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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., Competing Interests: Declaration of competing interest SDP has received lecture and/or advisory fees from Applied Therapeutics, Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Sanofi, Takeda Pharmaceuticals. He also receives research support from AstraZeneca and Boehringer Ingelheim. PF, MA, AB, CB, FC and MG have no potential conflicts to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

The events and people surrounding the discovery of insulin as an effective therapy for diabetes in 1921 represent a compelling story that is directly relevant to the lives, and indeed the existence, of tens of millions of people worldwide. This story begins in the 19th century with the recognition that diabetes is a disease of hyperglycemia that arises because of the absence of a pancreatic hormone, that rapidly leads to death in people classified as having "thin diabetes" and that is linked to serious end-organ damage and other health consequences in people identified as having "fat diabetes." It continues with the recognition that pancreatic extracts can treat this problem in de-pancreatectomized dogs, and culminates with the dogged determination of a young, newly certified Canadian physician, Frederick Banting. Together with his supervisor, Professor John J.R. MacLeod (head of physiology at the University of Toronto), Banting, Charles H. Best (a physiology student) and James Collip (a professor of biochemistry at the University of Alberta, on sabbatical leave in Toronto) repeated these dog experiments and then successfully tested a purified pancreatic extract in a 13-year-old boy with type 1 diabetes in January 1922. This first successful test was followed by the rapid development and dissemination of the technology for insulin production worldwide. These events and insulin therapy's lifesaving effects on people with type 1 diabetes led to the awarding of the 1923 Nobel Prize in Physiology or Medicine to Banting and MacLeod, who shared their awards with Best and Collip., (Copyright © 2021 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021. Published by Elsevier Masson SAS.)

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., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2020 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

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.

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The author acknowledges the potential conflict of interest in having a family member treated with nusinersen.

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Type 1 diabetes is associated with such complications as blindness, kidney failure, and nerve damage. Replacing C-peptide, a hormone normally co-secreted with insulin, has been shown to reduce diabetes-related complications. Interestingly, after nearly 30 years of positive research results, C-peptide is still not being co-administered with insulin to diabetic patients. The following review discusses the potential of C-peptide as an auxilliary replacement therapy and why it's not currently being used as a therapeutic.

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.

Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. Later, during the mid-1930s, clinical observations suggested a possible distinction between 'insulin-sensitive' and 'insulin-insensitive' diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms 'insulin-dependent' (indicating undetectable insulin levels) and 'non-insulin-dependent' (normal or high insulin levels) started to emerge. The next 30 years were characterised by pivotal progress in the field of immunology that were instrumental in demonstrating an immune-mediated loss of insulin-secreting β-cells in subjects with 'insulin-dependent' diabetes. At the same time, new experimental techniques allowing measurement of insulin 'impedance' showed a reduced peripheral effect of insulin in subjects with 'non-insulin-dependent' diabetes (insulin resistance). The difference between the two types of diabetes emerging from decades of observations and experiments was further formally recognised in 1979, when the definitions 'type I' and 'type II' diabetes were introduced to replace the former 'insulin-dependent' and 'non-insulin-dependent' terms. In the following years, many studies elucidated the natural history and temporal contribution of insulin resistance and β-cell insulin secretion in 'type II' diabetes. Furthermore, a central role for insulin resistance in the development of a cluster of cardiometabolic alterations (dyslipidaemia, inflammation, high blood pressure) was suggested. Possibly as a consequence of the secular changes in diabetes risk factors, in the last 10 years the limitation of a simple distinction between 'type I' and 'type II' diabetes has been increasingly recognised, with subjects showing the coexistence of insulin resistance and immune activation against β-cells. With the advancement of our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple 'glucocentric' view could result in a better patient phenotyping and therapeutic approach., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Studies have suggested sex differences in the mortality rate associated with type 1 diabetes. We did a meta-analysis to provide reliable estimates of any sex differences in the effect of type 1 diabetes on risk of all-cause mortality and cause-specific outcomes., Methods: We systematically searched PubMed for studies published between Jan 1, 1966, and Nov 26, 2014. Selected studies reported sex-specific estimates of the standardised mortality ratio (SMR) or hazard ratios associated with type 1 diabetes, either for all-cause mortality or cause-specific outcomes. We used random effects meta-analyses with inverse variance weighting to obtain sex-specific SMRs and their pooled ratio (women to men) for all-cause mortality, for mortality from cardiovascular disease, renal disease, cancer, the combined outcome of accident and suicide, and from incident coronary heart disease and stroke associated with type 1 diabetes., Findings: Data from 26 studies including 214 114 individuals and 15 273 events were included. The pooled women-to-men ratio of the SMR for all-cause mortality was 1·37 (95% CI 1·21-1·56), for incident stroke 1·37 (1·03-1·81), for fatal renal disease 1·44 (1·02-2·05), and for fatal cardiovascular diseases 1·86 (1·62-2·15). For incident coronary heart disease the sex difference was more extreme; the pooled women-to-men ratio of the SMR was 2·54 (95% CI 1·80-3·60). No evidence suggested a sex difference for mortality associated with type 1 diabetes from cancer, or accident and suicide., Interpretation: Women with type 1 diabetes have a roughly 40% greater excess risk of all-cause mortality, and twice the excess risk of fatal and nonfatal vascular events, compared with men with type 1 diabetes., Funding: None., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The aim of the article is an effort to capture the history of insulin production in Czechoslovakia. Information has been obtained mainly from two Czech journals: "Časopis lékařů českých" (published since 1862) and "Praktický lékař" (published since 1921). At first, imported insulin in the form of insulin injections or substances from which insulin was prepared appeared at the market in Czechoslovakia. During years 1923-1945, insulin was produced by five companies, since 1945 only by one company "Léčiva".

