Adult-onset Type 1 Diabetes Research Articles

An online tool using clinical factors to estimate the probability of partial clinical remission of adult-onset Type 1 diabetes

A type 1 diabetes (T1D) diagnosis is often followed by a period of reduced exogenous insulin requirement, with acceptable glucose control, called partial clinical remission (pCR). Various criteria exist to define pCR, which is associated with better clinical outcomes.We aimed to develop formulae and a related online calculator to predict the probability of pCR at 3- and 12-months post-T1D diagnosis.We analysed data from 133 adults at their T1D diagnosis (mean ± SD age: 27 ± 6 yrs., HbA1c 11.1 ± 2.0 %, 98 ± 22 mmol/mol), 3- and 12-months later. All patients were enrolled in the prospective observational InLipoDiab1 study (NCT02306005). We compared four definitions of pCR: 1) stimulated C-peptide >300 pmol/l; 2) insulin dose-adjusted HbA1c ≤9 %; 3) insulin dose <0.3 IU/kg/24 h; and HbA1c ≤6.4 % (46 mmol/mol); and 4) insulin dose <0.5 IU/kg/24 h and HbA1c <7 % (53 mmol/mol). Using readily available demographics and clinical chemistry data exhaustive search methodology was used to model pCR probability.There was low concordance between pCR definitions (kappa 0.10). The combination of age, HbA1c, diastolic blood pressure, triglycerides and smoking at T1D onset predicted pCR at 12-months with an area under the curve (AUC) = 0.87. HbA1c, triglycerides and insulin dose 3-mths post-diagnosis had an AUC = 0.89. A related calculator for pCR in adult-onset T1D is available at http://www.bit.ly/T1D-partial-remission.

Early-Life Factors Associated With Adult-Onset Type 1 Diabetes: A Swedish Nationwide Cohort and Family-Based Study.

Childhood-onset type 1 diabetes (T1D) is associated with perinatal factors, but data related to adult-onset T1D are scarce. This study aimed at investigating the association between early-life factors and adult-onset T1D in a Swedish nationwide cohort and family-based study. We included 1,813,415 individuals aged ≥18 years, born in Sweden 1983 to 2002, followed until 2020. T1D diagnosis (n = 3,283) was identified from the National Diabetes, Patient and Prescribed Drugs Registers, and perinatal exposures were obtained from the Medical Birth Register. We performed Cox proportional hazard (hazard ratio [95% CI]) regression with mutual adjustment for perinatal exposures, sex, birth year, and parental sociodemographic background and history of diabetes. We also compared T1D risks among siblings' groups identified from the Multiple Generation Register. The incidence rate of adult-onset T1D was 18.8 per 100,000 person-years. Year of birth (1.06 [1.01-1.10], per five additional years) and history of maternal (4.10 [3.09-5.43]) and paternal (6.24 [5.10-7.64]) T1D were associated with a higher incidence of adult-onset T1D, whereas female sex (0.69 [0.64-0.74]) and having parents born outside Sweden were associated with a lower incidence. Regarding perinatal exposures, only non-full-term birth (<39 weeks vs. ≥39 weeks) was associated with a higher incidence of adult-onset T1D (1.12 [1.04-1.22]). The sibling cohort results were consistent with the full cohort analysis. Perinatal factors seem to play a minor role in the development of adult-onset T1D compared with childhood-onset T1D, suggesting that triggers or accelerators of autoimmunity occurring later in life are more significant.

Type 1 Diabetes Genetic Risk in 109,954 Veterans With Adult-Onset Diabetes: The Million Veteran Program (MVP).

To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates. Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011-2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%). T1D characteristics increased progressively with higher genetic risk (P < 0.001 for trend). A GRS ≥90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and their characteristics resembled those of individuals with T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low-risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low GRS 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C-peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase antibodies (6.9% vs. 45.2%), all P < 0.001. Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble those of people with T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates.

Distinct signatures of gut microbiota and metabolites in different types of diabetes: a population-based cross-sectional study

Patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) present intestinal disturbances. Recent epidemiological data have showed that, worldwide, over half of newly diagnosed T1D patients were adults. However, the gut microbial alterations in adult-onset T1D are unclear. We aimed to identify the signatures of gut microbiota and metabolites in patients with adult-onset T1D systematically, comparing with T2D patients and healthy controls (HCs). This study enrolled 218 subjects from February 2019 to April 2022 (discovery cohort: 36HCs, 51 patients with adult-onset T1D and 56 patients with T2D; validation cohort: 28HCs, 27 patients with adult-onset T1D and 20 patients with T2D). Gut microbial profiles of the study subjects were investigated by metagenomic sequencing, and their faecal and serum metabolites were measured with targeted metabolomics. The study was registered on ClinicalTrials.gov (NCT05252728). Patients with adult-onset T1D had significant differences in the composition of bacteria and their metabolites, characterized by notable depletion of short-chain fatty acid-producing bacteria, especially Eubacterium rectale. This was associated with a severe loss of phenolic acids and their derivatives, including gallic acid (associated with glucose metabolism) and 3,4-dihydroxyhydrocinnamic acid (linked with glucose metabolism and pancreatic beta cell autoimmunity). A predictive model based on six bacteria and six metabolites simultaneously discriminated adult-onset T1D from T2D and HCs with high accuracy. Interestingly, bacterial-viral or bacterial-fungal trans-kingdom relationships, especially positive correlations between bacteriophages and beneficial bacteria, were significantly reduced in adult-onset T1D compared to HCs. Adult-onset T1D patients exhibit unique changes in host-microbiota-metabolite interactions. Gut microbiota and metabolite-based algorithms could be used as additional tools for differential diagnosis of different types of diabetes and beyond. National Key Research and Development Program of China, the National Natural Science Foundation of China.

1452-P: Type 1 Diabetes Subphenotypes—A Cluster Analysis

Adult-onset type 1 diabetes (T1D) is a chronic disease with progressive beta-cell destruction. However, individuals with adult-onset T1D are metabolically dissimilar. We aimed to identify metabolically distinct groups in a comprehensively phenotyped cohort of individuals with recent-onset T1D. Participants with T1D (n=550) were split by presence of glutamic-acid decarboxylase antibody (GADA) into a GADA- (n=95) and GADA+ groups (n=455). GADA+ was clustered using partitioning around medoids based on fasting C-peptide, glucose, triglycerides and HDL resulting in 2 distinguished GADA+ clusters. All 3 clusters were compared at baseline (first year of diabetes diagnosis) and after five years of follow-up using ANOVA, chi-squared test and logistic regression adjusted for age and sex. The larger GADA+ cluster (n=285) with younger age, lower BMI and lower C-peptide was termed “classic T1D”. The other GADA+ cluster (n=170) combined features of type 1 and type 2 diabetes and was named “mixed T1D”. Patients of the “mixed T1D” cluster did not gain weight over 5 years (p=0.29), which was not the case for “classic T1D” cluster (p&amp;lt;0.001, increased BMI with an effect size 0.07) and GADA-cluster (p=0.01, effect size 0.04) participants. The “classic T1D” cluster had the highest insulin sensitivity at baseline (p&amp;lt;0.001) that sharply decreased during five years of follow-up. At five years, there was no difference in insulin sensitivity across the 3 clusters (p=0.78). There were no differences in HbA1c levels across clusters neither at baseline (p=0.48) nor after 5 years (p=0.64). Classic T1D participants reported a higher incidence of hypoglycemia (OR 4.92, 95% CI 1.9-13.5, p=0.001). The incidence of both distal peripheral sensory (OR 2.89, 95%CI1.05-8.29, p= 0.041) and cardiac autonomic neuropathy (OR 9.61, 95%CI 2.35-49.8, p= 0.003), was higher in “mixed T1D”. Based on rapidly available laboratory variables, individuals with recent-onset adult type 1 diabetes can be stratified into clusters with different clinical course and complication risk Disclosure K.Prystupa: Other Relationship; Berlin-Chemie AG. S.M.Meyhöfer: Speaker's Bureau; Novo Nordisk, AstraZeneca, Lilly, Amgen Inc., Boehringer-Ingelheim, Novartis. O.P.Zaharia: None. N.Saatmann: None. M.Huttasch: None. K.Strassburger: None. V.Burkart: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. G.J.Bönhof: None. A.Strom: None. M.Heni: Advisory Panel; Boehringer-Ingelheim, Sanofi, Research Support; Boehringer Ingelheim Inc., Speaker's Bureau; Lilly, Bayer Inc., Sanofi, Boehringer-Ingelheim, Novo Nordisk, Amryt Pharma Plc. J.Seissler: None. J.Szendroedi: None. A.F.Pfeiffer: Advisory Panel; Abbott Diabetes, Speaker's Bureau; Novo Nordisk, Sanofi-Aventis Deutschland GmbH. M.W.Stumvoll: None.

1282-P: Interactive Tool to Estimate Probability of Partial Clinical Remission in Adult-Onset Type 1 Diabetes

