Diabetes autoantibodies do not predict progression to diabetes in adults: the Diabetes Prevention Program

Dabelea, Dana; Ma, Yong; Knowler, William C.; Marcovina, Santica M.; Saudek, Christopher D.; Arakaki, Richard; White, Neil H.; Kahn, Steven E.; Orchard, Trevor J.; Goldberg, Ronald; Palmer, Jerry P.; Hamman, Richard F.

doi:10.1111/dme.12437

Cited by 13 publications

(13 citation statements)

References 30 publications

(41 reference statements)

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“…In favour of general screening of adult patients with diabetes, patients with Type 2 and LADA cannot be identified by any single clinical feature short of diabetic ketoacidosis. However, the data are conflicting regarding the predictive value of GADA positivity for incident diabetes [14,38,[68][69][70][71].…”

Section: Clinical Presentationmentioning

confidence: 99%

Latent autoimmune diabetes of the adult: current knowledge and uncertainty

Laugesen

Østergaard

Leslie³

2015

Diabet. Med.

153

137

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Patients with adult-onset autoimmune diabetes have less Human Leucocyte Antigen (HLA)-associated genetic risk and fewer diabetes-associated autoantibodies compared with patients with childhood-onset Type 1 diabetes. Metabolic changes at diagnosis reflect a broad clinical phenotype ranging from diabetic ketoacidosis to mild non-insulin-requiring diabetes, also known as latent autoimmune diabetes of the adult (LADA). This latter phenotype is the most prevalent form of adult-onset autoimmune diabetes and probably the most prevalent form of autoimmune diabetes in general. Although LADA is associated with the same genetic and immunological features as childhood-onset Type 1 diabetes, it also shares some genetic features with Type 2 diabetes, which raises the question of genetic heterogeneity predisposing to this form of the disease. The potential value of screening patients with adult-onset diabetes for diabetes-associated autoantibodies to identify those with LADA is emphasized by their lack of clinically distinct features, their different natural history compared with Type 2 diabetes and their potential need for a dedicated management strategy. The fact that, in some studies, patients with LADA show worse glucose control than patients with Type 2 diabetes, highlights the need for further therapeutic studies. Challenges regarding classification, epidemiology, genetics, metabolism, immunology, clinical presentation and treatment of LADA were discussed at a 2014 workshop arranged by the Danish Diabetes Academy. The presentations and discussions are summarized in this review, which sets out the current ideas and controversies surrounding this form of diabetes.What’s new? Latent autoimmune diabetes of the adult (LADA) is an autoimmune diabetes defined by adult-onset, presence of diabetes associated autoantibodies, and no insulin treatment requirement for a period after diagnosis. Immunologically, glutamic acid decarboxylase 65 autoantibodies are by far the most common autoantibody in adult-onset diabetes. LADA is the most prevalent form of adult-onset autoimmune diabetes and probably the most prevalent form of autoimmune diabetes in general. LADA shares genetic features with both type 1 and type 2 diabetes. Phenotypically, LADA patients are often misdiagnosed as having type 2 diabetes. LADA patients generally have worse HbA1c levels than type 2 diabetes patients. Clinically, LADA patients tend to have a lower mean age at diabetes onset, lower body mass index and more frequent need for insulin treatment than patients with type 2 diabetes. Management of LADA may require a dedicated strategy, yet currently there is a paucity of randomized controlled trial data.

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Section: Clinical Presentationmentioning

confidence: 99%

Latent autoimmune diabetes of the adult: current knowledge and uncertainty

Laugesen

Østergaard

Leslie³

2015

Diabet. Med.

153

137

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“…A null association between GAD65 antibodies and development of type 2 diabetes reported in Northern Italy may reflect the small size of this study, which was underpowered to detect a true association [18]. The Diabetes Prevention Program also reported no association between GAD65 antibodies and development of type 2 diabetes [19]. However, the follow-up of the Diabetes Prevention Program cohort was very short (3.2 years) and included individuals of various ethnicities with different risks of diabetes, both of which may explain the null overall association.…”

Section: Discussionmentioning

confidence: 64%

“…In contrast, there are only a few population-based prospective studies exploring the association between autoimmunity and incident diabetes. Moreover, while some of these studies reported an association [15,16], others have been inconclusive [17][18][19]. In a recent meta-analysis Koopman et al reported that the pooled risk estimate of incident type 2 diabetes for GAD65 antibody positivity, compared with GAD65 antibody negativity, was 3.36 (95% CI 1.9, 5.9) [20].…”

Section: Introductionmentioning

confidence: 99%

Autoimmunity plays a role in the onset of diabetes after 40 years of age

et al. 2019

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Aims/hypothesis Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a casecohort study nested in the EPIC cohort. Methods GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood. Keywords Autoantibody. Autoimmunity. Genetic risk score. Incident diabetes. Type 1 diabetes. Type 2 diabetes Abbreviations EPIC European Prospective Investigation into Cancer and Nutrition GAD65 65 kDa isoform of GAD GRS Genetic risk score HUNT The Nord-Trøndelag Health Study rhGAD65 Recombinant human GAD65 ROC Receiver operating characteristic Electronic supplementary material The online version of this article (

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“…B cells can promote IR in humans and mice through modulating T cell function [30, 35], including the ability of B cells to support human Th17 function through contact-dependent mechanisms [30]. B cells also promote IR by shifting to a pro-inflammatory cytokine profile [30, 94] and by secreting autoantibodies [35], although a relationship between putative diabetogenic autoantibodies and adult-T2D progression is not established [95]. Obesity-associated increases in serum IgG only in children [96] and younger mice [35] further question the role of antibodies in adult disease.…”

Section: Lymphocytes As Sources Of Obesity/t2d–associated Inflammamentioning

confidence: 99%

Lymphocyte roles in metabolic dysfunction: of men and mice

Hogan

Nikolajczyk

2015

Trends in Endocrinology & Metabolism

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Type 2 diabetes (T2D) is a metabolic disease associated with obesity-related insulin resistance (IR) and chronic inflammation. Animal studies indicate IR can be caused and/or exacerbated by systemic/tissue-specific alterations in lymphocyte differentiation and function. Human studies also indicate obesity and/or inflammation promotes IR. Nevertheless, clinical trials with anti-inflammatory therapies have yielded modest impacts on established T2D. Unlike mouse models where obesity is predominantly associated with IR, 20–25% of obese people are metabolically healthy with high insulin sensitivity. The uncoupling of obesity from IR in humans but not in animal models advocates for a more comprehensive understanding of mediators/mechanisms in human obesity-promoted IR, and better integration of knowledge from human studies into animal experiments to efficiently pursue T2D prevention and treatment.

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Diabetes autoantibodies do not predict progression to diabetes in adults: the Diabetes Prevention Program

Cited by 13 publications

References 30 publications

Latent autoimmune diabetes of the adult: current knowledge and uncertainty

Latent autoimmune diabetes of the adult: current knowledge and uncertainty

Autoimmunity plays a role in the onset of diabetes after 40 years of age

Lymphocyte roles in metabolic dysfunction: of men and mice

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