Insulin discovery: A pivotal point in medical history.

The discovery of insulin in 1921 - due to the efforts of the Canadian research team based in Toronto - has been a landmark achievement in the history of medicine. Lives of people with diabetes were changed forever, considering that in the pre-insulin era this was a deadly condition. Insulin, right after its discovery, became the first hormone to be purified for human use, the first to be unraveled in its amino acid sequence and to be synthetized by DNA-recombinant technique, the first to be modified in its amino acid sequence to modify its duration of action. As such the discovery of insulin represents a pivotal point in medical history. Since the early days of its production, insulin has been improved in its pharmacokinetic and pharmacodynamic properties in the attempt to faithfully reproduce diurnal physiologic plasma insulin fluctuations. The evolution of insulin molecule has been paralleled by evolution in the way the hormone is administered. Once-weekly insulins will be available soon, and glucose-responsive "smart" insulins start showing their potential in early clinical studies. The first century of insulin as therapy was marked by relentless search for better formulations, a search that has not stopped yet. New technologies may have, indeed, the potential to provide further improvement of safety and efficacy of insulin therapy and, therefore, contribute to improvement of the quality of life of people with diabetes.

100 YEARS OF INSULIN: Pancreas pathology in type 1 diabetes: an evolving story.

We review the current knowledge of pancreas pathology in type 1 diabetes. During the last two decades, dedicated efforts toward the recovery of pancreas from deceased patients with type 1 diabetes have promoted significant advances in the characterization of the pathological changes associated with this condition. The implementation of autoantibody screening among organ donors has also allowed examining pancreas pathology in the absence of clinical disease, but in the presence of serological markers of autoimmunity. The assessment of key features of pancreas pathology across various disease stages allows driving parallels with clinical disease stages. The main pathological abnormalities observed in the pancreas with type 1 diabetes are beta-cell loss and insulitis; more recently, hyperexpression of HLA class I and class II molecules have been reproduced and validated. Additionally, there are changes affecting extracellular matrix components, evidence of viral infections, inflammation, and ER stress, which could contribute to beta-cell dysfunction and the stimulation of apoptosis and autoimmunity. The increasing appreciation that beta-cell loss can be less severe at diagnosis than previously estimated, the coexistence of beta-cell dysfunction, and the persistence of key features of pancreas pathology for years after diagnosis impact the perception of the dynamics of this chronic process. The emerging information is helping the identification of novel therapeutic targets and has implications for the design of clinical trials.

Evolución de la incidencia de diabetes mellitus tipo 1 (0-14 años) en la Comunidad de Madrid, 1997-2016 / Evolution of the incidence of type 1 diabetes mellitus in the Community of Madrid, 1997-2016

Introducción: El objetivo fue estimar la incidencia de diabetes tipo 1 (DM1) en la población infantil de la Comunidad de Madrid (CM) y su evolución entre 1997 y 2016, a partir de los datos médicos-administrativos del registro regional de DM1. Métodos: Fueron incluidos los casos de DM1 de menores de 15 años, notificados al registro regional o captados de fuentes secundarias: Asociación Diabéticos Españoles (1997-2013) y a partir de 2014 del conjunto mínimo básico de datos (CMBD) hospitalario. Se estimaron las tasas de incidencia anual por 100.000 personas-año. La comparación de las tasas se analizó mediante modelos de regresión de Poisson a través de razones de incidencia (RI). Resultados: Un total de 2658 casos fueron identificados como nuevos diagnósticos de DM1. La tasa de incidencia media de 1997-2013 fue de 13,7 casos por 100.000 personas-año. En el periodo 2014-2016, utilizando el CMBD se registraron 20,0 casos por 100.000. El grupo de edad con mayor incidencia fue el de 10-14 años en los 2periodos (16,6 vs. 25,5). En los niños, la edad de mayor incidencia fue de 10 a 14 años en ambos periodos (17,9 vs. 30,4) y en las niñas el de 5 a 9 años (17,0 vs. 25,1). Las tasas de incidencia descendieron ligeramente en ambos sexos hasta 2013 (de 15,0 a 11,6); en 2014-2016 la tasa de incidencia anual varió entre 18,4 y 21,1 casos (RI: 1,77). La incidencia permaneció estable en menores de 5 años y aumentó de 5 a 14 años. Conclusiones: La CM se sitúa entre las regiones de alta incidencia de DM1. En su primera fase, el registro regional infraestimaba la incidencia de DM1. Con la incorporación del CMBD como fuente de información, las estimaciones del segundo periodo (2014-2016) son posiblemente más próximas a la incidencia real de DM1. Los datos que presentamos sugieren la necesidad de conocer la evolución real de la incidencia de la enfermedad incorporando los registros digitales sanitarios. (AU)

