido por HbA1c >6,5%. O uso da razão glicemia de 2h pós-sobrecarga de 75g de glicose (2hPG) e AG (2hPG/AG) melhora a sensibilidade, reduz o número de diagnósticos incorretos por AG ou HbA1c >6,5% e possui um acurácia comparável ao TOTG, indicando que o uso de uma estratégia aplicando a razão da glicemia pós-prandial (GPP) real e AG (GPP/AG) pode ser mais conveniente para pacientes e aumentar o desempenho diagnóstico do teste. Estudos para validar esta estratégia são necessários. / The prevalence of diabetes mellitus (DM) is constantly increasing worldwide at an alarming rate. Due to its complications that cause greater morbidity, disability and mortality, DM represents a heavy burden on public health. Therefore, actions in both, diagnosis and treatment, are necessary to slow down the current tendency and avoid the development of DM complications. Recently, the glycated hemoglobin test (HbA1c) was introduced in the diagnostic criteria for DM. The HbA1c results are equally appropriate for diagnostic testing, though not necessarily detect DM in the same subjects detected by plasma glucose criteria. However, blood HbA1c levels may be influenced by any condition that changes the lifespan of erythrocytes and hemoglobin metabolism regardless of glycemia, resulting in the misdiagnosis of this population group. In addition, epidemiological studies have shown that postprandial glycemia has a higher risk of causing cardiovascular complications than chronic hyperglycemia and can be accurately assessed using the glycated albumin (GA) test rather than HbA1c. In this context, recent studies have shown that GA may be a marker for the diagnosis of DM and also be used as an alternative marker to HbA1c on many occasions. However, these studies have been conducted only in the Asian population and may not be applicable to other ethnic groups. Therefore, further investigations to validate the diagnostic performance of GA in the prediction of DM in different ethnic groups are necessary. In this study, we evaluated the GA performance in the diagnosis of DM in 242 Brazilian individuals with a mean age of 54.4 years (+ 13.0). Based on plasma glucose values during oral glucose tolerance test (OGTT), DM was detected in 31.8%. AG ≥16.8% presented similar accuracy for detecting DM as defined by a HbA1c >6.5%. The use of the 2-h plasma glucose after a 75-g OGTT and GA (2hPG/GA) ratio improves sensitivity, reduces the number of incorrect diagnoses by GA or HbA1c >6.5% and has an accuracy comparable to OGTT, indicating that the use of approach applying the postprandial glucose (PPG) and GA (PPG/GA) may be more convenient for patients and increase the diagnostic performance of the test. Studies to validate this approach are needed.

O diabetes mellitus (DM) é uma doença que está associada com aumento da morbidade, mortalidade e custos econômicos. O DM tipo 2 é a forma de diabetes mais comum, acometendo 85%-90% de todos os casos. O mau controle glicêmico é um fator determinante do desenvolvimento e progressão das complicações do DM. A hemoglobina glicada (A1C) se tornou a medida de referência para o controle de DM por mais de duas décadas. Existe um grande incentivo, tanto da perspectiva de saúde pública quanto da clínica, em detectar pessoas com risco futuro de desenvolver DM2, pois este é um forte fator de risco para doença cardiovascular. Também existem evidências que é possível prevenir ou retardar o DM nas pessoas com tolerância a glicose diminuída, desde que estes casos sejam identificados e tratados adequadamente. Os testes disponíveis hoje para o diagnóstico do DM, glicemia de jejum (GJ) e teste oral de tolerância à glicose (TOTG), carecem de sensibilidade e/ou especificidade. Recentes estudos têm evidenciado que a A1C pode ser uma nova ferramenta para diagnóstico do DM, sendo que diversos pontos de corte tem sido estudados. Maiores investigações para a validação do desempenho diagnóstico deste teste na predição do DM são necessárias para podermos utilizar esta ferramenta com segurança na triagem e diagnóstico do DM. / Diabetes mellitus (DM) is a disease associated with greater mortality and economical costs. Type 2 DM is the commonest form of DM, accounting for 85-90 % of its cases. Glycemic levels are a determinant factor for the development and progression of DM complications. Glycated hemoglobin (A1C) became the reference measure of glycemic control for more than two decades. There is a great incentive in detecting persons with future risk of developing DM, because this is a strong risk factor for cardiovascular disease. Also there are evidences that it is possible to prevent or to delay DM in persons with prediabetes, since identified and treated appropriately. Available tests for DM diagnosis, fasting glycemia (FG) and oral glucose tolerance test (OGTT), lack sensibility and/or specificity. Recent studies have shown that A1C can be a new tool for DM diagnosis and several cutoff points have been analyzed. However, the validation of this test as diagnostic modality to detect DM might be necessary in order to provide a useful tool for DM diagnosis.