Introduction: Type 1 diabetes (T1D) diagnosis is often (in adults) followed by a (‘honeymoon’) period of reduced insulin need, also called partial clinical remission (pCR), which is associated with better outcomes. Various definitions of pCR exist. Aim: To create an online calculator to predict probability of pCR in adult-onset T1D 12-mths post-diagnosis. Methods: We analysed data from 133 adults at T1D diagnosis (mean±SD age: 27±6, HbA1c: 11.1±2.0%, BMI: 22.5±3.7 kg/m2), 3-mths and 12-mths later. All were enrolled in the prospective observational InLipODiab (NCT02306005) study. We used 4 definitions for pCR 12-mths post-diagnosis: 1) insulin dose-adjusted HbA1c≤9%; 2) insulin dose&amp;lt;0.3U/kg/24h and HbA1c≤6.4%; 3) insulin dose&amp;lt;0.5U/kg/24h and HbA1c&amp;lt;7%; 4) stimulated C-peptide &amp;gt;300pmol/L. Exhaustive search was used to find the best models (based on AIC) based on usually available data at diagnosis and 3-mths. Calculator (Figure 1) available at http://www.bit.ly/T1D-partial-remission. Results: There was low concordance between pCR definitions (Cohen’s weighted kappa 0.01-0.61.) Combination of age, HbA1c, diastolic BP, triglycerides and smoking at T1D onset predicted pCR (12-mths) with AUC=0.84. HbA1c, triglycerides and insulin dose 3-mths post-diagnosis had an AUC=0.89. Conclusion: A new online calculator can predict pCR in adult-onset T1D for clinical and research use. Disclosure A.Grzelka-wozniak: None. A.S.Januszewski: None. J.Flotynska: None. A.Jenkins: Advisory Panel; Insulet Corporation, Board Member; Insulin for Life, Research Support; Abbott Diabetes, Medtronic, Hemsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), National Institutes of Health. D.Zozulinska-ziolkiewicz: Advisory Panel; Abbott, Lilly, Lilly, Novo Nordisk, Medtronic, Speaker's Bureau; Abbott, Ascensia Diabetes Care, Novo Nordisk, Medtronic, Boehringer-Ingelheim, AstraZeneca. A.Uruska: Other Relationship; Lilly, Boehringer-Ingelheim, AstraZeneca, Ascensia Diabetes Care, Sanofi.

Age of Diagnosis Does Not Alter the Presentation or Progression of Robustly Defined Adult-Onset Type 1 Diabetes.

To determine whether presentation, progression, and genetic susceptibility of robustly defined adult-onset type 1 diabetes (T1D) are altered by diagnosis age. We compared the relationship between diagnosis age and presentation, C-peptide loss (annual change in urine C-peptide-creatinine ratio [UCPCR]), and genetic susceptibility (T1D genetic risk score [GRS]) in adults with confirmed T1D in the prospective StartRight study, 1,798 adults with new-onset diabetes. T1D was defined in two ways: two or more positive islet autoantibodies (of GAD antibody, IA-2 antigen, and ZnT8autoantibody) irrespective of clinical diagnosis (n = 385) or one positive islet autoantibody and a clinical diagnosis of T1D (n = 180). In continuous analysis, age of diagnosis was not associated with C-peptide loss for either definition of T1D (P > 0.1), with mean (95% CI) annual C-peptide loss in those diagnosed before and after 35 years of age (median age of T1D defined by two or more positive autoantibodies): 39% (31-46) vs. 44% (38-50) with two or more positive islet autoantibodies and 43% (33-51) vs. 39% (31-46) with clinician diagnosis confirmed by one positive islet autoantibody (P > 0.1). Baseline C-peptide and T1D GRS were unaffected by age of diagnosis or T1D definition (P > 0.1). In T1D defined by two or more autoantibodies, presentation severity was similar in those diagnosed before and after 35 years of age: unintentional weight loss, 80% (95% CI 74-85) vs. 82% (76-87); ketoacidosis, 24% (18-30) vs. 19% (14-25); and presentation glucose, 21 mmol/L (19-22) vs. 21 mmol/L (20-22) (all P ≥ 0.1). Despite similar presentation, older adults were less likely to be diagnosed with T1D, insulin-treated, or admitted to hospital. When adult-onset T1D is robustly defined, the presentation characteristics, progression, and T1D genetic susceptibility are not altered by age of diagnosis.

Comparison of diabetes distress and depression screening results of emerging adults with type 1 diabetes onset at different ages: findings from the German early-onset T1D study and the German Diabetes Study (GDS)

