A retinopatia da prematuridade é uma doença ocular do desenvolvimento associada a um crescimento vascular retiniano anormal e ocorre somente em recém-nascidos com menos de 32 semanas de gestação e submetidos a longos períodos em incubadoras, tipicamente ricas em oxigênio. A doença possui duas fases: (1) a inibição do desenvolvimento normal de vasos na retina, decorrente da hiperóxia induzida pelo ambiente da incubadora; (2) neovascularização retiniana devido ao aumento de fatores de crescimento desencadeados pela pouca disponibilidade de oxigênio fora da incubadora. O objetivo deste trabalho é avaliar a função visual em um modelo animal de retinopatia da prematuridade, comparando-o a animais sadios. Eletrorretinogramas (ERGs) de campo total foram realizados em camundongos (Mus musculus) controle e camundongos submetidos hiperoxigenação em câmara hiperbárica (75% de oxigênio) durante o desenvolvimento retiniano pós-natal para entender as perdas visuais que ocorrem na retinopatia da prematuridade. Foram utilizados 122 animais, divididos em dois grupos: no grupo controle¸ ERGs foram realizados em P17 (n = 32), P30 (n = 26) e P60 (n = 44) com estimulação em comprimentos de onda distintos (LEDs com pico de emissão em 365 nm, 459 nm, 525 nm e 635 nm) para avaliação da atividade funcional da retina ao longo do desenvolvimento, não passando por nenhuma manipulação experimental adicional; no grupo experimental, os animais foram submetidos à hiperoxigenação de P7 a P12 para indução da angiogênese e avaliados com ERGs com estimulação em 459 nm em P17 (n = 7), P30 (n = 6) e P60 (n = 7), para acompanhar o desenvolvimento retiniano. Todos os animais foram adaptados ao escuro por pelo menos duas horas antes da realização dos experimentos. Em sessão de 40 a 60 minutos de duração, os animais foram submetidos a flashes de luz em intensidades crescentes. Amplitudes e latências das ondas a, b e potenciais oscilatórios foram medidas, e relações intensidade-resposta ajustadas com modelos matemáticos diferentes para comparação entre indivíduos e entre grupos. Os parâmetros obtidos com os ajustes foram comparados através de ANOVA e testes T de Student com as devidas correções de Bonferroni. Nos níveis luminosos testados, a onda b do ERG murino é majoritariamente dominada pela atividade dos bastonetes e a onda a majoritariamente dominada pelos cones. Os registros em animais em P17 e P30 do grupo controle foram similares aos realizados em P60 quanto à latência e amplitude de resposta, bem como quanto à sensibilidade e grau de cooperação entre os distintos elementos do ERG. Entretanto, as amplitudes máximas de resposta foram ligeiramente maiores em P30 para todos os comprimentos de onda e houve ligeira redução da sensibilidade absoluta ao longo do desenvolvimento. Para o grupo experimental, os animais em P17 sofreram as maiores perdas, com diminuições nas amplitudes de todos os componentes do ERG, sem prejuízo das latências ou sensibilidade. Também houve uma sucessiva recuperação das respostas ao longo do desenvolvimento animal. Esses achados indicam que o modelo de ROP em camundongos reproduz aspectos essenciais ao quadro patológico severo humano / The retinopathy of prematurity is an ocular developmental disorder associated with abnormal retinal vascular growth and occurs only in neonates younger than 32 weeks of gestation and undergoing long periods in incubators, typically rich in oxygen. The disease has two phases: (1) the inhibition of the normal development of vessels in the retina, due to the hyperoxia induced by the incubator environment; (2) retinal neovascularization due to the increase in growth factors triggered by the low availability of oxygen outside the incubator. The objective of this study is to evaluate the visual function in an animal model of retinopathy of prematurity, comparing it to healthy animals. Full-field electroretinogram (ERGs) were performed on control mice (Mus musculus) and that were exposed to a hyperbaric chamber (75% oxygen) during post-natal retinal development to understand the visual losses that occur in retinopathy of prematurity. We used 122 animals, divided into two groups: in the control group, ERGs were performed at P17 (n = 32), P30 (n = 26) and P60 (n = 44) with stimulation at different wavelengths (LEDs with peak of emission at 365 nm, 459 nm, 525 nm and 635 nm) for evaluation of the functional activity of the retina throughout the development, without any additional experimental manipulation; in the experimental group, animals were submitted to hyperoxogenation of P7 to P12 for induction of angiogenesis and evaluated with ERGs with stimulation at 459 nm in P17 (n = 7), P30 (n = 6) and P60 (n = 7) to follow up retinal development. All animals were dark adapted for at least two hours prior to the experiments. In sessions with 40 to 60 minutes, the animals were subjected to flashes of light at increasing intensities. Amplitudes and latencies