Introduction: The objective of this article was to estimate the type 1 diabetes mellitus (DM1) incidence in the child population of the Community of Madrid (CM) and its evolution between 1997 and 2016, using the medical-administrative data of the regional registry of DM1. Methods: DM1 cases of children under 15 years of age, reported to the regional registry or collected from secondary sources were included: Spanish Diabetics Association (1997-2013), and from 2014 on the Basic Minimum Data Set (BMDS). Annual incidence rates were estimated per 100 000 person-years. The comparison of the rates was analysed using Poisson regression models using incidence ratios (IR). Results: A total of 2658 cases were identified as new diagnoses of DM1. The mean incidence rate for 1997-2013 was 13.7 cases per 100 000 person-years. In the 2014-2016 period, 20 cases per 100 000 persons-years were registered using the BMDS. The age group with the highest incidence was 10-14 years in the 2periods (16.6 vs. 25.5). In boys, the age with the highest incidence was 10 to 14 years in both periods (17.9 vs 30.4), and in girls, the age of 5 to 9 years (17.0 vs 25.1). Incidence rates decreased slightly in both genders until 2013 (from 15.0 to 11.6). In 2014-2016, the annual incidence rate varied between 18.4 and 21.1 cases (IR: 1.77). The incidence remained stable in children under 5 years old and increased from 5 to 14 years old. Conclusions: The CM is among the regions with a high incidence of DM1. In its first phase, the regional registry underestimated the incidence of DM1, and with the incorporation of the MBDS as a source of information, the estimates for the second period (2014-2016) are possibly closer to the actual incidence of DM1. The data presented suggests the need to know the real evolution of the incidence of the disease by incorporating computerised health records. (AU)

BCG turns 100: its nontraditional uses against viruses, cancer, and immunologic diseases.

First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.

Living with Insulin: The story of insulin from people with diabetes.

The history of insulin is rightly considered one of the most beautiful stories in medicine which goes even further than the extraordinary result of tens of millions of lives saved. Without a doubt, it constitutes a major achievement for medical science which, especially in the last 50 years, has led to an impressive acceleration in the succession of new treatment opportunities. We are going to describe the history of insulin therapy, the history we lived from two different angles as people living with type 1 diabetes, and obviously also as diabetologists, but as diabetologists with diabetes. Without a doubt, insulin and his story constitutes a major achievement for medical science which has led to an impressive acceleration in the succession of new treatment opportunities. Care opportunities that have not only allowed fundamental improvements in outcomes, but have also and above all impacted the quality of life of people with diabetes. Summarizing one hundred years of insulin is no simple endeavor. In our view, it would be easier, and probably more befitting, to focus on the last 50 years, namely the period we have lived closely and personally together with insulin. More to the point, these last 50 years have witnessed a dramatic acceleration of research and innovation. In our opinion, it is precisely the innovations in insulin therapy introduced from the last decades that fully justify the description of events in this incredible period as "the miracle of insulin". We'll describe how the most important innovations introduced in the last decades had impact on what we have nowadays, as patients and diabetologits: today, we can finally adapt insulin therapy to the patient's life or lifestyle, reversing what was the perception of patients until 20 years, when insulin was considered, by the most, as an obstacle, which seemed insurmountable to some, to a free and unconstrained life.

1921-2021: From insulin discovery to islet transplantation in type 1 diabetes.

One century after the discovery of insulin, the French Health regulations have just authorized the reimbursement for islet transplantation. Intraportal islet allotransplantation from a pancreatic donor is indicated in patients with type 1 diabetes (T1D) complicated with lability or hypoglycemia unawareness, or in case of a functioning kidney graft; islet auto-transplantation may be indicated after pancreatic surgery.Compared with insulin even administered in closed-loop pumps, the specificity of islet allotransplantation is the restoration of C-peptide secretion. Long-term insulin-independence is observed when the engrafted islet mass is sufficient, at the cost of immunosuppression. Fewer low-glucose events and less glucose variability, are observed even with minimal functional islet graft, after islet transplantation as at onset of T1D, when a residual C-peptide secretion is maintained, an objective currently approached with less aggressive immuno-modulating therapies than in the past. Therefore, restoration or preservation of endogen insulin secretion is an important goal, allowing to maintain a long-term glucose balance with more than 70% of time in range 3.9-10mmol/L and less than 3% of time <3.9mmol/L, thus reducing the occurrence of diabetic complications. In the clinical setting, - the preservation of C-peptide at early stage of T1D, - the use of technological ressources (multi-injections, sensors, insulin pump, closed-loop systems) at later stages, - and islet transplantation when hypoglycemia awareness becomes impaired are complementary for a personalized care all along the life of T1D patients.