BackgroundDiabetes distress is increasingly considered one of the most important psychosocial issues in the care of people with type 1 diabetes (T1D). We analyse whether diabetes distress and depression screening results of emerging adults are associated with the age at T1D onset.MethodsData were taken from two cohort studies conducted at the German Diabetes Center, Düsseldorf, Germany. The 18–30-year-old participants had an age at onset either before the age of 5 years (childhood-onset long-term T1D study group, N = 749) or during adulthood (adult-onset short-term T1D study group from the German Diabetes Study (GDS), N = 163). Diabetes distress and depression screening were analysed by means of the 20-item Problem Areas in Diabetes (PAID-20) scale and the nine-item depression module from the Patient Health Questionnaire (PHQ-9). The average causal effect of age at onset was estimated by a doubly robust causal inference method.ResultsThe PAID-20 total scores were increased in the adult-onset study group [potential outcome mean (POM) 32.1 (95% confidence interval 28.0; 36.1) points] compared to the childhood-onset study group [POM 21.0 (19.6; 22.4) points, difference 11.1 (6.9; 15.3) points, p<0.001] adjusted for age, sex and haemoglobin A1c (HbA1c) levels. Moreover, more participants in the adult-onset group [POM 34.5 (24.9; 44.2) %] than in the childhood-onset group [POM 16.3 (13.3; 19.2) %] screened positive for diabetes distress [adjusted difference 18.3 (8.3; 28.2) %, p<0.001]. The PHQ-9 total score [difference 0.3 (-1.1; 1.7) points, p=0.660] and the proportion of participants with a positive screening result for depression [difference 0.0 (-12.7; 12.8) %, p=0.994] did not differ between the groups in the adjusted analyses.ConclusionsEmerging adults with short-term type 1 diabetes screened positive for diabetes distress more often than adults with type 1 diabetes onset during early childhood when age, sex and HbA1c values were considered confounding factors. Accounting for age at onset or the duration of diabetes may help explain the heterogeneity in the data when psychological factors are examined.

Birth Order, Caesarean Section, or Daycare Attendance in Relation to Child- and Adult-Onset Type 1 Diabetes: Results from the German National Cohort.

(1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection.

Epidemiology of Type 1 Diabetes.

Epidemiological research on type 1 diabetes (T1D) has traditionally focussed on the paediatric age group, but recent data in adults has confirmed it to be a disease of all ages with a wide clinical spectrum. We review the epidemiology and clinical features of T1D across the lifespan. While the peak incidence of T1D is still in early adolescence, T1D is now diagnosed more commonly in adulthood than childhood due to increasing recognition of adult-onset T1D and the length of the adult lifespan. It still follows the known geographic variations in incidence, being highest in Northern Europe and lowest in Asia. The onset of T1D in adulthood is usually less acute than in childhood and confers a lower, although still substantial, risk of complications and early mortality. Interventions to delay T1D onset are emerging and screening for those at risk at birth is increasingly available. Type 1 diabetes can develop at any age and may not present with ketosis or an immediate insulin requirement in adults. Macro- and microvascular complications are the greatest cause of excess morbidity and mortality in this population.

IgA-Type Enterovirus Antibodies Are Increased among Adults and Children with Recently Diagnosed Type 1 Diabetes.

Enteroviruses (EV) are among the leading environmental triggers of childhood-onset type 1 diabetes (T1D). Our aim was to determine the prevalence of antibodies against EV and their association with T1D in different age groups (n = 62), including young adults, and to compare these data with results from HLA-matched control participants (n = 62). IgA, IgG, and IgM antibodies against EV were detected. IgA EV antibodies were present in 46.8% of participants with T1D (median level 10.9 EIU) and in 11.3% of controls (median level 3.4 EIU). IgA EV positivity and higher level of IgA EV antibodies were both significant risk factors for T1D (odds ratio (OR) 8.33; 95% confidence interval (CI) 2.52–27.6; p = 0.0005 and OR 1.04; 95% CI 1.01–1.06; p = 0.0105, respectively). Importantly, the prevalence of IgA EV antibodies in the subgroups of both children and young adults was also significantly different between participants with T1D and their matched controls (p = 0.0089 and p = 0.0055, respectively). Such differences were not seen for IgG and IgM EV antibodies. However, IgG EV antibodies were associated with 65 kDa glutamic acid decarboxylase antibodies, but not with zinc transporter 8 and protein tyrosine phosphatase IA2 antibodies. The genotype frequency of PTPN22 (rs2476601) and IFIH1 (rs1990760) was not associated with EV positivity. This study showed that EV infections may be an important disease-promoting factor of T1D not only in childhood-onset but also in adult-onset T1D. However, to further confirm this association, direct virological studies are needed in the latter T1D group.

The Incidence of Adult-Onset Type 1 Diabetes: A Systematic Review From 32 Countries and Regions.

BACKGROUNDThe epidemiology of adult-onset type 1 diabetes (T1D) incidence is not well-characterized due to the historic focus on T1D as a childhood-onset disease.PURPOSEWe assess the incidence of adult-onset (≥20 years) T1D, by country, from available data.DATA SOURCESA systematic review of MEDLINE, Embase, and the gray literature, through 11 May 2021, was undertaken.STUDY SELECTIONWe included all population-based studies reporting on adult-onset T1D incidence and published from 1990 onward in English.DATA EXTRACTIONWith the search we identified 1,374 references of which 46 were included for data extraction. Estimates of annual T1D incidence were allocated into broad age categories (20–39, 40–59, ≥60, or ≥20 years) as appropriate.DATA SYNTHESISOverall, we observed the following patterns: 1) there is a paucity of data, particularly in low- and middle-income countries; 2) the incidence of adult-onset T1D is lowest in Asian and highest in Nordic countries; 3) adult-onset T1D is higher in men versus women; 4) it is unclear whether adult-onset T1D incidence declines with increasing age; and 5) it is unclear whether incidence of adult-onset T1D has changed over time.LIMITATIONSResults are generalizable to high-income countries, and misclassification of diabetes type cannot be ruled out.CONCLUSIONSFrom available data, this systematic review suggests that the incidence of T1D in adulthood is substantial and highlights the pressing need to better distinguish T1D from T2D in adults so that we may better assess and respond to the true burden of T1D in adults.