of a-waves, b-waves and oscillatory potentials were measured, and intensity-response relationships adjusted with different mathematical models for comparison between individuals and between groups. The parameters obtained with the adjustments were compared through ANOVA and Student\'s T tests with the appropriate Bonferroni correction. In the light levels tested, the murine ERG b-wave is dominated by rod activity and the a-wave is dominated by the cones. The records in animals at P17 and P30 of the control group were similar to those performed at P60 regarding the latency and amplitude of response, as well as the sensitivity and degree of cooperation between the different ERG elements. However, the maximum response amplitudes were slightly higher at P30 at all wavelengths and there was slight reduction of absolute sensitivity throughout development. For the experimental group, the animals at P17 suffered the greatest losses, with decreases in the amplitudes of all the components of the ERG, without prejudice to the latencies or sensitivity. There was also a successive recovery of responses throughout animal development. These findings indicate that the ROP model in mice reproduces aspects essential to the severe human pathology

Diabete melito é umas das principais endocrinopatias, caracterizada pela deficiência relativa ou absoluta de insulina, que pode resultar em diversas manifestações oculares, sendo as mais frequentes a retinopatia diabética e a catarata. Retinopatia diabética (RD) é uma microangiopatia que afeta primeiramente as arteríolas pré-capilares, capilares, vênulas pós-capilares e vasos de maior calibre, causando incompetência funcional e anatômica dos vasos retinianos. A hiperglicemia pode ser a causa mais provável da lesão retiniana, interferindo nas vias de metabolismo celular e no processo de transdução. Os achados fundoscópicos incluem: microaneurismas, dilatação e tortuosidade das vênulas retinianas, hiper-refletividade da área tapetal e exsudatos coriorretinianos. Como a catarata impossibilita a fundoscopia, a prevalência da retinopatia diabética nos cães não esta totalmente esclarecida, sugerindo que esta seja na forma não proliferativa. Objetivou-se neste estudo, determinar a prevalência das alterações fundoscópicas relacionadas à retinopatia diabética em cães, com auxílio de documentação fotográfica (retinografia) e tomografia de coerência óptica (OCT). Vinte e dois cães diabéticos, 18 fêmeas e quatro machos, com idade variando de seis a 15 anos, provenientes do Serviço de Oftalmologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, foram submetidos a acompanhamento por meio da retinografia durante o período de 12 meses. Para realização do exame de OCT foram selecionados oito cães dos 22 animais avaliados, quatro fêmeas e quatro machos, com idades variando de seis a 15 anos para compor o grupo diabete melito (GDM), e nove cães sendo cinco fêmeas e quatro machos, com idades entre quatro e 15 anos, sem quaisquer alterações oculares e não diabéticos formaram o grupo controle (GCO). Os cães diabéticos acompanhados durante 12 meses apresentaram alteração vascular, microaneurismas e hemorragias, e alterações na coloração e refletividade da área tapetal. Sendo que dois cães, dos 22 animais avaliados, apresentaram hemorragia em mancha no último período de avaliação, e um cão apresentou focos hemorrágicos durante todo o período de avaliação. A espessura e arquitetura retiniana realizada pela OCT nos cães diabéticos, demonstrou afinamento das camadas da retina e perda da estratificação em comparação com os animais controle (198 µm versus 219 µm, respectivamente), sendo esta redução estatisticamente significante. Com os achados retinográficos deste estudo podemos confirmar que as lesões são compatíveis com a RD não proliferativa sem comprometimento visual, e baseado nas imagens da OCT pode-se sugerir que a diabete melito, no cão, cause neuropatia retiniana como descrito em humanos diabéticos / Diabetes mellitus is one of the most frequent endocrine disorders, characterized by relative or absolute deficiency of insulin, which can induces several ocular manifestations, among them diabetic retinopathy and cataract. Diabetic Retinopathy is a microangiopathy that affects the precapillary, arterioles, capillaries, postcapillary venules, and the large vessels, causing them to be functionally and anatomically incompetent. Hyperglycemia seems to be the most probably cause of retinal damage, interfering in the cellular metabolism process and in transduction process. The fundoscopic findings are microaneurysm, retinal venular dilatation and tortuosity, hyperreflectivity of tapetal area and chorioretinal exsudates. Because the cataract precludes fundoscopic examination, the diagnosis of diabetic retinopathy in dogs is not completely elucidated, but suggests that disease is nonproliferative form. The aim of this study was to determine the prevalence