Alterations in Biomarkers Related to Glycemia, Lipid Metabolism, and Inflammation up to 20 Years Before Diagnosis of Type 1 Diabetes in Adults: Findings From the AMORIS Cohort

Objective: Type 1 diabetes is described to have an acute onset, but autoantibodies can appear several years preceding diagnosis. This suggests a long preclinical phase, which may also include metabolic parameters. Here we assessed whether elevations in glycaemic, lipid, and other metabolic biomarkers were associated with future <a>type 1 diabetes</a> risk in adults. Research Design and Methods: We studied 591,239 individuals from the Swedish AMORIS cohort followed from 1985-1996 to 2012. Through linkage to national patient, diabetes, and prescription registers, we identified incident type 1 diabetes. Using Cox regression models, we estimated hazard ratios for biomarkers at baseline and incident type 1 diabetes. We additionally assessed trajectories of biomarkers during the 25 years before type 1 diabetes diagnosis in a nested case-control design. Results: We identified 1,122 type 1 diabetes cases during follow-up (average age at diagnosis: 53.3 years). The biomarkers glucose, fructosamine, triglycerides, the apolipoprotein B/A-I ratio, uric acid, alkaline phosphatase, and BMI were positively associated with type 1 diabetes risk. A higher apolipoprotein A-I was associated with a lower type 1 diabetes incidence. Already 15 years before diagnosis, type 1 diabetes cases had higher mean glucose, fructosamine, triglycerides, and uric acid levels compared to controls. Conclusion: Alterations in biomarker levels related to glycaemia, lipid metabolism, and inflammation are associated with clinically diagnosed type 1 diabetes risk, and these may be elevated many years preceding diagnosis.

Download Full-text

DR15-DQ6 remains dominantly protective against type 1 diabetes throughout the first five decades of life

Diabetologia ◽

10.1007/s00125-021-05513-4 ◽

2021 ◽

Author(s):

Nicholas J. Thomas ◽

John M. Dennis ◽

Seth A. Sharp ◽

Akaal Kaur ◽

Shivani Misra ◽

...

Keyword(s):

Type 1 Diabetes ◽

Major Type ◽

Diabetes Incidence ◽

Diabetes Diagnosis ◽

Risk Haplotype ◽

Adult Onset ◽

Uk Biobank ◽

Onset Type ◽

Increased Risk

Abstract Aims/hypothesis Among white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased. Methods In two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0–18 years, 19–30 years and 31–50 years. Results DR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, all p < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5–18 years OR 0.16 (95% CI 0.08, 0.31); age 19–30 years OR 0.10 (0.04, 0.23); and age 31–50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes. Conclusions/interpretation HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life. Graphical abstract

Download Full-text

Increase in Prevalence of Diabetic Ketoacidosis at Diagnosis Among Youth With Type 1 Diabetes: The SEARCH for Diabetes in Youth Study

10.2337/figshare.14489001.v1 ◽

2021 ◽

Author(s):

Elizabeth T Jensen ◽

Jeanette M Stafford ◽

Sharon Saydah ◽

Ralph B D'Agostino, Jr ◽

Lawrence M Dolan ◽

...

Keyword(s):