Time trends in incidence of diabetes mellitus in Austrian children and adolescents <15 years (1989-2017).

OBJECTIVE: To analyze the time trends of nationwide diabetes incidence <15 years of age from 1989 until 2017 in Austria. METHODS: The Austrian Diabetes Incidence Study Group registers all newly diagnosed patients with diabetes mellitus <15 years of age in a prospective population-based study. The diabetes type was classified on the basis of clinical and laboratory findings according to American Diabetes Association criteria. Time trends were estimated by Joinpoint analysis. RESULTS: 1311 patients were diagnosed with type 1 diabetes (T1D) between 1989 and 1999 and 4624 patients with any type of diabetes (1999-2017). T1D accounted for the majority of cases (94.2%), 1.8% were classified as type 2 (T2D) and 4.0% as other specific types of diabetes (1999-2017). In the total cohort (age 0 to <15 years), a constant increase until 2012 (annual percent change [APC] 4.5, 95% confidence interval [CI]: 3.94, 5.06) was observed, followed by a leveling off with a corresponding drop (APC 0.28, 95%CI: -3.94, 4.69). This observation was mainly driven by the dynamic in the youngest age group (0-4 years) with a steep increase until 2007 (APC 7.1, 95%CI: 5.05, 9.19) and a decrease from 2007 to 2017 (APC -0.86, 95%CI: 4.41, 2.82). No significant increase of T2D <15 years was detected. Over the observed time period (APC = 3.7, 95%CI: -0.30, 7.78). CONCLUSIONS: The incidence of T1D is declining in young children aged 0 to 4 years, but is still rising in children 5 to 14 years in Austria. Incidence of T2D did not increase significantly and other specific types of diabetes occur twice as often compared to T2D.

Incidence of type 1 diabetes in 0 to 14 year olds in Australia from 2002 to 2017.

OBJECTIVE: To determine the incidence of childhood onset type 1 diabetes in Australia from 2002 to 2017, and analyze incidence rate trends by calendar year, sex, and age at diagnosis. RESEARCH DESIGN AND METHODS: Children newly diagnosed with type 1 diabetes aged <15 years between 2002 and 2017 were identified from the National Diabetes Register, estimated to be ~99% complete. Data were obtained for diagnosis year, sex, age, and residential State/Territory at time of diagnosis. Population estimates by year, sex, single year of age, and State/Territory were obtained from the Australian Bureau of Statistics and Poisson regression used to examine incidence and trends by calendar year, sex, and age group at diagnosis. RESULTS: Between 2002 and 2017, there were 16 783 newly diagnosed cases of type 1 diabetes in children aged < 15 years (8684 boys: 8099 girls), giving a mean incidence of 25.0/1 00 000 person years (95%CI: 24.6, 25.4). A sinusoidal pattern in the incidence rate trend was observed with 5-yearly cycles providing the best model fit. No significant difference was observed in boys compared to girls (IRR 0.98 [95%CI: 0.95, 1.01]). Compared to 0 to 4 year olds, the mean incidence was 75% higher in 5 to 9 year olds, and 224% higher in 10 to 14 year olds. A decreasing incidence rate trend was observed in 0 to 4 year old boys and girls. CONCLUSIONS: This study reports updated incidence and incidence rate trends in children and adolescents diagnosed with type 1 diabetes in Australia. A cyclical pattern in incidence trend persists, with an overall decreasing trend observed only in the youngest age group.

Increasing incidence of type 1 diabetes among Hong Kong children and adolescents: The Hong Kong Childhood Diabetes Registry 2008 to 2017.