of fundus changes related to diabetic retinopathy in dogs, with photography documentation (fundus camera) and optical coherence tomography (OCT). Twenty-two diabetic dogs, 18 females and four males, from six to 15 years, from Serviço de Oftalmologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, underwent monitoring by retinography during the period 12 months. For the OCT examination were selected eight dogs of the 22 evaluated animals, four females and four males, from six to 15 years formed the group diabetes mellitus (GDM), and nine dogs with five females and four males, from 4 to 15 years, with no ocular alterations and non-diabetic formed the control group (GC). Diabetic dogs followed for 12 months showed vascular changes, microaneurisms and hemorrhage, and changes in colour and reflections of tapetal area. Two dogs, among the 22 animals studied, presented hemorrhage stain in the last period, and one dog presented hemorrhage focus throughout the evaluation period. The thickness and retinal architecture performed by OCT in diabetic dogs showed thinning of the retinal layers with loss of stratification compared to control animals (198 µm versus 219 µm, respectively), with a statistically significant difference. Based on fundus findings of this study we can confirm that the lesions are compatible with DR nonproliferative without visual impairment. The OCT images may suggest that diabetes mellitus in the dog causes retinal neuropathy as described in diabetic humans

Orientador: Eliane Chaves Jorge / Resumo: Introdução: A retinopatia da prematuridade (ROP) é uma doença vaso proliferativa multifatorial e uma das principais causas de cegueira infantil no mundo. O exame oftalmológico seriado identifica a forma grave da doença, porém pode causar estresse e instabilidade cardiorrespiratória nos neonatos prematuros. O algoritmo ROPScore, aferido na sexta semana de vida é efetivo em predizer o risco de ROP e diminuir o número de exames necessários para o diagnóstico. No entanto, nos casos em que a doença grave é precoce ou se desenvolve em neonatos mais maduros, o ROPScore seria mais efetivo se aferido antes da sexta semana de vida. Objetivo: avaliar a acurácia do ROPScore aferido na segunda semana de vida quando comparada com a da sexta semana. Métodos: Realizou-se um estudo coorte prospectivo de neonatos pré-termos com peso ao nascimento (PN) ≤1500 g e / ou idade gestacional (IG) ≤ 32 semanas. O ROPScore foi aplicado na 2ª e na 6ª semanas de vida. Curvas ROC foram utilizadas para determinar os melhores valores de sensibilidade, especificidade e seus valores preditivos positivos (VPP) e negativos (VPN) para o desenvolvimento de ROP em qualquer estágio (RQE) e ROP grave (RG). Resultados: Dos 282 RNPT, 40 (14,2%) desenvolveram ROP e 27 (9,5%) a sua forma grave. A sensibilidade do ROPScore na 2ª semana para prever ROP em qualquer estadiamento foi de 92,5% e de 92,8% na ROP grave. Na 6ª semana foi de 90% e 92,6% respectivamente. O VPN foi alto tanto na 2ª (99%) como na 6ª (98%) semanas, pa... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Retinopathy of prematurity (ROP) is a multifactorial proliferative vessel disease and one of the leading causes of childhood blindness in the world. Serial ophthalmic examination identifies the severe form of the disease but may cause cardiorespiratory stress and instability in preterm infants. The ROPScore algorithm, measured in the sixth week of life, is effective in predicting ROP risk and decreasing the number of tests required for diagnosis. However, in cases where the severe disease is early or develops in more mature neonates, ROPScore would be more effective if measured before the sixth week of life. Objective: to evaluate the accuracy of ROPScore measured in the second week of life when compared to the sixth week. Methods: A prospective cohort study of preterm newborns with birth weight (BW) ≤1500 g and/or gestational age (GA) ≤ 32 weeks was performed. ROPScore was applied in the 2nd and 6th weeks of life. ROC curves were used to determine the best values of sensitivity, specificity and positive predictive values (PPV) and negative predictive value (NPV) for the development of ROP at any stage (RQE) and severe ROP (RG). Results: Of the 282 preterms, 40 (14.2%) developed ROP and 27 (9.5%) developed their severe form. The sensitivity of ROPScore at 2nd week to predict ROP at any stage was 92.5% and 92.8% at ROP. In the 6th week, it was 90% and 92.6% respectively. The NPV was high in both the second (99%) and the sixth (98%) weeks, for ROP in any stage and s... (Complete abstract click electronic access below) / Mestre

"January 2003." Bibliography: 10.1-10.11 leaves. This thesis presents results from the Katherine Region Diabetic Retinopathy Study (1993-1996). These results provide the first detailed information on the basic epidemiology of diabetic retinopathy and impaired vision in an Aboriginal diabetic population.

