Laura M. Jacobsen

Type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic β-cell loss and leads to hyperglycaemia. Although the age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of β-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 — all of which are proteins associated with secretory granules in β-cells — are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent β-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected.

Errors in the diagnosis and management of necrotizing otitis externa

OBJECTIVE: Necrotizing otitis externa (NOE) is a life-threatening condition that may be difficult to distinguish from other clinical entities. The purpose of this study was to assess the pitfalls associated with contemporary diagnosis and management of NOE. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Patients given the diagnosis of NOE or one of its typical presenting complaints over the past 14 years were identified by diagnostic and radiology codes. Charts were reviewed for history, findings, treatment, and outcomes. RESULTS: Fifty-one patients with NOE were identified. The annual case numbers rose steadily. A risk factor was known in 46 patients. Gallium single-photon emission computed tomography was accurate for the presence (44 of 46 patients) and resolution of disease. Prolonged systemic antimicrobial therapy (mean 15 weeks, range 4–59 weeks) was required. Microbial cultures influenced therapy in only 50 percent. Two diabetic men died with disease. Of the cases seen at the request of otolaryngologists, 68 percent were for indications other than NOE (e.g., chronic otitis media). With a known risk such as diabetes, the mean time to diagnosis was 6.9 months. History of and clinical appearance overlapping with benign otitis were the primary reasons for diagnostic delay. CONCLUSION: NOE remains a life-threatening condition that requires prolonged antimicrobial therapy. Its incidence may be on the rise. NOE may develop in patients with benign otitis media and externa, and must be considered in all patients with temporal bone inflammation, especially those with risk factors and those who fail to improve with more conservative measures.

Current and future efforts toward the prevention of type 1 diabetes.

Great strides have been made in our understanding of the natural history of ‘pre‐type 1’ diabetes as well as in the post diagnosis period. For now, an inability to successfully prevent the disease limits screening outside of the research setting. While studies of both humans with various levels of risk for type 1 diabetes as well as animal models for the disease have increased our understanding of the disorder, the development of a safe and effective therapeutic intervention capable of reversing or preventing type 1 diabetes remains elusive. Worldwide primary, secondary, and tertiary prevention studies have been undertaken and both past and current studies are extensively reviewed in this manuscript. Intervention studies in new‐onset and established type 1 diabetes patients have to date shown fairly limited success with most effects seen within the first 6–12 months post therapy. Long‐term outcome remains to be determined. Improved and innovative trial designs, more rapid testing of both antigen specific and combination therapies in different populations (at‐risk, new‐onset, and established type 1 diabetes), continuing to fill the mechanistic voids in the etiopathogenesis of type 1 diabetes, and the development of validated biomarkers will hasten efforts toward reversing and preventing the disease. For successful prevention, therapy must be safe and must target not only effective control of the autoimmune process culminating in type 1 diabetes but also protection or replacement of lost β‐cell function.

Presumptive Type 1 Diabetes With Comorbidities and Rapid Progression Despite Numerous Insulin-Positive Islets

The subject was a 26-year-old African American female diagnosed with type 1 diabetes at the age of 11 years, treated with insulin injections, who died because of an anoxic brain injury likely secondary to diabetic ketoacidosis. The patient was found with agonal respirations and had acidosis along with severe hyperglycemia on arrival to the emergency department. In the 15 years since being diagnosed with diabetes, she had developed significant signs of cardiovascular disease including …

Pancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA

Context Monogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes. Objective Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology. Methods We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed. Results Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates. Conclusions Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.