Type 1 Diabetes ◽

Temporal Trends ◽

Sociodemographic Factors ◽

Diabetes Diagnosis ◽

Adjusted Relative Risk ◽

Incident Type ◽

Health Insurance Status ◽

Search Site ◽

Over Time

Objective: We previously reported a high (~30%), but stable prevalence of DKA at youth-onset diagnosis of type 1 diabetes (2002 and 2010). Given the changing demographics of youth-onset type 1 diabetes, we sought to evaluate temporal trends in the prevalence of DKA at diagnosis of type 1 diabetes from 2010 to 2016 among youth <20 years of age and evaluate whether any change observed was associated with changes in sociodemographic distribution of those recently diagnosed. Research Design and Methods: We calculated prevalence of DKA within 1 month of type 1 diabetes diagnosis by year and evaluated trends over time (2010-2016) (n=7,612 incident diabetes cases, mean (SD) age 10.1 (4.5) at diagnosis). To assess whether trends observed were attributable to the changing distribution of sociodemographic factors among youth with incident type 1 diabetes, we estimated an adjusted relative risk (aRR) of DKA in relation to calendar year, adjusting for age, sex, race/ethnicity, income, education, health insurance status, language, season of diagnosis, and SEARCH site. Results: DKA prevalence increased from 35.3% (95% CI: 32.2, 38.4) in 2010, to 40.6% (95% CI: 37.8, 43.4) in 2016 (p for trend=0.01). Adjustment for sociodemographic factors did not substantively change the observed trends. We observed a 2% annual increase in prevalence of DKA at or near diagnosis of type 1 diabetes (crude RR: 1.02; 95% CI: 1.01, 1.04 and aRR: 1.02; 95% CI: 1.01, 1.04; p=0.01 for both). Conclusions: Prevalence of DKA at or near type 1 diabetes diagnosis has increased from 2010 to 2016, following the high but stable prevalence observed from 2002-2010. This increase does not seem to be attributable to the changes in distribution of sociodemographic factors over time.

Download Full-text

Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S.

10.2337/figshare.14384324 ◽

2021 ◽

Author(s):

Vibha Anand ◽

Ying Li ◽

Bin Liu ◽

Mohamed Ghalwash ◽

Eileen Koski ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cohort Studies ◽

Prospective Cohort ◽

Diabetes Risk ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Diabetes Incidence ◽

Prospective Cohort Studies ◽

Hla Dr

OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and to estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODS: Prospective cohorts in Finland, Germany, Sweden and the US have followed 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTS: In the infant-toddler cohort, 1413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two or three autoantibodies at seroconversion: 45% (95% CI 40-52%), 85% (78-90%), and 92% (85-97%), respectively. Among those with single autoantibody, their status two years after seroconversion predicted diabetes risk: 12% (10-25%) if reverting to autoantibody negative, 30% (20-40%) if retaining single autoantibody, and 82% (80-95%) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single autoantibody. Their 15-year diabetes incidence for higher vs. lower risk genotypes was 40% (28-50%) vs. 12% (5-38%). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies ranging from 20%/year to 6%/year in children developing multi-positivity ≤2 years or >7.4 years, respectively. CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.

Download Full-text

Increase in Prevalence of Diabetic Ketoacidosis at Diagnosis Among Youth With Type 1 Diabetes: The SEARCH for Diabetes in Youth Study

10.2337/figshare.14489001 ◽

2021 ◽

Author(s):

Elizabeth T Jensen ◽

Jeanette M Stafford ◽

Sharon Saydah ◽

Ralph B D'Agostino, Jr ◽

Lawrence M Dolan ◽

...

Keyword(s):

Type 1 Diabetes ◽

Temporal Trends ◽

Sociodemographic Factors ◽

Diabetes Diagnosis ◽

Adjusted Relative Risk ◽

Incident Type ◽

Health Insurance Status ◽

Search Site ◽

Over Time

Objective: We previously reported a high (~30%), but stable prevalence of DKA at youth-onset diagnosis of type 1 diabetes (2002 and 2010). Given the changing demographics of youth-onset type 1 diabetes, we sought to evaluate temporal trends in the prevalence of DKA at diagnosis of type 1 diabetes from 2010 to 2016 among youth <20 years of age and evaluate whether any change observed was associated with changes in sociodemographic distribution of those recently diagnosed. Research Design and Methods: We calculated prevalence of DKA within 1 month of type 1 diabetes diagnosis by year and evaluated trends over time (2010-2016) (n=7,612 incident diabetes cases, mean (SD) age 10.1 (4.5) at diagnosis). To assess whether trends observed were attributable to the changing distribution of sociodemographic factors among youth with incident type 1 diabetes, we estimated an adjusted relative risk (aRR) of DKA in relation to calendar year, adjusting for age, sex, race/ethnicity, income, education, health insurance status, language, season of diagnosis, and SEARCH site. Results: DKA prevalence increased from 35.3% (95% CI: 32.2, 38.4) in 2010, to 40.6% (95% CI: 37.8, 43.4) in 2016 (p for trend=0.01). Adjustment for sociodemographic factors did not substantively change the observed trends. We observed a 2% annual increase in prevalence of DKA at or near diagnosis of type 1 diabetes (crude RR: 1.02; 95% CI: 1.01, 1.04 and aRR: 1.02; 95% CI: 1.01, 1.04; p=0.01 for both). Conclusions: Prevalence of DKA at or near type 1 diabetes diagnosis has increased from 2010 to 2016, following the high but stable prevalence observed from 2002-2010. This increase does not seem to be attributable to the changes in distribution of sociodemographic factors over time.

