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SYNDROMES OF KETOSIS-PRONE DIABETES.
Balasubramanyam, A
Transactions of the American Clinical and Climatological Association. 2019;:145-155
Abstract
Ketosis-prone diabetes (KPD) is a heterogeneous condition characterized by patients who present with diabetic ketoacidosis but lack the phenotype of autoimmune type 1 diabetes. Here I review progress in our understanding of KPD and its place in the expanding universe of "atypical diabetes." I focus on investigations of our collaborative research group at Baylor College of Medicine and the University of Washington using a longitudinally followed, heterogeneous, multiethnic cohort of KPD patients. We have identified clinically and pathophysiologically distinct KPD subgroups, separable by the presence or absence of islet autoimmunity and the presence or absence of beta cell functional reserve. The resulting "Aß" classification of KPD accurately predicts long-term glycemic control and insulin dependence. I describe key characteristics of the KPD subgroups, their natural histories, and our investigations into their immunologic, genetic, and metabolic etiologies. These studies serve as a paradigm for the investigation of atypical forms of diabetes.
2.
Are Anti-Retinal Autoantibodies a Cause or a Consequence of Retinal Degeneration in Autoimmune Retinopathies?
Adamus, G
Frontiers in immunology. 2018;:765
Abstract
Autoantibodies (AAbs) against various retinal proteins have been associated with vision loss in paraneoplastic and non-paraneoplastic autoimmune retinopathies (AR). There are two major paraneoplastic syndromes associated anti-retinal AAbs, cancer-associated retinopathy (CAR), and melanoma-associated retinopathy. Some people without a cancer diagnosis may present symptoms of CAR and have anti-retinal AAbs. The etiology and pathogenesis of those entities are not fully understood. In this review, we provide evidence for the role of AAbs in retinal death and degeneration. Studies of epitope mapping for anti-recoverin, anti-enolase, and anti-carbonic anhydrase II revealed that although patients' AAbs may recognize the same retinal protein as normal individuals they bind to different molecular domains, which allows distinguishing between normal and diseased AAbs. Given the great diversity of anti-retinal AAbs, it is likely some antibodies have greater pathogenic potential than others. Pathogenic, but not normal antibodies penetrate the target cell, reach their specific antigen, induce apoptosis, and impact retinal pathophysiology. Photoreceptors, dying by apoptosis, induced by other than immunologic mechanisms produce substantial amounts of metabolic debris, which consequently leads to autoimmunization and enhanced permeability of the blood-retinal barrier. AAbs that were made as a part of anti-cancer response are likely to be the cause of retinal degeneration, whereas others, generated against released antigens from damaged retina, contribute to the progression of retinopathy. Altogether, AAbs may trigger retinal degeneration and may also exacerbate the degenerative process in response to the release of sequestered antigens and influence disease progression.
3.
LADA and CARDS: a prospective study of clinical outcome in established adult-onset autoimmune diabetes.
Hawa, MI, Buchan, AP, Ola, T, Wun, CC, DeMicco, DA, Bao, W, Betteridge, DJ, Durrington, PN, Fuller, JH, Neil, HA, et al
Diabetes care. 2014;(6):1643-9
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Abstract
OBJECTIVE Diabetes-associated autoantibodies can be detected in adult-onset diabetes, even when initially non-insulin requiring, i.e., with latent autoimmune diabetes. We aimed to identify adult-onset autoimmune diabetes in patients with established "type 2 diabetes" participating in the Collaborative Atorvastatin Diabetes Study (CARDS) to characterize their phenotype and clinical outcome. RESEARCH DESIGN AND METHODS We prospectively studied 2,425 European patients with presumed type 2 diabetes (mean age 62 years, diabetes duration 7.9 years) for outcomes at 3.9 years after randomization to either atorvastatin or placebo. Subjects were screened for autoantibodies to GAD (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc-transporter 8 (ZnT8A). RESULTS A total of 173 patients (7.1%) had GADA, of whom 11 (0.5%) and 5 (0.2%) were also positive for IA-2A and ZnT8A, respectively. At baseline, 44% of GADA-positive patients were not on insulin. Fewer autoantibody-positive than autoantibody-negative patients had metabolic syndrome (64 vs. 80%), and more were on insulin (56 vs. 17%) (P < 0.0001 for each) without lower HbA1c (69 mmol/mol [8.5%] vs. 62 mmol/mol [7.8%]). The frequency of microvascular and macrovascular events was similar in both cohorts, independent of atorvastatin. CONCLUSIONS Adult-onset autoimmune diabetes was prevalent, even in patients with established diabetes presumed to have type 2 diabetes. After 11.8 years' diabetes duration, nearly half the patients with autoimmune diabetes were not on insulin treatment and almost two-thirds had metabolic syndrome. The type of diabetes, whether autoimmune diabetes or type 2 diabetes, did not impact the risk of microvascular disease.
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The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: results from the TODAY study.
Klingensmith, GJ, Pyle, L, Arslanian, S, Copeland, KC, Cuttler, L, Kaufman, F, Laffel, L, Marcovina, S, Tollefsen, SE, Weinstock, RS, et al
Diabetes care. 2010;(9):1970-5
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Abstract
OBJECTIVE To determine the frequency of islet cell autoimmunity in youth clinically diagnosed with type 2 diabetes and describe associated clinical and laboratory findings. RESEARCH DESIGN AND METHODS Children (10-17 years) diagnosed with type 2 diabetes were screened for participation in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Measurements included GAD-65 and insulinoma-associated protein 2 autoantibodies using the new National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH) standardized assays, a physical examination, and fasting lipid, C-peptide, and A1C determinations. RESULTS Of the 1,206 subjects screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive; of these, 71 (5.9%) were positive for a single antibody, and 47 were positive (3.9%) for both antibodies. Diabetes autoantibody (DAA) positivity was significantly associated with race (P < 0.0001), with positive subjects more likely to be white (40.7 vs. 19%) (P < 0.0001) and male (51.7 vs. 35.7%) (P = 0.0007). BMI, BMI z score, C-peptide, A1C, triglycerides, HDL cholesterol, and blood pressure were significantly different by antibody status. The antibody-positive subjects were less likely to display characteristics clinically associated with type 2 diabetes and a metabolic syndrome phenotype, although the range for BMI z score, blood pressure, fasting C-peptide, and serum lipids overlapped between antibody-positive and antibody-negative subjects. CONCLUSIONS Obese youth with a clinical diagnosis of type 2 diabetes may have evidence of islet autoimmunity contributing to insulin deficiency. As a group, patients with DAA have clinical characteristics significantly different from those without DAA. However, without islet autoantibody analysis, these characteristics cannot reliably distinguish between obese young individuals with type 2 diabetes and those with autoimmune diabetes.