Master of Public Health / OBJECTIVES: In Australia, diabetes causes significant morbidity and mortality. Whilst the need to prevent diabetes and its complications has been widely recognised, the capacity of health care systems - which organise diabetes care - to facilitate prevention has not been fully established. METHODS: A series of seven population-based case-control studies were used to examine the effectiveness of the Australian health care system and its capacity to manage diabetes. Six of the studies compared the patterns of care of patients who had developed advanced diabetes complications in 2000 (cases), to similar patients who remained free of the condition (controls) across Australia and for various risk groups. A secondary study investigated the role of treating GPs in the development of the outcome. RESULTS: A strong relationship between the patterns of care and the development of advanced diabetes complications was found and is described in Chapter 4. In Chapter 5, this same relationship was investigated for each Australian state and territory, and similar findings were made. The study in Chapter 6 investigated whether late diagnosis or the patterns of care was the stronger risk factor for advanced diabetes complications, finding that the greatest risk was associated with the latter. In Chapter 7 the influence of medical care during the pre-diagnosis period was explored, and a strong relationship between care obtained in this period and the development of advanced complications was found. In Chapter 8, which investigated the role of socio-economic status in the development of advanced complications, found that the risk of advanced diabetes complications was higher in low socio-economic groups. Chapter 9 investigated geographic isolation and the development of advanced diabetes complications and found that the risk of advanced complications was higher in geographically isolated populations. Finally, Chapter 10, which utilised a provider database, found that some GP characteristics were associated with the development of advanced diabetes complications in patients. CONCLUSION: A number of major risk factors for the development of advanced complications in Australia was found. These related to poorer diabetes management, later diagnosis, low socioeconomic status and geographic isolation. Strategies must be devised to promote effective diabetes management and the early diagnosis of diabetes across the Australian population.

"January 2003." / Bibliography: 10.1-10.11 leaves. / 1 v. : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis presents results from the Katherine Region Diabetic Retinopathy Study (1993-1996). These results provide the first detailed information on the basic epidemiology of diabetic retinopathy and impaired vision in an Aboriginal diabetic population. / Thesis (Ph.D.)--University of Adelaide, Dept. of Public Health, 2003

<p>Plasma activity of the enzyme semicarbazide-sensitive amine oxidase (SSAO; EC.1.4.3.6) has been reported to be high in disorders such as diabetes mellitus, chronic congestive heart failure and liver cirrhosis. Little is known of how the activity is regulated and, consequently, the cause for these findings is not well understood. Due to the early occurrence of increased enzyme activity in diabetes, in conjunction with the production of highly cytotoxic substances in SSAO-catalysed reactions, it has been speculated that there could be a causal relationship between high SSAO activity and vascular damage. Aminoacetone and methylamine are the best currently known endogenous substrates for human SSAO and the resulting aldehyde-products are methylglyoxal and formaldehyde, respectively. Both of these aldehydes have been shown to be implicated in the formation of advanced glycation end products (AGEs).</p><p>This thesis is based on studies exploring the regulation of SSAO activity and its possible involvement in the development of vascular damage. The results further strengthen the connection between high SSAO activity and the occurrence of vascular damage, since type 2 diabetic patients with retinopathy were found to have higher plasma activities of SSAO and lower urinary concentrations of methylamine than patients with uncomplicated diabetes. From studies on mice, it was also found that an SSAO inhibitor potently reduces the incorporation of methylamine-metabolite in the tissues. By quantifying SSAO-gene expression in alloxan-induced diabetes, increased transcription could be ruled out as a cause for the increased enzyme activity, thereby opening up for the possibility that the activity is regulated post-translationally. In fact, increased enzyme activity in adipose tissue was accompanied by decreased mRNA-levels, suggesting that the gene expression could be negatively controlled by the enzyme activity.</p>