The definition of optimal glycemic control in pregnancies affected by diabetes remains enigmatic. Diabetes phenotypes are heterogeneous. Moreover, fetal macrosomia insidiously occurs even with excellent glycemic control. Current blood glucose (BG) targets (FBG ≤95, 1-h post-prandial <140, 2 h <120 mg/dL) have improved perinatal outcomes, but arguably they have not normalized. The conventional management approach has been to replicate a pattern of glycemia in normal pregnancy. Although these patterns are lower than previously appreciated, a randomized controlled trial (RCT) has never compared current vs. lower glucose targets powered on maternal/fetal outcomes. This paper provides historical context to the current targets by reviewing evidence supporting their evolution. Using lower targets (FBG <90, 1 h <122, 2 h <110, mean BG ≤95 mg/dL) may help normalize outcomes, but phenotypic differences (type 1 vs. type 2 vs. gestational diabetes) might require different glycemic goals. There remains a critical need for well-designed RCTs to confirm optimal glycemic control that minimizes both small for and large for gestational age across pregnancies affected by diabetes.

Over the 50 years from 1964 to 2014, outcomes for children with type 1 diabetes have improved significantly, because of both technological advancements and changes in management philosophy. For the child with type 1 diabetes in 2014, intensive management with multiple daily injections or insulin pump therapy and the support of a specialist multidisciplinary team is now standard care. The main treatment goal is no longer the avoidance of hypoglycaemia, but the minimisation of hyperglycaemia and glucose variability, thereby reducing the risk of microvascular complications. However, the inherent burden of care and diligence required by patients and families, if they are to maintain optimal diabetes control, have not changed and may even have increased. While the long sought-after cure for diabetes remains elusive, artificial pancreas or closed-loop systems hold the most promise for improving the burden of care in the near term for children and adolescents with type 1 diabetes., (© 2014 The Author. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Diabetes mellitus, an endocrine disorder affecting glucose metabolism, has been crippling mankind for the past two centuries. Despite the advancements in the understanding pertaining to its pathogenesis and treatment, the currently available therapeutic options are far from satisfactory. The growing diabetic population increases the gravity of the situation. The shortcomings of the conventional drug delivery systems necessitate the need to delve into other routes. On account of its merits over other routes, the transdermal approach has drawn the interest of the researchers around the world. The transdermal drug delivery systems are aimed to achieve therapeutic concentrations of the drug through skin. These systems are designed so that the drug can be delivered at a pre-determined and controlled rate. This makes it particularly conducive to treat chronic disorders like diabetes. Correspondingly, the adverse effects and inconvenience concomitant with oral and parentral route are circumvented. This article attempts to outline the development of transdermal drug delivery systems to optimize diabetes pharmacotherapy. It not only covers the transdermal approaches adopted to fine-tune insulin delivery, but also, discusses various transdermal drug delivery systems fabricated to improve the therapeutic performance of oral hypoglycaemic agents. Such formulations include the advanced drug delivery systems, namely, transferosomal gels, microemulsions, self-dissolving micropiles, nanoparticles, insulin pumps, biphasic lipid systems, calcium carbonate nanoparticles, lecithin nanoparticles; physical techniques such as iontophoresis and microneedles and, drugs formulated as transdermal patches. In addition to this, the authors have also shed light on the future prospects and patented and commercial formulations of antidiabetic agents.

