Winner's curse: The sad aftermath of the discovery of insulin.

Every young researcher dreams of making a great discovery, but few achieve it. If they do, success does not guarantee happiness. There is little satisfaction in discovering something if others get the credit, and those who achieve fame must face the 'winner's curse' of living up to their reputation. Few discoveries have been more dramatic than the isolation of insulin which, as Michael Bliss said, resembled a secular miracle. And yet, as he also pointed out, this great discovery brought little happiness to those who made it. Some were sidelined, and Banting and Best were saddled with the winner's curse. Here, we look at the ways in which a great discovery can haunt its discoverers.

Islet autoimmunity in children with Down's syndrome.

There is an unexplained excess of type 1 diabetes and other organ-specific autoimmune diseases in children with Down's syndrome, but the immunogenetic characteristics of diabetes in Down's syndrome have not been investigated. We studied the frequency of islet autoantibodies in 106 children with Down's syndrome and no history of autoimmunity and analyzed HLA class II genotypes in 222 children with Down's syndrome, 40 children with Down's syndrome and type 1 diabetes, 120 age- and sex-matched children with type 1 diabetes, and 621 healthy control subjects. Co-occurrence of at least two islet autoantibody markers was observed in 6 of 106 nondiabetic children with Down's syndrome compared with 13 of 2,860 healthy age-matched children (P < 0.001). There was an excess of diabetes-associated HLA class II genotypes in children with Down's syndrome and type 1 diabetes compared with age- and sex-matched healthy control subjects (P < 0.001). Down's syndrome children with type 1 diabetes were, however, less likely to carry the highest risk genotype DR4-DQ8/DR3-DQ2 than children with type 1 diabetes from the general population (P = 0.01) but more likely to carry low-risk genotypes (P < 0.0001). The frequency of subclinical islet autoimmunity is increased in Down's syndrome, and susceptibility to type 1 diabetes in Down's syndrome is partially HLA mediated. Other factors, possibly including genes on chromosome 21, may increase the penetrance of type 1 diabetes in Down's syndrome.

Is puberty an accelerator of type 1 diabetes in IL6-174CC females?

The pubertal peak in onset of type 1 diabetes occurs earlier in girls than boys. We postulated that this sex difference might be mediated in part by estrogen or by genes regulated by estrogen, such as the interleukin-6 (IL6) gene. Previous studies concerning the role of an estrogen-sensitive single nucleotide polymorphism (SNP) in the IL6 promoter in type 1 diabetes have proved contradictory. We therefore selected a large, genetically homogenous population-based cohort, analyzed by age at onset and sex, to test the hypothesis that the IL6-174G>C SNP affects age at onset of type 1 diabetes in females but not in males. We found that the IL6-174CC genotype was significantly less frequent in females diagnosed after than in those diagnosed before the age of 10 years (19 vs. 13%, P = 0.016). No genotype difference was observed in males stratified for age at onset. Among children diagnosed after age 10, the median age of onset was 11.9 years (intraquartile range 10.7-14.6) in 34 girls homozygous for IL6-174C compared with 13.2 years (11.6-15.4) in 229 girls with other genotypes and 13.5 years (12.0-15.6) in 339 males with any IL6-174 genotype (P = 0.012). These data support the hypothesis that pubertal changes may contribute to accelerated onset of type 1 diabetes in genetically susceptible females. This phenomenon may be orchestrated by the action of estrogen on the IL6 promoter.

The rise of childhood type 1 diabetes in the 20th century.

The incidence of childhood type 1 diabetes increased worldwide in the closing decades of the 20th century, but the origins of this increase are poorly documented. A search through the early literature revealed a number of useful but neglected sources, particularly in Scandinavia. While these do not meet the exacting standards of more recent surveys, tentative conclusions can be drawn concerning long-term changes in the demography of the disease. Childhood type 1 diabetes was rare but well recognized before the introduction of insulin. Low incidence and prevalence rates were recorded in several countries over the period 1920-1950, and one carefully performed study showed no change in childhood incidence over the period 1925-1955. An almost simultaneous upturn was documented in several countries around the mid-century. The overall pattern since then is one of linear increase, with evidence of a plateau in some high-incidence populations and of a catch-up phenomenon in some low-incidence areas. Steep rises in the age-group under 5 years have been recorded recently. The disease process underlying type 1 diabetes has changed over time and continues to evolve. Understanding why and how this produced the pandemic of childhood diabetes would be an important step toward reversing it.

