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

Rolandsson, Olov; Hampe, Christiane S.; Sharp, Stephen J.; Ardanaz, Eva; Boeing, Heiner; Fagherazzi, Guy; Mancini, Francesca Romana; Nilsson, Peter M.; Overvad, Kim; Chirlaque, María Dolores; Dorronsoro, Miren; Gunter, Marc J.; Kaaks, Rudolf; Key, Timothy J.; Khaw, Kay Tee; Kühn, Tilman; Palli, Domenico; Panico, Salvatore; Sacerdote, Carlotta; Sánchez, María José; Severi, Gianluca; Spijkerman, Annemieke M.W.; Tumino, Rosario; Schouw, Yvonne T. van der; Riboli, Elio; Forouhi, Nita G.; Langenberg, Claudia; Wareham, Nicholas J.

doi:10.1007/s00125-019-05016-3

Cited by 18 publications

(26 citation statements)

References 40 publications

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“…It seems reasonable to conclude from these studies that autoimmunity does not play a major role in the development of adult-onset diabetes among older adults. Certainly, in population-based studies of adults with diabetes the frequency of GADA is low, as with this present European study, while in clinic-based studies, that GADA frequency tends to be 5-10%, whether in China or Europe [4,[9][10][11]. Prospective data from HUNT indicated that incident diabetes cases, who were overweight with a family history of diabetes plus GADA positivity, as compared with GADA negative cases, had an OR for diabetes risk of 7.5.…”

Section: Gada and Grs Predicts Adult-onset Diabetessupporting

confidence: 52%

“…This underestimation, together with the likely reduced sensitivity for GADA using this highly specific GADA assay and the likely failure to identify all autoimmune cases as only GADA were tested means that the actual numbers of autoimmune cases will probably be higher than estimated. That said, attributable risk in this population of adult-onset diabetes with GADA is very low at 1.8%, so even a substantial error would have little impact on the overall risk of autoimmune diabetes in adults aged over 40 years [4]. However, the risk of GADA-positive cases developing autoimmune diabetes would likely be much higher in younger adults, as autoimmune diabetes is more prevalent in this age group than in older adults.…”

Section: Disease Identity and Uncertaintymentioning

confidence: 88%

“…Nor would it explain the predominance of GADA in all adult-onset diabetes cohorts when other diabetes-associated autoantibodies can be detected, but at far lower frequency, or the marked drop in GADA positivity with increasing age at diagnosis in adults [14]. Nevertheless, there will be a false-positive rate, even with the state-of-the-art GADA assay employed by Rolandsson et al [4], plus an unquantified, likely low, falsenegative rate. GADA can be transient and, while invariably predominant, do consistently underestimate the percentage of diabetes cases with diabetes-associated autoantibodies e.g.…”

Section: Disease Identity and Uncertaintymentioning

confidence: 97%

“…In this issue of Diabetologia, Rolandsson and colleagues have leveraged two of these three markers, i.e. GADA and GRS, in European Prospective Investigation into Cancer and Nutrition (EPIC), a large cohort of individuals (over 340,000 participants over 40 years of age and free of known diabetes at baseline), followed for 10 years to determine the potential for these markers to identify those at risk of diabetes [4]. For those with GADA initially, there was indeed an increased risk that diabetes would develop during follow-up (HR 1.78 for GADA positive vs GADA negative).…”

Section: Gada and Grs Predicts Adult-onset Diabetesmentioning

confidence: 99%

“…Rolandsson et al emphasise the importance of scale in their data and the notion that autoimmune damage could contribute to the development of adult-onset diabetes, whether defined clinically as insulin dependent or non-insulin dependent [4]. Certainly, individuals with adult-onset diabetes who have a high type 1 diabetes GRS and high-titre GADA are at risk of progressing to insulin dependence [19].…”

Section: Disease Risk Scale and Certaintymentioning

confidence: 99%

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Allostasis and the origins of adult-onset diabetes

Leslie

Vartak

2019

Diabetologia

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Section: Gada and Grs Predicts Adult-onset Diabetessupporting

confidence: 52%

Section: Disease Identity and Uncertaintymentioning

confidence: 88%

Section: Disease Identity and Uncertaintymentioning

confidence: 97%

Section: Gada and Grs Predicts Adult-onset Diabetesmentioning

confidence: 99%

Section: Disease Risk Scale and Certaintymentioning

confidence: 99%

See 3 more Smart Citations

Allostasis and the origins of adult-onset diabetes

Leslie

Vartak

2019

Diabetologia

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The clinical consequences of heterogeneity within and between different diabetes types

et al. 2020

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Advances in molecular methods and the ability to share large population-based datasets are uncovering heterogeneity within diabetes types, and some commonalities between types. Within type 1 diabetes, endotypes have been discovered based on demographic (e.g. age at diagnosis, race/ethnicity), genetic, immunological, histopathological, metabolic and/or clinical course characteristics, with implications for disease prediction, prevention, diagnosis and treatment. In type 2 diabetes, the relative contributions of insulin resistance and beta cell dysfunction are heterogeneous and relate to demographics, genetics and clinical characteristics, with substantial interaction from environmental exposures. Investigators have proposed approaches that vary from simple to complex in combining these data to identify type 2 diabetes clusters relevant to prognosis and treatment. Advances in pharmacogenetics and pharmacodynamics are also improving treatment. Monogenic diabetes is a prime example of how understanding heterogeneity within diabetes types can lead to precision medicine, since phenotype and treatment are affected by which gene is mutated. Heterogeneity also blurs the classic distinctions between diabetes types, and has led to the definition of additional categories, such as latent autoimmune diabetes in adults, type 1.5 diabetes and ketosis-prone diabetes. Furthermore, monogenic diabetes shares many features with type 1 and type 2 diabetes, which make diagnosis difficult. These challenges to the current classification framework in adult and paediatric diabetes require new approaches. The 'palette model' and the 'threshold hypothesis' can be combined to help explain the heterogeneity within and between diabetes types. Leveraging such approaches for therapeutic benefit will be an important next step for precision medicine in diabetes.

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Adult-onset autoimmune diabetes identified by glutamic acid decarboxylase autoantibodies: a retrospective cohort study

et al. 2021

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Aims/hypothesis Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice. Methods We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM. Results Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (noninsulin therapy group) during the follow-up period (median 3.0 years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA 1c levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA 1c levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan-Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22 kg/m 2 , HbA 1c < 75 mmol/mol [9.0%] and GADAb <10.0 U/ml) did not require insulin therapy for 4 years. Conclusions/interpretation Higher BMI (≥22 kg/m 2 ), lower HbA 1c (<75 mmol/mol [9.0%]) and lower GADAb levels (<10.0 U/ ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb.Keywords Adult-onset autoimmune diabetes . Glutamic acid decarboxylase antibody . Latent autoimmune diabetes in adults . Non-insulin-dependent . Slowly progressive insulin-dependent (type 1) diabetes mellitus Abbreviations GADAb GAD antibodies LADA Latent autoimmune diabetes in adults ROC Receiver operating characteristic SPIDDM Slowly progressive insulin-dependent (type 1) diabetes mellitus

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

Cited by 18 publications

References 40 publications

Allostasis and the origins of adult-onset diabetes

Allostasis and the origins of adult-onset diabetes

The clinical consequences of heterogeneity within and between different diabetes types

Adult-onset autoimmune diabetes identified by glutamic acid decarboxylase autoantibodies: a retrospective cohort study

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