To ensure that the resources of the health care sector are used effectively, new technologies need to be evaluated before implementation to examine if they generate health outcomes at an acceptable cost. This information can be collected by performing health economic evaluations in which the costs and health outcomes of different technologies are compared. To estimate the effect on health care budgets, there is also a need for information about the prevalence of the specific disease. Health outcomes in health economic evaluations are often measured in quality-adjusted life years (QALYs), which are calculated by multiplying the remaining life years after an intervention by a weight representing the health-related quality of life (HRQoL) during those years. This thesis aims to provide deeper knowledge of the health economic aspects of diabetic retinopathy (DR), an eye complication that affects patients with diabetes and may in the worst case lead to blindness. The focus is on three empirical and two methodological health economic research questions. The empirical research areas cover prevalence, costs, and HRQoL related to patients with DR. The methodological research questions explore the performance of different methods for estimation of QALY weights. This is of interest since it has been argued that the most common methods for estimating QALY weights may not capture all relevant vision-related aspects of quality of life. The analyses comprehend the validity of different methods for estimating QALY weights among patients with DR and if the results of one of the specific methods for estimating QALY weights, the time trade-off (TTO) exercise, are affected by patients’ subjective life expectancy (SLE). The empirical results demonstrate that DR is seen in approximately 40% and 30% of patients with type I and type II diabetes respectively, indicating that the prevalence of DR has decreased in both of these patient groups. Healthcare costs vary considerably between different severity levels of the disease, being estimated at €26, €257, €216, and €433 per patient per year for background retinopathy, proliferative diabetic retinopathy (PDR), diabetic macular oedema (DMO), and PDR combined with DMO respectively. Blindness due to DR is associated with an increased use of transportation services, caregiving services, and assistive technologies as well as productivity losses. This suggests that preventing the progression of DR may lower healthcare costs. Patients with vision impairment due to DR have lowered HRQoL in various dimensions, but the diagnosis of DR in itself has only a limited effect on HRQoL. The results on the methodological research questions show that different methods for estimating QALY weights seem to give different results. In comparison to EQ-5D, the Health Utilities Index Mark 3 (HUI-3) is the most sensitive method for detecting differences in QALY weights due to DR, and if decisions are to be made based on values from the general public, it can be recommended for use in cost-utility analyses of interventions directed at DR. Neither of the direct methods, TTO and the visual analogue scale, seems to be sensitive to differences in visual function, and more research is needed concerning the role of vision in people’s responses to the TTO exercises. In TTO exercises with time frames based on actuarial life expectancy, the patients’ SLE has an effect on their willingness to trade off years for full health. Thus, applying time frames deviating from patients’ SLE may result in biased QALY weights. Such bias may appear stronger within patient populations than within the general public. In conclusion, this thesis offers estimates for prevalence, costs, and QALY weights that can be used in economic evaluations of interventions directed at DR and as benchmarks for future DR research in order to follow up consequences of changes in diabetes care. In addition, it demonstrates that the choice of method for estimating QALY weights may have an impact on whether an intervention is considered cost-effective.

Plasma activity of the enzyme semicarbazide-sensitive amine oxidase (SSAO; EC.1.4.3.6) has been reported to be high in disorders such as diabetes mellitus, chronic congestive heart failure and liver cirrhosis. Little is known of how the activity is regulated and, consequently, the cause for these findings is not well understood. Due to the early occurrence of increased enzyme activity in diabetes, in conjunction with the production of highly cytotoxic substances in SSAO-catalysed reactions, it has been speculated that there could be a causal relationship between high SSAO activity and vascular damage. Aminoacetone and methylamine are the best currently known endogenous substrates for human SSAO and the resulting aldehyde-products are methylglyoxal and formaldehyde, respectively. Both of these aldehydes have been shown to be implicated in the formation of advanced glycation end products (AGEs). This thesis is based on studies exploring the regulation of SSAO activity and its possible involvement in the development of vascular damage. The results further strengthen the connection between high SSAO activity and the occurrence of vascular damage, since type 2 diabetic patients with retinopathy were found to have higher plasma activities of SSAO and lower urinary concentrations of methylamine than patients with uncomplicated diabetes. From studies on mice, it was also found that an SSAO inhibitor potently reduces the incorporation of methylamine-metabolite in the tissues. By quantifying SSAO-gene expression in alloxan-induced diabetes, increased transcription could be ruled out as a cause for the increased enzyme activity, thereby opening up for the possibility that the activity is regulated post-translationally. In fact, increased enzyme activity in adipose tissue was accompanied by decreased mRNA-levels, suggesting that the gene expression could be negatively controlled by the enzyme activity.