George S. Eisenbarth will remain in our memories as a brilliant scientist and great collaborator. His quest to discover the cause and prevention of type 1 (autoimmune) diabetes started from building predictive models based on immunogenetic markers. Despite his tremendous contributions to our understanding of the natural history of pre-type 1 diabetes and potential mechanisms, George left us with several big questions to answer before his quest is completed.

George Eisenbarth's pioneering and visionary research has provided a critical foundation that will be built on in the years ahead as we progress toward prevention of type 1 diabetes. His almost 30-year old model that type 1 diabetes was a chronic and predictable autoimmune disease with multiple identifiable progressive stages with a potential for interventions to prevent progression to symptomatic diabetes has stood the test of time. To deliver on the Eisenbarth vision and his "unfinished journey," the field needs: (1) to improve detection of risk of type 1 diabetes, (2) to improve staging and prediction of progression, (3) to perform smaller, shorter, practical, and an increased number of prevention clinical trials, and (4) to increase awareness of the potential for risk detection, staging, and prevention of type 1 diabetes and benefit/risk of prevention.

Pancreatic islet cell transplantation is a promising cellular-based therapy for type 1 diabetes mellitus. This procedure involves portal venous injection of islet cells and affords 1-year insulin independence in as many as 80% of recipients. Although transplant surgeons represent historical drivers of islet therapy, requirement for image guidance and transcatheter techniques has fostered collaboration with interventional radiologists, who are positioned to play a significant role in clinical performance of islet transplantation and in basic science research in this field. This review article aims to familiarize interventional radiologists with islet cell transplantation patient selection, procedure technique, clinical outcomes, and future clinical and research avenues., (Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.)

2012 marks the 90th year since the purification of insulin and the miraculous rescue from death of youngsters with type 1 diabetes. In this review, we highlight several previously unappreciated or unknown events surrounding the discovery. (i) We remind readers of the essential contributions of each of the four discoverers--Banting, Macleod, Collip, and Best. (ii) Banting and Best (each with his own inner circle) worked not only to accrue credit for himself but also to minimize credit to the other discoverers. (iii) Banting at the time of the insulin research was very likely suffering from post-traumatic stress disorder (PTSD) that originated during his heroic service as a surgeon in World War I on the Western Front in 1918, including an infected shrapnel wound that threatened amputation of his arm. His war record along with the newly discovered evidence of a suicide threat goes along with his paranoia, combativeness, alcohol excess, and depression, symptoms we associate with PTSD. (iv) Banting's eureka idea, ligation of the pancreatic duct to preserve the islets, while it energized the early research, was unnecessary and was bypassed early. (v) Post discovery, Macleod uncovered many features of insulin action that he summarized in his 1925 Nobel Lecture. Macleod closed by raising the question--what is the mechanism of insulin action in the body?--a challenge that attracted many talented investigators but remained unanswered until the latter third of the 20th century., (Copyright © 2012 John Wiley & Sons, Ltd.)