Routine Islet Autoantibody Testing in Clinically Diagnosed Adult-Onset Type 1 Diabetes Can Help Identify Misclassification and the Possibility of Successful Insulin Cessation
Abstract:OBJECTIVE
Recent joint American Diabetes Association and European Association for the Study of Diabetes guidelines recommend routine islet autoantibody testing in all adults newly diagnosed with type 1 diabetes. We aimed to assess the impact of routine islet autoantibody testing in this population.
RESEARCH DESIGN AND METHODS
We prospectively assessed the relationship between islet autoantibody status (GADA, IA-2A, and ZNT8A)… Show more
“…However, the gains seen with a T1DGRS are more modest than previously reported, likely because in SEARCH, the combination of available clinical features and islet-autoantibodies close to diagnosis provide very high accuracy, with limited room for further improvement in discrimination measures like AUCROC. As previously demonstrated, the clinical utility of these risk scores is greatest in those who are hard to classify on other features, for example islet-autoantibody negative suspected T1D, or those with single positive antibodies and suspected T2D (36, 37).…”
ObjectiveWith the high prevalence of pediatric obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D).MethodsWe studied 2,966 youth with diabetes in the prospective SEARCH study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting c-peptide ≥250 pmol/L (≥0.75ng/ml) after >3 years (median 74 months) of diabetes duration. Models included clinical measures at baseline visit, at a mean diabetes duration of 11 months (age, BMI, sex, waist circumference, HDL-C), with and without islet autoantibodies (GADA, IA-2A) and a Type 1 Diabetes Genetic Risk Score (T1DGRS).ResultsModels using routine clinical measures with or without autoantibodies and T1DGRS were highly accurate in identifying participants with c-peptide ≥0.75 ng/ml (17% of participants; 2.3% and 53% of those with and without positive autoantibodies) (area under receiver operator curve [AUCROC] 0.95-0.98). In internal validation, optimism was very low, with excellent calibration (slope=0.995-0.999). Models retained high performance for predicting retained c-peptide in older youth with obesity (AUCROC 0.88-0.96), and in subgroups defined by self-reported race/ethnicity (AUCROC 0.88-0.97), autoantibody status (AUCROC 0.87-0.96), and clinically diagnosed diabetes types (AUCROC 0.81-0.92).ConclusionPrediction models combining routine clinical measures at diabetes diagnosis, with or without islet autoantibodies or T1DGRS, can accurately identify youth with diabetes who maintain endogenous insulin secretion in the range associated with type 2 diabetes.
“…However, the gains seen with a T1DGRS are more modest than previously reported, likely because in SEARCH, the combination of available clinical features and islet-autoantibodies close to diagnosis provide very high accuracy, with limited room for further improvement in discrimination measures like AUCROC. As previously demonstrated, the clinical utility of these risk scores is greatest in those who are hard to classify on other features, for example islet-autoantibody negative suspected T1D, or those with single positive antibodies and suspected T2D (36, 37).…”
ObjectiveWith the high prevalence of pediatric obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D).MethodsWe studied 2,966 youth with diabetes in the prospective SEARCH study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting c-peptide ≥250 pmol/L (≥0.75ng/ml) after >3 years (median 74 months) of diabetes duration. Models included clinical measures at baseline visit, at a mean diabetes duration of 11 months (age, BMI, sex, waist circumference, HDL-C), with and without islet autoantibodies (GADA, IA-2A) and a Type 1 Diabetes Genetic Risk Score (T1DGRS).ResultsModels using routine clinical measures with or without autoantibodies and T1DGRS were highly accurate in identifying participants with c-peptide ≥0.75 ng/ml (17% of participants; 2.3% and 53% of those with and without positive autoantibodies) (area under receiver operator curve [AUCROC] 0.95-0.98). In internal validation, optimism was very low, with excellent calibration (slope=0.995-0.999). Models retained high performance for predicting retained c-peptide in older youth with obesity (AUCROC 0.88-0.96), and in subgroups defined by self-reported race/ethnicity (AUCROC 0.88-0.97), autoantibody status (AUCROC 0.87-0.96), and clinically diagnosed diabetes types (AUCROC 0.81-0.92).ConclusionPrediction models combining routine clinical measures at diabetes diagnosis, with or without islet autoantibodies or T1DGRS, can accurately identify youth with diabetes who maintain endogenous insulin secretion in the range associated with type 2 diabetes.