High Illicit Drug Abuse and Suicide in Organ Donors With Type 1 Diabetes

Organ donors with type 1 diabetes represent a unique population for research. Through a combination of immunological, metabolic, and physiological analyses, researchers utilizing such tissues seek to understand the etiopathogenic events that result in this disorder. The Network for Pancreatic Organ Donors with Diabetes (nPOD) program collects, processes, and distributes pancreata and disease-relevant tissues to investigators throughout the world for this purpose (1). Information is also available, through medical records of organ donors, related to causes of death and psychological factors, including drug use and suicide, that impact life with type 1 diabetes. We reviewed the terminal hospitalization records for the first 100 organ donors with type 1 diabetes in the nPOD database, noting cause, circumstance, and mechanism of death; laboratory results; and history of illicit drug use. Donors were 45% female and 79% Caucasian. Mean age at time of death was 28 years (range 4–61) with mean disease duration of 16 years (range 0.25–52). Causes of death, based on death certificate, are presented …

T Cell Receptor Profiling in Type 1 Diabetes

Purpose of ReviewThe genetic susceptibility and dominant protection for type 1 diabetes (T1D) associated with human leukocyte antigen (HLA) haplotypes, along with minor risk variants, have long been thought to shape the T cell receptor (TCR) repertoire and eventual phenotype of autoreactive T cells that mediate β-cell destruction. While autoantibodies provide robust markers of disease progression, early studies tracking autoreactive T cells largely failed to achieve clinical utility.Recent FindingsAdvances in acquisition of pancreata and islets from T1D organ donors have facilitated studies of T cells isolated from the target tissues. Immunosequencing of TCR α/β-chain complementarity determining regions, along with transcriptional profiling, offers the potential to transform biomarker discovery.SummaryHerein, we review recent studies characterizing the autoreactive TCR signature in T1D, emerging technologies, and the challenges and opportunities associated with tracking TCR molecular profiles during the natural history of T1D.

Errors in the Diagnosis and Management of Necrotizing Otitis Externa

OBJECTIVES Necrotizing otitis externa (NOE) is a life-threatening condition that may be difficult to distinguish from other clinical entities. The purpose of this study was to assess the pitfalls associated with contemporary diagnosis and management of NOE. STUDY DESIGN Retrospective chart review. METHODS Patients given the diagnosis of NOE or one of its typical presenting complaints over the past 14 years were identified by diagnostic and radiology codes. Charts were reviewed for history, findings, treatment, and outcomes. RESULTS Fifty-one patients with NOE were identified. The annual number of cases rose throughout the study period. A risk factor was known in 46. The gallium SPECT study was accurate for the presence (44 of 46 patients) and resolution of disease. Prolonged systemic antimicrobial therapy (mean 15 weeks, range 4-59) was required. Microbial cultures influenced therapy in only 50%. Two diabetic men died with disease (a 44 year old with a renal transplant and an 87 year old with severe renal failure). Of the cases seen at the request of otolaryngologists, 68% were for indications other than NOE (eg, chronic otitis media). With a known risk such as diabetes, the mean time to diagnosis was 6.9 months. CONCLUSION NOE remains a life-threatening condition that requires prolonged antimicrobial therapy. Its incidence may be on the rise. NOE may mimic more benign conditions. NOE must be considered in all patients with temporal bone inflammation, especially those with risk factors and those that fail to improve with more conservative measures.

Presymptomatic screening for autoimmune β-cell disorder: Baby steps toward prevention?