Experiences of adults with adult-onset type 1 diabetes: a cross-sectional study.

Type 1 diabetes (T1D) is a chronic, autoimmune disease where the pancreas does not produce enough insulin. T1D requires ongoing management across the lifespan through insulin regulation, monitoring of blood glucose levels, and adherence to strict diet and exercise plans. The most recent National Diabetes Services Scheme Australian Diabetes Map indicates that 129 210 Australians currently have T1D. Traditionally considered a childhood disease, more than half of all T1D diagnoses actually occur in adults aged >20 years. The aim of this study was to examine the experiences of individuals living with adult-onset T1D in relation to their diagnosis experience, access to health care, and post-diagnostic wellbeing. An exploratory, cross-sectional study was undertaken. Participants completed an online survey delivered via Qualtrics detailing their experiences with adult-onset T1D. The survey contained four domains: (1) demographic information; (2) diagnosis experience; (3) access to care; and (4) post-diagnostic wellbeing, including the Hospital Anxiety and Depression Scale (HADS); and the Diabetes Distress Scale (T1-DDS). Data analysis was conducted using STATA SE (v16). Descriptive statistics (means, counts) were used to describe continuous data, and frequencies and odds ratios were used to describe categorical data. One hundred and twenty adults (mean age 49 years; 78% female) with adult-onset T1D (mean age at diagnosis 37 years) completed the survey. The most common symptoms prior to diagnosis were excess thirst, fatigue, frequent urination, and unintended weight loss. Half (50%) the sample received their T1D diagnosis from a general practitioner (GP). Several participants reported being misdiagnosed by their GP initially, representing an unadjusted odds ratio of 3.1 (95% CI 1.5, 6.2). Nearly half of all participants presented with anxiety (mean 7 (s.d. 4)) on the HADS, and most reported moderate levels of diabetes-related distress according to the T1-DDS. These findings provide a starting point to understanding the experiences of adults living with adult-onset T1D and can be used to raise awareness of their challenges and needs. These exploratory findings can also be used to inform a larger, population-based study.

The Unfavorable Impact of DR9/DR9 Genotype on the Frequency and Quality of Partial Remission in Type 1 Diabetes.

Partial remission (PR) is a specific stage in type 1 diabetes (T1D). Although human leukocyte antigen (HLA) class II loci are the strongest genetic determinants in T1D, the relationship between PR and HLA remains unclear. To investigate the association between PR status and HLA genotypes in patients with T1D. A total of 237 patients with T1D were included. PR was defined according to C-peptide ≥300 pmol/L. The frequency of PR and peak C-peptide levels during remission phase were compared according to HLA status. Clinical characteristics including age of onset and diabetes autoantibodies were collected. All analyses were duplicated when subjects were divided into childhood- and adult-onset T1D. The median follow-up time was 24 months, 65.8% (156/237) of patients with T1D went into PR. DR9/DR9 carriers had a lower PR rate (44.2% vs 70.6%, P = .001) and were less likely to enter PR (OR = 0.218, 95% CI 0.098-0.487, P < .001) than the non-DR9/DR9 carriers, observed in both childhood- and adult-onset T1D. Besides, the peak C-peptide level during PR phase was also lower in DR9/DR9 carriers, and more notable in adult-onset T1D. When compared with non-DR9/DR9 carriers, T1D with DR9/DR9 genotype presented an older age of onset and a lower positivity of zinc transporter 8 antibody (ZnT8A), and the lower trend of ZnT8A was only found in adult-onset T1D (P = .049). Patients with T1D carrying susceptible DR9/DR9 are less prone to undergo PR. Additionally, the recovery extent of β-cell function during the PR phase tends to be lower in adults carrying DR9/DR9, which might be associated with ZnT8A.