HbA1c and glucose are the most widely used indicators for glucose control, but they havesome disadvantages. Improving the diagnosis of diabetes is always ongoing, other markersare needed as a complement when standard measurements are not sufficient. One alternativeis analysis of fructosamine, which is commercially available and inexpensive.The main aim with this study was to validate a colorimetric method for analyzingfructosamine including investigation of precision, linearity and stability. Fructosamine valueswas compared with HbA1c values with and without genetic variations in the hemoglobingene. An investigation on if serum albumin concentration affects fructosamine values wasalso performed. The colorimetric method was also compared with an enzymatic method foranalysis of frutcotsamine.Blood samples were analyzed as HbA1c on Cobas 6000 c501 and for analysis of thegenetic variants Capillarys 3 TERA was used. Plasma was collected and analyzed onMindray BS-380 as fructosamine and albumin.The methods in this study were comparable and the colorimetric method had greatprecision and linearity. The correlation between HbA1c and fructosamine was R2= 0,402.Fructosamine was not affected by genetic variations in the hemoglobin molecule and may bea useful indicator of high glucose and could replace analysis of HbA1c. Fructosamine wasnot affected by albumin. The enzymatic method was shown to correlate better with HbA1cthan the colorimetric method.In conclusion, analyzing fructosamine could be an alternative to HbA1c when patientshave genetic variants and would improve the glycemic control.

A prevalência de diabetes mellitus (DM) está aumentando constantemente em todo o mundo a uma taxa alarmante. Devido às suas complicações que causam uma maior morbidade, invalidez e mortalidade, o DM representa um enorme problema para a saúde pública. Com isso, ações, tanto em diagnóstico como em tratamento, são necessárias para desacelerar a tendência atual e prevenir o desenvolvimento das complicações do DM. Recentemente, a hemoglobina glicada (HbA1c) foi introduzida nos critérios diagnósticos de DM. Os resultados de HbA1c são igualmente apropriados para o diagnóstico, apesar de não necessariamente detectarem DM nos mesmos indivíduos detectados pelos critérios de glicemia. No entanto, os níveis de HbA1c podem ser influenciados por qualquer condição que altere a vida útil dos eritrócitos e metabolismo da hemoglobina, independentemente da glicemia, resultando em erro diagnóstico neste grupo da população com estas condições. Além disso, estudos epidemiológicos revelaram que a glicemia pós-prandial tem um maior risco de causar complicações cardiovasculares em relação à hiperglicemia persistente e pode ser acessada com precisão usando a albumina glicada (AG) e não a HbA1c. Nesse contexto, estudos recentes têm evidenciado que a AG pode ser um marcador para diagnóstico do DM e também ser utilizado como um marcador alternativo à HbA1c para o controle glicêmico. No entanto, esses estudos, foram realizados apenas na população asiática e podem não ser aplicáveis a outros grupos étnicos. Por isso, mais investigações para a validação do desempenho diagnóstico da AG na predição do DM em diferentes grupos etnicos são necessárias. Neste estudo avaliamos o desempenho da AG no diagnóstico do DM em 242 indivíduos brasileiros com idade média de 54,4 anos (+ 13,0). Baseando-se nos valores de glicose plasmática durante o teste oral de tolerância à glicose (TOTG), o DM foi detectado em 31,8%. AG ≥16,8% apresentou acurácia similar para a detecção de DM conforme definido por HbA1c >6,5%. O uso da razão glicemia de 2h pós-sobrecarga de 75g de glicose (2hPG) e AG (2hPG/AG) melhora a sensibilidade, reduz o número de