Type 1 diabetes affects 1.54 per 1000 youth in the United States and the incidence is increasing 3% to 4% per year. The prevalence and incidence of type 1 diabetes mandate ongoing efforts to improve our capacity to alter the natural history of the disease. While the immunologic and metabolic changes associated with type 1 diabetes are often measurable years before symptoms emerge, type 1 diabetes largely remains a clinical diagnosis made on the basis of polyuria, nocturia, polydipsia, polyphagia, weight loss, and all too often, diabetic ketoacidosis (DKA). Nevertheless, using a combination of genetic (human leukocyte antigen, HLA) and serologic (islet autoantibodies) data, progression to type 1 diabetes is predicted with ever improving accuracy. The Diabetes Prevention Trial-Type 1, the Type 1 Diabetes TrialNet Pathway to Prevention study, and The Environmental Determinants of Diabetes in the Young (TEDDY) have all demonstrated the utility of islet-specific autoantibody testing in identifying people with pretype 1 diabetes. Longitudinal follow-up has provided us with a robust data set upon which to predict progression to type 1 diabetes. First-degree relatives of patients with type 1 diabetes who have a single autoantibody have relatively low rates of progression (14.5%). However, risk of progression to type 1 diabetes in children with ≥2 autoantibodies approaches 70% at 10 years of follow-up and 84% at 15 years. Progression to type 1 diabetes is even faster if autoimmunity develops prior to 3 years of age, an observation that has immense implications for potential development of population screening programs. Given our capacity to predict the progression of type 1 diabetes both immunologically and metabolically, the Juvenile Diabetes Research Foundation, the Endocrine Society, and the American Diabetes Association recently published a position statement supporting the concept of staging type 1 diabetes. These staging guidelines define stage 1 as presymptomatic euglycemic autoimmunity (≥2 autoantibodies), stage 2 as presymtomatic dysglycemic autoimmunity (impaired glucose tolerance testing), and stage 3 as symptomatic type 1 diabetes. We support the concept of staging but believe there should be even greater public health emphasis on the presymptomatic autoimmune state as an opportunity for early detection of type 1 diabetes. Herein, we endorse the viewpoint that individuals with 2 or more islet autoantibodies should be diagnosed with an independent disease state known as autoimmune β-cell disorder (ABCD). The distinctions between stage 1 type 1 diabetes and ABCD might effectively be labeled as semantic. As such, we do not argue that 1 set of terminology should fully replace the other, rather, we want to emphasize that additional tools are urgently needed to increase awareness of preclinical type 1 diabetes. We seek to promote the use of ABCD in parallel with staging of type 1 diabetes in order to maximize awareness among pediatric and adult primary care providers of children and adults at risk for type 1 diabetes. Diagnosing patients with ABCD will improve understanding of the natural history of the disease among primary care providers and patients, promote participation in prevention and intervention studies, allow for early diagnosis of type 1 diabetes, and lay the groundwork for general population screening for type 1 diabetes risk. While the logistical and economic challenges associated with identifying children with ABCD are not trivial, the tools needed to achieve this aim are readily accessible should we choose to commit the resources to targeting early diagnosis. To identify children with ABCD, one might consider using family history of type 1 diabetes; however, more than 85% of those who develop type 1 diabetes have no family history of the disease. Alternatively, one might consider genetic screening, as specific HLA types increase risk for type 1 diabetes. However, the majority of those with at-risk HLA types do not, in fact, develop the disease. Currently, the most effective way to identify children with ABCD is via diabetes-specific autoantibody testing. Targeted “screening” of high-risk family members, as is done in Type 1 Diabetes TrialNet, remains a critical tool but is incapable of identifying the majority of those who will ultimately develop type 1 diabetes. There is little debate that population screening will ultimately be required in order to identify all future type 1 diabetes patients. While some might suggest that such an approach is currently impractical, the Fr1da Study in Germany, in which children are being screened as part of their general pediatric care, has demonstrated efficacy and acceptance among general practitioners and families.

Understanding Pre-Type 1 Diabetes: The Key to Prevention

While the incidence of type 1 diabetes continues to rise by 3% each year, the ability to prevent this disease remains elusive. Hybrid closed loop devices, artificial pancreas systems, and continuous glucose monitoring technology have helped to ease the daily burden for many people living with type 1 diabetes. However, the artificial pancreas is not a cure; more research is needed to achieve our ultimate goal of preventing type 1 diabetes. The preceding decades have generated a wealth of information regarding the natural history of pre-type 1 diabetes. Islet autoimmunity in the form of multiple autoantibodies is known to be highly predictive of progression to disease. Staging systems have been devised to better characterize pre-type 1, direct mechanistic understanding of disease, and guide the design of prevention studies. However, there are no evidence-based recommendations for practitioners caring for autoantibody patients other than to encourage enrollment in research studies. Close monitoring of high-risk patients in natural history studies markedly reduces diabetic ketoacidosis rates at diagnosis and research participation is critical to finding a means of preventing type 1 diabetes. The discovery of an effective preventative strategy for type 1 diabetes will justify universal risk screening for all children.