OBJECTIVE: The incidence of childhood-onset type 1 diabetes (T1D) has been reported to be rising but there is also evidence that it has been attenuated in recent years. We described the time trends and the incidence of T1D in children in Hong Kong from 2008 to 2017 and compared with the previous local registry in 1997 to 2007. METHODS: Data were extracted from the Hong Kong Childhood Diabetes Registry, which was established in 2016. It consists of a retrospective registry (including all childhood diabetes diagnosed in 2008 to 2015) and a prospective registry (including all T1D children diagnosed from 2016 onwards). All T1D children diagnosed at the age of less than 18 years from 1 January 2008 to 31 December 2017 and managed in the public system were included in this study. RESULTS: For the incident years in the 2008 to 2017 period, a total of 498 children with T1D was identified. The crude incidence rate was 4.3 per 100 000 person/year (95% confidence interval 3.96-4.72), which was much higher than the last registry of 2.2 per 100 000 persons/year. Using general linear model, the increment is statistically significant (P = .02). When compared to the last registry, the rate of increment had attenuated, with annual increment in crude incidence in the two periods for T1D <15 years changing from 4.3% to 3.5% (P = .02). CONCLUSIONS: The incidence of T1D children increased significantly in the past two decades in Hong Kong, but the rate of increase had attenuated in recent years.

Hundred Years of Insulin Therapy: Purified Early Insulins.

BACKGROUND: The discovery of insulin has changed dramatically the outcome of patients with type 1 diabetes, giving them the possibility to survive. This is of particular concern due to the fact that type 1 diabetes most frequently occurs in children who were destined to die in ketoacidosis coma. AREAS OF UNCERTAINTY: From insulin discovery to the availability of human insulin and human insulin analogs to be used in diabetes therapy, a series of problems have arisen as the difficulty of insulin purifications, the animal insulin used by the first researches were in fact contaminated by proteins, fats, and other impurities, and the presence of side effects such as allergy, antibodies generation, and lipoatrophy. DATA SOURCE LITERATURE: Data strictly related to the argument have been searched in Pub Med and used. RESULTS: Starting from insulin discovery in 1921 to nowadays, significant efforts have been made by a series of researches to purify animal insulin, discover the molecular structure of human insulin, and develop methods to synthetize human insulin and then insulin analogs. CONCLUSIONS: The history of insulin discovery here reported is fascinating; insulin is a hormone, a product of biotechnology, a field of research that saved and save the life of many diabetic patients.

The re-emerging association between tuberculosis and diabetes: Lessons from past centuries.

The association between tuberculosis (TB) and diabetes mellitus (DM) had a common place in the literature up to the first half of the 20th century, but virtually disappeared with the discovery of insulin to treat DM and antibiotics to cure TB. In the late 1990s the literature began to re-emerge with the worldwide increase in type 2 DM, particularly in TB-endemic countries. Today, type 2 DM is the most prevalent comorbidity among TB patients and the World Health Organization considers it a threat to TB control. We summarize the literature on TB and DM up to the 1960s. Then we evaluate unique aspects of this comorbidity in older times, such as the frequent diabetic comas that suggest challenges for proper DM management as insulin was being implemented, or the absence of antibiotics to cure TB. Despite the unique aspects of each study period, the literature across times is consistent in key aspects of the association. Namely, a higher TB prevalence among DM (versus non-DM patients), the importance of glucose control and chronic DM on TB susceptibility and the higher risk of death among patients with the co-morbidity. From the older literature, we can infer the likely contribution of type 1 DM to TB (in addition to type 2), regardless of their differing autoimmune or metabolic pathophysiology, respectively. Furthermore, in the older literature there was a notable reporting of DM development among TB patients, even though DM usually preceded TB. This observation deserves further epidemiological and basic studies to elucidate this intriguing aspect of the relationship between TB and DM.

Diabetes, from the Origins of the Problem to the Nobel Prize. Bioethics.

Analysis of scientific works from the creation of an experimental model of diabetes before discovery insulin was done. Emphasized is the priority of the Russian pathologist L. W. Sobolew (1876-1919) in the discovery of the endocrine function of the pancreas in experimental animals - rabbits, dogs, cats. In 1923 Canadian scientists Banting and Macleod were awarded the Nobel prize for the discovery of insulin. However, the methods and the idea of Nobel laureates were the same that had been developed 20 years earlier by the Russian scientists. Currently, the incidence of diabetes and related pathologies of organs and systems are growing. The use of animals in experimental biology and medicine will continue for the foreseeable future. The benefits to science and medicine derived from the use of animals in research are undeniable, but this process inevitably increases the responsibility of researchers. It is required constant work on improvement of the experimental methods in order to minimize pain, stress, and the number of animals used in the experiment.