diagnósticos incorretos por AG ou HbA1c >6,5% e possui um acurácia comparável ao TOTG, indicando que o uso de uma estratégia aplicando a razão da glicemia pós-prandial (GPP) real e AG (GPP/AG) pode ser mais conveniente para pacientes e aumentar o desempenho diagnóstico do teste. Estudos para validar esta estratégia são necessários. / The prevalence of diabetes mellitus (DM) is constantly increasing worldwide at an alarming rate. Due to its complications that cause greater morbidity, disability and mortality, DM represents a heavy burden on public health. Therefore, actions in both, diagnosis and treatment, are necessary to slow down the current tendency and avoid the development of DM complications. Recently, the glycated hemoglobin test (HbA1c) was introduced in the diagnostic criteria for DM. The HbA1c results are equally appropriate for diagnostic testing, though not necessarily detect DM in the same subjects detected by plasma glucose criteria. However, blood HbA1c levels may be influenced by any condition that changes the lifespan of erythrocytes and hemoglobin metabolism regardless of glycemia, resulting in the misdiagnosis of this population group. In addition, epidemiological studies have shown that postprandial glycemia has a higher risk of causing cardiovascular complications than chronic hyperglycemia and can be accurately assessed using the glycated albumin (GA) test rather than HbA1c. In this context, recent studies have shown that GA may be a marker for the diagnosis of DM and also be used as an alternative marker to HbA1c on many occasions. However, these studies have been conducted only in the Asian population and may not be applicable to other ethnic groups. Therefore, further investigations to validate the diagnostic performance of GA in the prediction of DM in different ethnic groups are necessary. In this study, we evaluated the GA performance in the diagnosis of DM in 242 Brazilian individuals with a mean age of 54.4 years (+ 13.0). Based on plasma glucose values during oral glucose tolerance test (OGTT), DM was detected in 31.8%. AG ≥16.8% presented similar accuracy for detecting DM as defined by a HbA1c >6.5%. The use of the 2-h plasma glucose after a 75-g OGTT and GA (2hPG/GA) ratio improves sensitivity, reduces the number of incorrect diagnoses by GA or HbA1c >6.5% and has an accuracy comparable to OGTT, indicating that the use of approach applying the postprandial glucose (PPG) and GA (PPG/GA) may be more convenient for patients and increase the diagnostic performance of the test. Studies to validate this approach are needed.

Introduktion/Bakgrund: Diabetes är ett stort och växande hälsoproblem. Vården av denna sjukdom är långsiktig och innebär stort eget ansvar från patienten. Brister i denna egenvård kan leda till framtida komplikationer, vilket ofta är fallet. Smarta mobiltelefoner och dess mobila applikationer kan erbjuda nya sätt att hantera sjukdomen.  Syfte: Att beskriva effekter av mobila applikationer i samband med egenvård vid diabetes.  Metod: Litteraturstudie med induktiv ansats som genomförts enligt Polit och Becks (2020) nio steg. Artikelsökning utfördes i CINAHL och PubMed. Resultatets baserades på 11 artiklar och samtliga har kvalitetsgranskats.  Resultat: Appanvändande kopplades till förbättrat HbA1c, förbättrat blodsocker, ökad testfrekvens av blodsocker, minskad förekomst av hyperglykemi, samt förbättrat hälsotillstånd i viss bemärkelse. Ingen förbättring kunde ses gällande kroppsvikt, eller hypoglykemi. Utfallet av interventionen korrelerade med deltagarnas följsamhet till appen.  Slutsats: Mobila applikationer kan vara en god omvårdnadsintervention, dock behövs mer forskning om mobila applikationer från ett omvårdnadsperspektiv.