One repeated transplantation of allogeneic umbilical cord mesenchymal stromal cells in type 1 diabetes: an open parallel controlled clinical study

BackgroundThe preservation or restoration of β cell function in type 1 diabetes (T1D) remains as an attractive and challengeable therapeutic target. Mesenchymal stromal cells (MSCs) are multipotent cells with high capacity of immunoregulation, which emerged as a promising cell-based therapy for many immune disorders. The objective of this study was to examine the efficacy and safety of one repeated transplantation of allogeneic MSCs in individuals with T1D.MethodsThis was a nonrandomized, open-label, parallel-armed prospective study. MSCs were isolated from umbilical cord (UC) of healthy donors. Fifty-three participants including 33 adult-onset (≥ 18 years) and 20 juvenile-onset T1D were enrolled. Twenty-seven subjects (MSC-treated group) received an initial systemic infusion of allogeneic UC-MSCs, followed by a repeat course at 3 months, whereas the control group (n = 26) only received standard care based on intensive insulin therapy. Data at 1-year follow-up was reported in this study. The primary endpoint was clinical remission defined as a 10% increase from baseline in the level of fasting and/or postprandial C-peptide. The secondary endpoints included side effects, serum levels of HbA1c, changes in fasting and postprandial C-peptide, and daily insulin doses.ResultsAfter 1-year follow-up, 40.7% subjects in MSC-treated group achieved the primary endpoint, significantly higher than that in the control arm. Three subjects in MSC-treated group, in contrast to none in control group, achieved insulin independence and maintained insulin free for 3 to 12 months. Among the adult-onset T1D, the percent change of postprandial C-peptide was significantly increased in MSC-treated group than in the control group. However, changes in fasting or postprandial C-peptide were not significantly different between groups among the juvenile-onset T1D. Multivariable logistic regression assay indicated that lower fasting C-peptide and higher dose of UC-MSC correlated with achievement of clinical remission after transplantation. No severe side effects were observed.ConclusionOne repeated intravenous dose of allogeneic UC-MSCs is safe in people with recent-onset T1D and may result in better islet β cell preservation during the first year after diagnosis compared to standard treatment alone.Trial registrationChiCTR2100045434. Registered on April 15, 2021—retrospectively registered, http://www.chictr.org.cn/

244-OR: Toward Improved Identification of Adult-Onset Type 1 Diabetes (T1D): Clinical Characteristics Associated with T1D Polygenic Risk Scores in the Million Veteran Program (MVP)

Adult onset T1D is often misdiagnosed as T2D, leading to poor metabolic control and increased risk of microvascular complications and cardiovascular morbidity and mortality. We examined characteristics associated with a T1D genetic risk score in Veterans, a population where new diagnoses are generally presumed to be T2D, since persons with typical juvenile-onset T1D are excluded from military service. A 30 SNP T1D genetic risk score (GRS), previously validated with the Wellcome Trust Case Control Consortium (WTCCC), was applied to 111,663 Veterans with diabetes in the MVP. Patients were stratified by T1D GRS centile groups (≤5th, &amp;gt;5th-≤36th, &amp;gt;36th-≤50th, and &amp;gt;50th) which corresponded to T1D specificity in the WTCCC of 29%, 53%, 90%, and 95%, respectively. Typical T1D clinical characteristics were significantly more common (p&amp;lt;0.001) across increasing GRS centile groups: diabetic ketoacidosis 1.07%, 1.34%, 1.95%, 3.55%; hypoglycemia prompting an emergency department visit 3.95%, 3.84%, 4.45%, 5.45%; random plasma glucose &amp;lt;50 mg/dl at a primary care visit 8.05%, 7.99%, 9.01%, 12.43%; years to starting outpatient insulin Rx 4.40, 4.31, 3.97, 3.38; any use of a T1D ICD code 16.56%, 17.76%, 20.90%, 27.62%; low C-peptide if tested 2.91%, 9.75%, 18.96%, 32.55%; and GAD antibody (+) if tested 8.80%, 23.39%, 32.73%, 45.00%. Among the 5% tested, years to starting insulin fell significantly (p&amp;lt;0.001) in lowest to highest centile groups, from 2.59 to 1.28 yr for GAD(-), and from 1.77 vs. 0.90 yr for GAD(+). Conclusions: The 10% of US Veterans with diabetes in MVP in the two highest T1D GRS centile groups have characteristics suggestive of T1D, although only 5% were tested for GAD antibodies, and most had no use of T1D diagnosis codes. Since adult-onset T1D may be misdiagnosed as T2D in settings where T2D is more common, genetic analyses and/or clinical characteristics may warrant definitive testing and appropriate management. Disclosure P. K. Yang: None. M. K. Rhee: None. C. Mercado: None. R. A. Oram: Consultant; Self; Janssen Research &amp; Development, LLC. M. Vujkovic: None. P. Reaven: Research Support; Self; AstraZeneca, Dexcom, Inc. K. Cho: None. L. S. Phillips: Other Relationship; Self; Diasyst Inc., Research Support; Self; AbbVie Inc., Eli Lilly and Company, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Kowa Pharmaceuticals America, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Pharma Ltd., Pfizer Inc., Sanofi-Aventis. A. Leong: None. S. Jackson: None. B. R. Charest: None. M. N. Weedon: None. Y. J. Cheng: None. Y. V. Sun: None. S. Raghavan: None. E. M. Litkowski: None. B. T. Legvold: None. Funding U.S. Department of Veterans Affairs (CSP2008, I01CX001899, I01CX001737); National Institutes of Health (R18DK066204, R21AI156161, U01DK091958, U01DK098246, UL1TR002378)