Download Full-text

HbA1c levels in children with type 1 diabetes and correlation to diabetic retinopathy

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2017-0417 ◽

2018 ◽

Vol 31 (4) ◽

pp. 369-374 ◽

Cited By ~ 2

Author(s):

Rebecka Andreasson ◽

Charlotte Ekelund ◽

Mona Landin-Olsson ◽

Charlotta Nilsson

Keyword(s):

Type 1 Diabetes ◽

Diabetic Retinopathy ◽

Glycosylated Hemoglobin ◽

Acute Onset ◽

Diabetes Diagnosis ◽

Adequate Treatment ◽

The Mean ◽

Hba1c Levels

AbstractBackground:Type 1 diabetes mellitus (T1D) is a metabolic disease causing hyperglycemia due to β-cell destruction. Despite adequate treatment, complications such as diabetic retinopathy (DR) are common. The first aim was to investigate if acute onset of type 1 diabetes differed between those who had developed retinopathy and who had not after 15 years from diagnosis. The second aim was to investigate if mean glycosylated hemoglobin (HbA1c) levels affect the time to development of DR.Methods:The medical records of all children and adolescents diagnosed with type 1 diabetes during 1993–2001 in our area in Sweden were studied retrospectively and the mean HbA1ceach year until the development of retinopathy was investigated. In total 72 patients were included and the follow-up time was between 15 and 23 years. Gender, p-glucose, age and HbA1cat diagnosis were analyzed for possible correlations to years to retinopathy.Results:HbA1cwas significantly higher among those who had developed DR after 15 years from diagnosis, 98±9.2 (n=25) vs. 86±9.2 (n=46; p=0.025). A negative correlation was found between age at diagnosis and years to DR (rs=−0.376; p=0.026). Mean HbA1clevels at years 6–10 after diabetes diagnosis correlated significantly (rs=−0.354, p=0.037) to years until retinopathy. Mean HbA1clevels at years 1–15 after diabetes diagnosis were significantly higher at years 2–3 and years 5–8 for those who had developed retinopathy after 15 years from diagnosis.Conclusions:Higher HbA1clevels shortened the time to development of retinopathy. It is therefore important to keep HbA1cas close to normal as possible.

Download Full-text

Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S.

10.2337/figshare.14384324.v3 ◽

2021 ◽

Author(s):

Vibha Anand ◽

Ying Li ◽

Bin Liu ◽

Mohamed Ghalwash ◽

Eileen Koski ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cohort Studies ◽

Prospective Cohort ◽

Diabetes Risk ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Diabetes Incidence ◽

Prospective Cohort Studies ◽

Hla Dr

OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and to estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODS: Prospective cohorts in Finland, Germany, Sweden and the US have followed 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTS: In the infant-toddler cohort, 1413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two or three autoantibodies at seroconversion: 45% (95% CI 40-52%), 85% (78-90%), and 92% (85-97%), respectively. Among those with single autoantibody, their status two years after seroconversion predicted diabetes risk: 12% (10-25%) if reverting to autoantibody negative, 30% (20-40%) if retaining single autoantibody, and 82% (80-95%) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single autoantibody. Their 15-year diabetes incidence for higher vs. lower risk genotypes was 40% (28-50%) vs. 12% (5-38%). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies ranging from 20%/year to 6%/year in children developing multi-positivity ≤2 years or >7.4 years, respectively. CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.

Download Full-text