Sammanfattning Diabetes mellitus karakteriseras av högt blodsocker och är ett samlingsnamn för olika diabetessjukdomar där typ 1-diabetes och typ 2-diabetes är de vanligaste sjukdomarna. Kroppens blodglukoshalter regleras av hormonet insulin som är ett nödvändigt hormon för att kroppens celler ska kunna ta upp kolhydrater, aminosyror och fett. Vid typ 1-diabetes förstörs bukspottkörtelns insulinproducerande betaceller av kroppens eget immunförsvar. Viktiga transplantationsmetoder för att återställa bukspottkörtelns endokrina funktion är pancreas- och öcellstransplantation som båda resulterat i främst minskade akuta hypoglykemier men även förbättrade blodsockervärden och insulinfrihet. Pancreastransplantation är en mer riskfylld operation jämfört med öcellstransplantation och studier har visat på mer postoperativa komplikationer men längre och högre insulinfrihet hos patienter som genomgått pancreastransplantation. Tanken utvecklades till att jämföra litteratur som behandlar studier som jämför pancreas- och öcellstransplantation hos diabetiker avseende komplikationer, glukoskontroll och insulinfrihet. Syftet med arbetet var att göra en jämförelse mellan litteratur som behandlar pancreastransplantation respektive öcellstransplantation hos patienter med diabetes mellitus för att utröna vilken behandling som ger minst komplikationer och behov av insulinbehandling efter transplantation och en uppföljningstid på minst 1 år. Litteraturstudien baseras på 6 kohortstudier som alla erhölls via databasen PubMed. Studierna är utförda i Schweiz, USA, Tjeckien, Kanada och utgår från i grunden samma frågeställning men har delvis olika patienturval och metoder. Studie 2 och studie 5 har betydligt högre studiepopulation än övriga studier vilket ger högre bevisvärde för resultatet i dessa studier. Resultatsammanställningen visar att på både kort och lång sikt är komplikationsrisken betydligt större hos patienter efter pancreastransplantation jämfört med öcellstransplantation. Allvarliga, omedvetna hypoglykemier, som är livshotande tillstånd, är ovanliga hos patienter efter båda typerna av transplantation. På både kort och lång sikt visar pancreastransplanterade patienter betydligt lägre HbA1c-värden och betydligt högre C-peptidvärden jämfört med öcellstransplanterade patienter. Resultatet visar, i linje med tidigare resultat, att insulinfriheten består hos fler pacreastransplanterade patienter och under längre tid jämfört med öcellstransplanterade patienter. Efter 5 år är >50% av pancreastransplanterade patienter insulinfria medan motsvarande siffra hos öcellstransplanterade patienter är <10%.För att besvara syftet har litteraturstudien visat att vid jämförelse mellan litteratur som behandlar pancreastransplantation respektive öcellstransplantation hos patienter med diabetes mellitus ger öcellstransplantation minst akuta komplikationer men pancreastransplantation högst insulinfrihet, minst behov av insulinbehandling, efter transplantation och en uppföljningstid på minst ett år. / Abstract Diabetes mellitus is characterized by hyperglycemia and is a collective name for different diabetic diseases. Type 1 diabetes and type 2 diabetes are the most common diseases. Insulin, which is the regulatory hormone for the body`s blood glucose levels, is necessary for the body`s cells to be able to absorb nutrition like carbohydrates, amino acids and fat. In type 1 diabetes the pancreas insulin-producing beta cells are destroyed by the body`s own immune system. Important transplantation methods to restore pancreatic endocrine function are whole pancreas transplantation and islet transplantation. Both methods of transplantation mainly decreased acute hypoglycaemia and improved blood sugar levels and insulin therapy. Pancreas transplantation is a more risky operation compared to islet transplantation. Patients who have gone through pancreatic transplantation in general have shown more postoperative complications but at the same time also longer periods without insulin therapy compared to patients who have gone through islet transplantation. The aim of this study was to make a comparison between literature dealing with pancreatic transplantation and islet transplantation regarding complications, glucose control and insulin requirements with a follow-up time of at least 1 year. The literature study is based on 6 cohort studies, all obtained through the PubMed database. The studies were conducted in Switzerland, USA, Czech Republic, Canada and are basically based on the same question but have partly different patient selection and methods. Study 2 and study 5 have a significantly higher study population than other