High familial risk and genetic susceptibility in early onset childhood diabetes.

Early onset type 1 diabetes is associated with rapid beta-cell failure and high levels of HLA-mediated genetic susceptibility. We examined familial risk of disease in relation to age at onset in 1,299 families participating in the Bart's Oxford population-based family study of type 1 diabetes. Risk of diabetes was estimated by survival analysis in 1,430 siblings and 2,419 parents and related to age at onset in the proband. Unaffected relatives at high risk were identified by measurement of islet autoantibodies, and HLA class II genotyping was performed in probands where DNA was available (573 children). The cumulative risk of diabetes by age 20 years was 11.7% in siblings of probands diagnosed before age 5 years, compared with 3.6% for ages 5-9 years and 2.3% for ages 10-14 years (P < 0.0001). In parents, the cumulative risk by age 40 years was 5.9% if the proband was diagnosed before age 5 years, compared with 3.7% for ages 5-9 years and 3.7% for ages 10-14 years (P = 0.04). Of 1,169 unaffected siblings tested at study entry, 7.3% had two or more autoantibody markers if the proband was diagnosed before age 5 years, compared with 2.2 and 2.4%, respectively, for ages 5-9 and 10-14 years (P = 0.002). The frequency of the highest risk genotype decreased with increasing age at onset. Of children diagnosed before age 5 years, 52% were heterozygous for HLA DRB1*03-DQA1*0501-DQB1*02/DRB1*04-DQA1*0301-DQB1*0302 compared with 32% and 33%, respectively, for children diagnosed at ages 5-9 and 10-14 years (P < 0.001). Diabetes with onset before age 5 years is therefore a marker of high familial risk.

Activating mutations in the KCNJ11 gene encoding the ATP-sensitive K+ channel subunit Kir6.2 are rare in clinically defined type 1 diabetes diagnosed before 2 years.

We have recently shown that permanent neonatal diabetes can be caused by activating mutations in KCNJ11 that encode the Kir6.2 subunit of the beta-cell ATP-sensitive K(+) channel. Some of these patients were diagnosed after 3 months of age and presented with ketoacidosis and marked hyperglycemia, which could have been diagnosed as type 1 diabetes. We hypothesized that KCNJ11 mutations could present clinically as type 1 diabetes. We screened the KCNJ11 gene for mutations in 77 U.K. type 1 diabetic subjects diagnosed under the age of 2 years. One patient was found to be heterozygous for the missense mutation R201C. She had low birth weight, was diagnosed at 5 weeks, and did not have a high risk predisposing HLA genotype. A novel variant, R176C, was identified in one diabetic subject but did not cosegregate with diabetes within the family. In conclusion, we have shown that heterozygous activating mutations in the KCNJ11 gene are a rare cause of clinically defined type 1 diabetes diagnosed before 2 years. Although activating KCNJ11 mutations are rare in patients diagnosed with type 1 diabetes, the identification of a KCNJ11 mutation may have important treatment implications.

The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes.

The incidence of childhood type 1 diabetes has risen over the past 50 years. We compared the frequency of HLA class II haplotypes in 194 patients diagnosed more than 50 years ago and 582 age-matched and sex-matched individuals diagnosed between 1985 and 2002. The proportion of high-risk susceptibility genotypes was increased in the earlier cohort (p=0.003), especially in those diagnosed at age 5 years or younger, which is consistent with the hypothesis that the rise of type 1 diabetes is due to a major environmental effect.

Association of intercellular adhesion molecule-1 gene with type 1 diabetes.

Intercellular adhesion molecule-1 (ICAM-1) functions via its ligands, the leucocyte integrins, in adhesion of immune cells to endothelial cells and in T cell activation. The third immunoglobulin-like extracellular domain binds integrin Mac-1 and contains a common non-conservative aminoacid polymorphism, G241R. Phenotypically, ICAM-1 has been associated with type 1 diabetes, a T-cell-mediated autoimmune disease. We assessed two independent datasets, and noted that R241 was associated with lower risk of type 1 diabetes than is G241 (3695 families, relative risk 0.91, p=0.03; 446 families, 0.60, p=0.006). Our data indicate an aetiological role for ICAM-1 in type 1 diabetes, which needs to be confirmed in future genetic and functional experiments.