1119-P: Improving Clinical Utility of GAD65 Autoantibodies by Electrochemiluminescence Assay When Identifying Autoimmune Adult-Onset Diabetes

Aims: It is important to differentiate the two major phenotypes of adult-onset diabetes, autoimmune type 1 diabetes (T1D) and non-autoimmune type 2 diabetes (T2D). Serum GAD65 autoantibodies (GADA) are the most sensitive biomarker for adult-onset autoimmune T1D, but the clinical value of GADA by current standard radio-binding assays (RBA) remains questionable. The present study focused on the clinical utility of GADA differentiated by a new electrochemiluminescence (ECL) assay in patients with adult-onset diabetes. Methods: Two cohorts of individuals recently diagnosed with diabetes at ≥20 years of age were analyzed including 771 patients 30-70 years olds from the Action LADA study and 2,063 patients 20-45 year olds from the Diabetes in Young Adults (DiYA) study. Clinical characteristics including requirement of early insulin treatment, BMI, and development of multiple islet autoantibodies were analyzed according to the status of RBA-GADA and ECL-GADA, respectively. Results: GADA was the most prevalent and predominant autoantibody, &amp;gt;90% in both cohorts with any positive autoantibody. GADA positivity by either RBA or ECL assay significantly discriminated clinical T1D from T2D. However, patients with ECL-GADA in both cohorts were at greatest risk of insulin treatment, multiple islet autoantibodies and lower BMI (all p&amp;lt;0.0001). Among patients GADA positive by RBA, 32.4% (90/278) in the Action LADA study and 25.6% (32/125) in the DiYA study were negative by ECL assay. Patients with GADA detectable by RBA, not confirmed by ECL, had a phenotype more similar to T2D and these RBA-GADA had lower affinity compared to GADA confirmed by ECL assay. Conclusion: The ECL-GADA assay offers advantages over the RBA-GADA in identification of adult-onset diabetes patients at higher risk of early insulin dependency. Disclosure X. Jia: None. L. Yu: None. R. D. Leslie: None. The action lada consortium: n/a. The diabetes in young adults (diya) study group: n/a. Y. Gu: None. T. Vartak: None. D. Miao: None. F. Dong: None. S. T. Jerram: None. M. Rewers: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; RTI, Research Support; Self; Janssen Research &amp; Development, LLC, JDRF. A. Ferrara: None. J. M. Lawrence: None. Funding JDRF (2-SRA-2019-695-S-B); National Institutes of Health (DK32083); 5th Framework Program of the European Union; Centers for Disease Control and Prevention (1U18DP006289)

Comparison of differences in bone microarchitecture in adult- versus juvenile-onset type 1 diabetes Asian males versus non-diabetes males: an observational cross-sectional pilot study

PurposeEvidence about bone microarchitecture in Asian type 1 diabetes (T1D) patients is lacking. We assessed the bone microarchitecture in T1D patients versus controls and compare the differences between juvenile-onset and adult-onset T1D patients.MethodsThis cross-sectional study recruited 32 Asian males with T1D and 32 age-, sex-, and body mass index (BMI)-matched controls. Dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) for ultradistal nondominant radius and tibia were performed. The data were analyzed using Student’s t test and analysis of covariance.ResultsAmong the patients, 15 had juvenile-onset T1D, with a median disease duration of 11 years, and 17 had adult-onset T1D, with a median disease duration of 7 years. At the radius, adult-onset and juvenile-onset T1D patients had lower total volumetric bone mineral density (vBMD), trabecular vBMD, trabecular bone volume fraction (BV/TV), and trabecular thickness (Tb.Th) (p < 0.05) than the control subjects. After adjusting for BMI, disease duration, and insulin dose, juvenile-onset patients tended to have lower trabecular vBMD, BV/TV, Tb.Th, and intracortical porosity (Ct.Po) than adult-onset patients. At the tibia, adult-onset patients displayed lower total vBMD, lower Ct. vBMD, and higher Ct.Po (p < 0.05), while juvenile-onset patients had lower Tb.Th and standard deviation of trabecular number (1/Tb.N.SD) (p < 0.05) than control subjects. After adjustment for covariates, adult-onset patients tended to have higher cortical pore diameter (Ct.Po.Dm) than juvenile-onset patients.ConclusionsT1D patients were associated with compromised bone microarchitecture, adult-onset and juvenile-onset T1D patients demonstrated some differences in cortical and trabecular microarchitecture.