studies, which gives higher evidence of the results of these studies. The results compilation shows that in both the short and the long term, the risk of complications is significantly greater in patients after pancreatic transplantation compared to islet transplantation. In both the short and long term, pancreatic transplant patients show significantly lower HbA1c values and significantly higher C-peptide values compared to islet transplant patients. Severe unconscious hypoglycaemia is a life-threatening condition. However, severe unconscious hypoglycaemia is uncommon in patients after both types of transplantation. The result shows, in line with previous results, that insulin freedom persists in higher number of pancreatic transplant patients and for longer period of time compared to islet transplant patients. After 5 years >50% of pancreatic transplant patients are insulin free while the corresponding number in islet transplant patients is <10%. In summary, data presented in this literature study show that islet transplantation give less acute complications, but that whole pancreas transplantation results in better glucose control for a longer time period.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第22888号 / 社医博第112号 / 新制||社医||11(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 川上 浩司, 教授 今中 雄一, 教授 稲垣 暢也 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

Pharmacometrics is widely used in drug development. Models are developed to describe pharmacological measurements with data gathered from a clinical trial. The information can then be applied to, for instance, safely establish dose-response relationships of a substance. Glycated hemoglobin (HbA1c) is a common biomarker used by models within antihyperglycemic drug development, as it reflects the average plasma glucose level over the previous 8-12 weeks. There are five different nonlinear mixed-effects models that describes HbA1c-formation. They use different biomarkers such as mean plasma glucose (MPG), fasting plasma glucose (FPG), fasting plasma insulin (FPI) or a combination of those. The aim of this study was to compare their performances on a population and an individual level using model averaging (MA) and to explore if reduced trial durations and different treatment could affect the outcome. Multiple weighting methods were applied to the MA workflow, such as the Akaike information criterion (AIC), cross-validation (CV) and a bootstrap model averaging method. Results show that in general, models that use MPG to describe HbA1c-formation on a population level could potentially outperform models using other biomarkers, however, models have shown similar performance on individual level. Further studies on the relationship between biomarkers and model performances must be conducted, since it could potentially lay the ground for better individual HbA1c-predictions. It can then be applied in antihyperglycemic drug development and to possibly reduce sample sizes in a clinical trial. With this project, we have illustrated how to perform MA on the aforementioned models, using different biomarkers as well as the difference between model weights on a population and individual level.

IntroductionFreeStyle Libre (FSL) has mostly been used by patients with type 1 diabetes. In 2019, newrecommendations were announced regarding prescriptions to patients with type 2 diabetes(T2D) who have insulin treatment (basal/bolus), HbA1c > 70 mmol/mol and/or repeatedhypoglycemic events despite great effort to adjust insulin doses.AimTo evaluate if HbA1c improves with FSL compared with self-monitoring of blood glucose. Thesecondary aim was to investigate if patients with recurrent hypoglycemic events experiencedless hypoglycemic events.MethodsThis study was designed as a retrospective systematic review of medical records of patientswith T2D in Region Örebro County (RÖC) who have received an FSL 1st of January to 13th ofSeptember 2019. A control group (n = 142) was created from the National Diabetes Register tothe indication group HbA1c > 70 mmol/mol. A paired sample t-test was used to assess theprimary endpoint.ResultsHbA1c decreased significantly from 73 mmol/mol to 65 mmol/mol (p <0.001) in the wholestudy population (n = 58). Indication group HbA1c > 70 mmol/mol (n = 38) had the greatestchange, 80 mmol/mol to 68 mmol/mol (p <0.001). The mean HbA1c in the control group was82 mol/mol. There were 15 patients in the indication group with hypoglycemic events (n = 20)who experienced less hypoglycemic events.ConclusionFSL has a positive effect on the metabolic control in patients with T2D who have HbA1c > 70mmol/mol when starting with FSL in RÖC.