Survival of the fittest? Natural selection in islet transplantation.

The full potential of cadaveric islet transplantation will only be realized by avoiding both pretransplant insults programming islets for subsequent death and posttransplant triggers for apoptosis and necrosis. The immediate blood mediated inflammatory response causes significant islet loss in the immediate posttransplant period. However, if we focus on this alone we will miss many opportunities to improve transplanted islet survival. Even when single donor islet transplants become the norm, there will still be more patients who might benefit from islet transplants than grafts available. Input from "transplanters" and diabetologists is essential in order to select appropriate patients for islet transplantation.

Smoke or fire? Acute pancreatitis and the liraglutide trials.

Over the past few years, substantial clinical data have been presented showing that incretin-based therapies are effective glucose-lowering agents. Specifically, glucagon-like peptide 1 receptor agonists demonstrate an efficacy comparable to insulin treatment with minimal hypoglycemia and have favorable effects on body weight. Thus, many of the unmet clinical needs noted from prior therapies are addressed by these agents. However, even after many years of use, many continue to raise concerns about the long-term safety of these agents and, in particular, the concern with pancreatitis. This clearly remains a complicated topic. Thus, in this issue of Diabetes Care, we continue to update our readers on this very important issue by presenting two studies evaluating incretin-based medications and risk of pancreatitis. Both have undergone significant revisions based on peer review that provided significant clarification of the data. We applaud both author groups for being extremely responsive in providing the additional data and revisions requested by the editorial team. As such, because of the critical peer review, we feel both articles achieve the high level we require for Diabetes Care and are pleased to now present them to our readers. In keeping with our aim to comprehensively evaluate this topic, we asked for additional commentaries to be prepared. In the narrative outlined below, Prof. Edwin A.M. Gale provides a commentary on the report that focuses on clinical trials of liraglutide in the treatment of diabetes. In the narrative that follows Prof. Gale's contribution, Dr. Laurent Azoulay provides a commentary about the remaining uncertainty in this area and also discusses the results from a nationwide population-based case-control study. From the journal's perspective, both of the articles on pancreatitis and incretin-based therapies reported in this issue have been well vetted, and we feel both of the commentaries are insightful.

Productivity of authors in the field of diabetes: bibliographic analysis of trial publications.

OBJECTIVE: To determine whether trial publications of glucose lowering drugs are dominated by a small group of highly prolific authors ("supertrialists") and to identify some of their characteristics. DESIGN: Bibliographic analysis of trial publications. DATA SOURCES AND REVIEW METHODS: We searched PubMed for all randomised controlled trials (RCTs) relating to glucose lowering drugs published between 1 January 1993 and 31 December 2013. From these publications we identified the 110 most prolific authors using PubReMiner. The 991 RCTs they published were examined for various characteristics such as author number, commercial sponsorship, company authorship, conflicts of interest, etc. The track record of the top 11 authors was studied in more detail. MAIN OUTCOME MEASURE: Proportion of articles published by the top 110 and the top 11 authors. RESULTS: 3782 articles from 13,592 authors were identified. The top 110 authors were named in 1227 (32.4%) of all articles, and the top 11 authors in 397 (10.5%) of all articles. The top 110 authors published 991 RCTs for a median of 20 (range 4-77) RCTs per author; the top 11 published 354 RCTs for a median of 42 (36-77) RCTs per author. Of the 110 top authors, 48 were employed by a pharmaceutical company. Of the 991 RCTs, 906 were commercially sponsored. Of 704 articles that could be assessed for conflicts of interest, only 42 (6%) were considered fully independent. Medical writing assistance was acknowledged in 439 (44.3%) of 991 RCTs. CONCLUSION: The past two decades have seen an explosive increase in the number of published clinical trials regarding glucose lowering treatment. Some authors have made a disproportionate contribution to the therapeutic evidence base; one third of the RCT evidence base on glucose lowering drug treatment for diabetes was generated by <: 1% of authors. Of these, 44% were company employees and 56% were academics who work closely with the pharmaceutical companies.