“…Participants included in this study were identified from 6 UK cohorts recruited from primary and secondary care and had uniform islet-autoantibody assessment (14): the Genetics of Diabetes Audit and Research Tayside Study (GoDarts) (15), Diabetes Alliance for Research in England (DARE) (16), Predicting Response to Incretin Based Agents in Type 2 Diabetes (PRIBA) (17), MRC MASTERMIND Progressors (18) and StartRight Studies (19; 20). A comparison cohort of participants with type 1 diabetes were also identified from DARE.…”
ObjectiveWe investigated whether further characterisation of full-length (f-) GADA responses could identify early insulin requirement in adult-onset diabetes.Research Design and MethodsIn 179 f-GADA positive participants diagnosed with type 2 diabetes, we assessed the association of truncated (t-)GADA positivity, f-GADA IgG subclasses, and f-GADA affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. These characteristics were compared to f-GADA positive type 1 diabetes (n=141) and f-GADA negative type 2 diabetes (n=6420) cohorts.Resultst-GADA positivity was lower in f-GADA positive without early insulin in comparison to f-GADA positive type 2 diabetes requiring insulin within 5 years, and type 1 diabetes (75% vs. 91% and 95% respectively, p<0.0001). t-GADA positivity (in those f-GADA positive) identified a group with a higher type 1 diabetes genetic susceptibility (mean T1D GRS 0.248 vs. 0.225, p=0.003), lower C-peptide (1156 pmol/L vs. 4289 pmol/L, p=1×10-7), and increased IA-2A positivity (23% vs. 6%, p=0.03). In survival analysis, t-GADA positivity was associated with early insulin requirement compared with those only positive for f-GADA, independently from age of diagnosis, f-GADA titre and duration of diabetes [adjusted HR 5.7 (95% CI 1.4, 23.5), p=0.017]. Early insulin requirement was not associated with an IgG1-restricted f-GADA response (p=0.81) or a high affinity f-GADA response (p=0.89).ConclusionsThe testing of t-GADA in f-GADA positive individuals with type 2 diabetes identifies those who have genetic and clinical characteristics comparable to type 1 diabetes and stratifies those at higher risk of early insulin requirement.Article HighlightsProgression to insulin therapy is highly variable in adult-onset GADA positive diabetes.We further characterised GADA characteristics in adult-onset diabetes and assessed whether these are associated with early insulin requirement.Truncated GADA positivity was associated with a type 1 diabetes like phenotype and stratified risk of early insulin requirement. Those GADA positive who were negative for truncated GADA had the characteristics and progression of classical type 2 diabetes. Assessing full-length GADA IgG subclass and affinity did not further stratify risk of progression.t-GADA assessment remains underutilised in clinical practice, but could assist correct therapy allocation in adult-onset diabetes.
“…As we have recently reviewed this explanation for the characteristics of LADA in detail, and this group is diagnosed clinically with type 2 diabetes, we have focused on conventional type 1 diabetes for the remainder of this article [ 4 ] Fig. 2 The prevalence of GADA positivity for an assay and threshold with 97.5% specificity (positive defined as >10 units/ml) for: (1) a control population without diabetes (HbA 1c <48 mmol/mol [<6.5%]) (data from [ 66 ]); (2) individuals with HNF1A and HNF4A MODY (T. J. McDonald, University of Exeter, UK, unpublished data associated with [ 67 ]); (3) individuals aged ≥18 years, with recently diagnosed diabetes that was initially treated as type 2 diabetes (without initial insulin for >2 weeks) (A. G. Jones, University of Exeter, UK, unpublished data from the StartRight Study [ 31 , 37 ]); and (4) individuals with long-duration type 2 diabetes, aged ≥35 years at diagnosis, with a clinical diagnosis of type 2 diabetes, absence of insulin requirement within 6 months of diagnosis and with median diabetes duration of 11 years (data from [ 6 ]). This figure is available as part of a downloadable slideset …”
Section: Adult-onset Type 1 Diabetes Is Difficult To Diagnose and Mis...mentioning
confidence: 99%
“…Therefore, unsurprisingly, misclassification of clinically diagnosed cases is commonly reported, with misclassification frequency increasing with onset age [ 28 – 32 ]. Studies defining type 1 diabetes by insulin deficiency have shown persistently retained C-peptide (in the type 2 diabetes range) in approximately 1 in 6 of those with longstanding clinically diagnosed type 1 diabetes, with low islet-antibody positivity rates and genetic susceptibility inconsistent with type 1 diabetes in these cases [ 28 , 31 ]. Conversely, around 1 in 3 of those with type 1 diabetes defined by the development of severe insulin deficiency are treated without insulin at diagnosis, with 47% of these individuals still reporting type 2 diabetes at 17 years of diabetes duration [ 29 , 30 ].…”
Section: Adult-onset Type 1 Diabetes Is Difficult To Diagnose and Mis...mentioning
confidence: 99%
“…In contrast, when a clinical diagnosis of adult-onset type 1 diabetes is confirmed by autoantibody positivity, genetic predisposition to type 1 diabetes appears unaffected by onset age but is modestly reduced relative to childhood-onset cases [ 32 , 38 ]. Adults, but not children, with islet-autoantibody negativity had substantially lower type 1 diabetes genetic susceptibility than those who were islet-autoantibody positive, consistent with the presence of non-autoimmune diabetes [ 31 , 32 ].…”
Section: The Marked Changes In Characteristics Of Clinically Diagnose...mentioning
Diagnosing type 1 diabetes in adults is difficult since type 2 diabetes is the predominant diabetes type, particularly with an older age of onset (approximately >30 years). Misclassification of type 1 diabetes in adults is therefore common and will impact both individual patient management and the reported features of clinically classified cohorts. In this article, we discuss the challenges associated with correctly identifying adult-onset type 1 diabetes and the implications of these challenges for clinical practice and research. We discuss how many of the reported differences in the characteristics of autoimmune/type 1 diabetes with increasing age of diagnosis are likely explained by the inadvertent study of mixed populations with and without autoimmune aetiology diabetes. We show that when type 1 diabetes is defined by high-specificity methods, clinical presentation, islet-autoantibody positivity, genetic predisposition and progression of C-peptide loss remain broadly similar and severe at all ages and are unaffected by onset age within adults. Recent clinical guidance recommends routine islet-autoantibody testing when type 1 diabetes is clinically suspected or in the context of rapid progression to insulin therapy after a diagnosis of type 2 diabetes. In this moderate or high prior-probability setting, a positive islet-autoantibody test will usually confirm autoimmune aetiology (type 1 diabetes). We argue that islet-autoantibody testing of those with apparent type 2 diabetes should not be routinely undertaken as, in this low prior-prevalence setting, the positive predictive value of a single-positive islet antibody for autoimmune aetiology diabetes will be modest. When studying diabetes, extremely high-specificity approaches are needed to identify autoimmune diabetes in adults, with the optimal approach depending on the research question. We believe that until these recommendations are widely adopted by researchers, the true phenotype of late-onset type 1 diabetes will remain largely misunderstood.
Graphical Abstract
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