Background/aim. The incidence of microvascular complications has been reported to be unchanged the last decades. However, in randomized clinical trials it has been shown that improved metabolic control can reduce the development of long term complications. It has been debated whether it is possible to achieve the same results in an unselected population. In a previous study we found a decreased incidence of overt nephropathy, but unchanged incidence of severe laser treated retinopathy in a population of patients with type 1 diabetes diagnosed in childhood. The aim of the present study was to investigate the incidence 10 years later in the same population and to analyse the importance of possible risk factors. In another previous study we found a high prevalence of subclinical neuropathy among young diabetic patients despite intensive insulin therapy since diagnosis. The aim of the present study was to examine if intensive treatment is more effective in preventing early diabetic complications other than neuropathy. The incidence of type 1 diabetes has doubled in Sweden the last decades. The reason must be environmental factors. These, as well as more intensive insulin regimens from onset of diabetes, might also lead to different disease process. We wanted to analyse if clinical characteristics at onset had changed the last 25 years and if there was any secular trend of C-peptide secretion. We also intended to investigate if longer persistence of C-peptide secretion could be of importance for prevention of long term complications. Methods. The whole study population consisted of all 478 patients with type 1 diabetes diagnosed before the age of 15 during the years 1961 - 2000, living in the catchment area of the Paediatric Clinic, University Hospital, Linköping, Sweden. For the statistical analysis the population was divided into five–year cohorts according to time of onset of diabetes. The cumulative proportion of severe retinopathy and overt nephropathy in 269 patients with onset of diabetes 1961 - 1985 was computed with survival analysis. Multivariable regression models were used to analyse the importance of metabolic control, diabetes duration, blood pressure, smoking, BMI, lipids and persisting C-peptide secretion. The prevalence of all grades of retinal changes, nephropathy and neuropathy, defined as abnormal nerve conduction, was estimated in the late 1990s in a subgroup of 80 children and adolescents with mean 13 years of diabetes duration. Clinical characteristics at onset, duration of partial remission and regularly measurements of fasting and stimulated C-peptide secretion the first five years after onset were analysed in 316 patients with onset of diabetes 1976 - 2000. Results. The cumulative proportion of severe laser treated retinopathy showed a significant declining trend the last decades. The decrease was significant between the oldest cohort with diabetes onset 1961 - 1965 and the cohorts with diabetes onset 1971 - 1975 and 1976 - 1980. The cumulative proportion of overt nephropathy also declined with a significant decrease between the oldest cohorts and all the following cohorts. After 25 years of diabetes duration it was 30% and 8% in the two oldest cohorts respectively and remained largely unchanged after 30 years. Diabetes duration and long term HbA1c were the only significant independent risk factors for both retinopathy and nephropathy. The risk of overt nephropathy increased substantially when HbA1c was above 8.5%, while the risk of severe retinopathy increased already when HbA1c exceeded 7.5%. The prevalence of neuropathy was 59%, of retinopathy 27% and of nephropathy 5% in the population of young patients after mean 13 years of diabetes duration. During the last 25 years the clinical characteristics at onset were unchanged as well as duration of partial remission and magnitude and persistence of C-peptide secretion. Conclusions. In this unselected population the cumulative proportion of severe retinopathy and overt nephropathy decreased over the last decades. Diabetic nephropathy has probably been prevented and not just postponed. Good glycaemic control was the most important factor to avoid complications, with the necessity of a lower level of HbA1c to escape retinopathy than nephropathy. Intensive insulin regimens from diabetes onset was not sufficient to entirely escape early diabetic complications after mean 13 years of diabetes duration, even if the prevalence of retinopathy and especially nephropathy was lower than usually reported. The clinical picture at onset of diabetes was unchanged the last 25 years. There was no secular trend of partial diabetes remission or C-peptide secretion during the first years after diagnosis.