1683-P: Analysis of Type 1 Diabetes Genetic Risk Score Shows 1 in 8 People with Clinically Diagnosed Adult-Onset T1D Are Misdiagnosed, and Presenting Features at Diagnosis Do Not Identify Those Misdiagnosed

Aims: Accurate initial diagnosis of adult-onset type 1 diabetes (T1D) is important. We aimed to estimate the rate of misdiagnosis in clinically-diagnosed adult T1D. We also assessed the utility of Islet autoantibodies and presenting features to identify misdiagnosed-T1D. Methods: We used a T1D-genetic risk score (T1D-GRS) to estimate misdiagnosed-T1D in 1112 white-Europeans adults clinically-diagnosed with T1D (age diagnosis &amp;gt;18y) from the ADDRESS-2 study. We used 1924 gold-standard T2D as a non-T1D control. All patients were recruited &amp;lt;6m from diagnosis and insulin treated. We assessed clinical features and autoantibodies (GADA, IA-2A, ZNT8A) in misdiagnosed and true-T1D. Results: People with one (n=309), two (n=285) or three (n=300) autoantibodies had a similar T1D-GRS suggesting people with ≥1 antibody positive had true-T1D (mean GRS 0.270 vs. 0.269 vs. 0.273, p=0.13). People without antibody had T1D-GRS (0.243, n=218) between true-T1D (0.271, n=894, ≥1ab+ve) and T2D (0.229, n=1924, p&amp;lt;0.0001) suggesting presence of non-T1D in antibody negative group. The estimated proportion of non-T1D in antibody negative group was 67% (n=146/218) which was 13% of the whole cohort (95% CI 11-15%). Misdiagnosis was higher in people diagnosed 30-75y (21%) vs. 18-30y (6%, p&amp;lt;0.001). Misdiagnosed-T1D and true-T1D had similar rates of polyuria (91% vs. 95%), weight loss (85% vs. 88%) and DKA (38% vs. 43%) (all p&amp;gt;0.05). Misdiagnosed-T1D were more likely to be male (81% vs. 59%), older (40y vs. 32y), had higher BMI (28 vs. 24) and HbA1c (105 vs. 91 mmol/mol) compared to true-T1D (all p&amp;lt;0.001). Conclusion: Initial misdiagnosis of T1D is common in people diagnosed &amp;gt;30y (21%). When clinically-diagnosed with T1D at diagnosis, negative islet autoantibodies but not severe hyperglycaemia/DKA identify misdiagnosed people. Disclosure K.A. Patel: None. N. Thomas: None. M.N. Weedon: None. H.C. Walkey: None. A. Kaur: None. A.J. Williams: None. S. Misra: None. N. Oliver: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Dexcom, Inc., Roche Diabetes Care. Speaker's Bureau; Self; Dexcom, Inc., Sanofi. D.G. Johnston: None. A.T. Hattersley: None. Funding Diabetes UK; JDRF; Diabetes Research &amp; Wellness Foundation

Type 1 diabetes onset at young age is associated with compromised bone quality.

Women with type 1 diabetes (T1D) are at increased risk for fracture. We studied the association of T1D and young age at T1D onset (T1D onset before 20 years) on bone structural quality. 24 postmenopausal women with T1D (mean age 60.9 years, mean T1D duration 41.7 years) and 22 age, sex- and body mass index (BMI)-matched controls underwent dual X-ray absorptiometry (DXA) measured areal bone mineral density (aBMD) at the lumbar spine, hip and distal radius. Bone mass, geometry and estimated bone strength were assessed at distal and shaft of non-dominant radius and tibia using peripheral quantitative computed tomography (pQCT). Postmenopausal women with T1D had lower trabecular volumetric bone mineral density (vBMD) (LSM ± SEM; 166.1 ± 8.2 vs 195.9 ± 8.3 mg/cm3, p = 0.02) and compressive bone strength (24.6 ± 1.8 vs 30.1 ± 1.9 mg2/mm4, p = 0.04) at the distal radius compared to controls adjusting for age, BMI and radius length. At the distal radius, patients with young onset T1D had lower total vBMD (258.7 ± 19.7 vs 350.8 ± 26.1 mg/cm3, p = 0.02) and trabecular vBMD (141.4 ± 11.6 vs 213.6 ± 15.4 mg/cm3, p = 0.003) compared to adult onset T1D patients adjusting for age, BMI and the radius length. At the tibial shaft, young onset T1D patients had larger endosteal circumference (39.1 ± 1.2 vs 32.1 ± 1.6 mm, p = 0.005) with similar periosteal circumference (67.1 ± 0.9 vs 65.1 ± 1.2 mm, p = 0.2) resulting in reduced cortical thickness (4.4 ± 0.1 vs 5.2 ± 0.1 mm, p = 0.004) compared to adult onset T1D patients adjusting for age, BMI and the tibia length. There was no difference in the lumbar spine, femoral neck, total hip and distal radius DXA-measured aBMD between subjects with T1D and controls. T1D is associated with lower trabecular vBMD at the distal radius. T1D onset before age 20 is associated with cortical bone size deficits at the tibial shaft.