CGM Metrics Predict Imminent Progression to Type 1 Diabetes: Autoimmunity Screening for Kids (ASK) Study

Objective: Children identified with stage 1 type 1 diabetes are at high risk for progressing to stage 3 (clinical) diabetes and require accurate monitoring. Our aim was to establish CGM metrics that could predict imminent progression to diabetes. <p>Methods: In the Autoimmunity Screening for Kids study, 91 children persistently islet autoantibody positive (median age 11.5 y, 48% non-Hispanic White, 57% female) with a baseline CGM were followed for development of diabetes for a median of 6 (range:0.2-34) months. Of these, 16 (18%) progressed to clinical diabetes in a median of 4.5 (range:0.4-29 months. </p> <p>Results: Compared to non-progressors, progressors had significantly higher average sensor glucose (119 vs 105 mg/dL) and increased glycemic variability: SD 27 vs 16, CV 21 vs 15, MODD 24 vs 16 and MAGE 43 vs 26. Progressors spent 21% of <a>time above 140 mg/dl </a>(TA140) and 8% above 160 mg/dl, compared to 3% and 1%, respectively, for non-progressors. <a>In survival analyses, the risk of progression to diabetes in one year was 80% in those with TA140 >10%; in contrast, it was only 5% in the other participants. </a><a>Performance of prediction by receiver operating curve analyses showed area under the curve of <u>></u>0.89 for both individual and combined CGM metric models</a>. </p> <p>Conclusions<a>: </a><a>TA140 >10% is associated with a high risk of progression to clinical diabetes within the next year</a> in autoantibody positive children. CGM should be included in the ongoing monitoring of high-risk children<a></a><a> a</a>nd could be used as potential entry criteria for prevention trials. </p>

CGM Metrics Predict Imminent Progression to Type 1 Diabetes: Autoimmunity Screening for Kids (ASK) Study

Objective: Children identified with stage 1 type 1 diabetes are at high risk for progressing to stage 3 (clinical) diabetes and require accurate monitoring. Our aim was to establish CGM metrics that could predict imminent progression to diabetes. <p>Methods: In the Autoimmunity Screening for Kids study, 91 children persistently islet autoantibody positive (median age 11.5 y, 48% non-Hispanic White, 57% female) with a baseline CGM were followed for development of diabetes for a median of 6 (range:0.2-34) months. Of these, 16 (18%) progressed to clinical diabetes in a median of 4.5 (range:0.4-29 months. </p> <p>Results: Compared to non-progressors, progressors had significantly higher average sensor glucose (119 vs 105 mg/dL) and increased glycemic variability: SD 27 vs 16, CV 21 vs 15, MODD 24 vs 16 and MAGE 43 vs 26. Progressors spent 21% of <a>time above 140 mg/dl </a>(TA140) and 8% above 160 mg/dl, compared to 3% and 1%, respectively, for non-progressors. <a>In survival analyses, the risk of progression to diabetes in one year was 80% in those with TA140 >10%; in contrast, it was only 5% in the other participants. </a><a>Performance of prediction by receiver operating curve analyses showed area under the curve of <u>></u>0.89 for both individual and combined CGM metric models</a>. </p> <p>Conclusions<a>: </a><a>TA140 >10% is associated with a high risk of progression to clinical diabetes within the next year</a> in autoantibody positive children. CGM should be included in the ongoing monitoring of high-risk children<a></a><a> a</a>nd could be used as potential entry criteria for prevention trials. </p>

Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children

OBJECTIVE: To utilize islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. <p>RESEARCH DESIGN AND METHODS: Prospective cohort studies in Finland, Germany, Sweden and the US followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonized for diabetes risk analyses.</p> <p>RESULTS: Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n=909), GADA (n=1076) or IA-2A (n=714), when stratified by quartiles of titer, ranging from 19% (GADA 1^st quartile) to 60% (IA-2A 4^th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6^th, 52.4^th and 10.2^nd percentile of children specifically positive for each of IAA, GADA and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n=954) and multiple (n=527) autoantibodies could be stratified from 6% to 75% (p<0.0001). The thresholds effectively identified children with 50% or higher 5-year risk when considering age-specific autoantibody screening (57-65% positive predictive value and 56-74% sensitivity for ages 1-5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy.</p> <p>CONCLUSIONS: This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.</p>

Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children

OBJECTIVE: To utilize islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. <p>RESEARCH DESIGN AND METHODS: Prospective cohort studies in Finland, Germany, Sweden and the US followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonized for diabetes risk analyses.</p> <p>RESULTS: Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n=909), GADA (n=1076) or IA-2A (n=714), when stratified by quartiles of titer, ranging from 19% (GADA 1^st quartile) to 60% (IA-2A 4^th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6^th, 52.4^th and 10.2^nd percentile of children specifically positive for each of IAA, GADA and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n=954) and multiple (n=527) autoantibodies could be stratified from 6% to 75% (p<0.0001). The thresholds effectively identified children with 50% or higher 5-year risk when considering age-specific autoantibody screening (57-65% positive predictive value and 56-74% sensitivity for ages 1-5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy.</p> <p>CONCLUSIONS: This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.</p>

Identifying the lungs as a susceptible site for allele-specific regulatory changes associated with type 1 diabetes risk

Type 1 diabetes (T1D) etiology is complex. We developed a machine learning approach that ranked the tissue-specific transcription regulatory effects for T1D SNPs and estimated their relative contributions to conversion to T1D by integrating case and control genotypes (Wellcome Trust Case Control Consortium and UK Biobank) with tissue-specific expression quantitative trait loci (eQTL) data. Here we show an eQTL (rs6679677) associated with changes to AP4B1-AS1 transcript levels in lung tissue makes the largest gene regulatory contribution to the risk of T1D development. Luciferase reporter assays confirmed allele-specific enhancer activity for the rs6679677 tagged locus in lung epithelial cells (i.e. A549 cells; C > A reduces expression, p = 0.005). Our results identify tissue-specific eQTLs for SNPs associated with T1D. The strongest tissue-specific eQTL effects were in the lung and may help explain associations between respiratory infections and risk of islet autoantibody seroconversion in young children.

Dynamics of gut microbiome - mediated bile acid metabolism in progression to islet autoimmunity

Previous studies suggest that the human gut microbiome is dysregulated in islet autoimmunity, preceding the clinical onset of type 1 diabetes (T1D). The microbiota of the gut plays an important role in the regulation of bile acid (BA) metabolism. However, not much is known about the regulation of BAs during progression to T1D. Here, we analyzed BAs in a longitudinal series of serum (n= 333) and stool (n= 304) samples, collected at 3, 6, 12, 18, 24 and 36 months of age, from children who developed a single islet autoantibody (P1Ab), multiple islet autoantibodies (P2Ab), and controls (CTRs) who remained autoantibody (AAb) negative during the follow-up. In addition, we analyzed the stool microbiome by shotgun metagenomics in a subgroup of these children (n=111). Factor analysis showed that age had the strongest impact on BA and microbiome profiles. We found that, at an early age, the systemic BA (including taurine and glycine conjugates) and microbial secondary BA pathways were altered in the P2Ab group as compared to the P1Ab or CTR groups. Our findings thus suggest that dysregulated BA metabolism in early life may contribute to the risk and pathogenesis of T1D.

A case of monogenic diabetes mellitus caused by a novel heterozygous RFX6 nonsense mutation in a 14-year-old girl

Objectives Monogenic diabetes mellitus (DM) is a single gene disorder, primarily characterized by impairment in the development or function of pancreatic beta cells. Case presentation A 14-year-old girl was initially diagnosed with type 2 DM. The patient did not have any anti-islet autoantibody and showed acanthosis nigricans. She was managed with long-acting insulin and oral hypoglycemic agent, but HbA1c was still 9.3% after 1 year of management. Her mother already had type 2 DM at 46-year-old and was on medication. Under the possibility of familial monogenic DM, targeted exome sequencing was performed which included 29 genes associated with monogenic DM. Nonsense mutation of the gene RFX6 (c.2661T>A, p.Tyr887∗) was found. After adding Glucagon-like peptide-1 (GLP-1) receptor agonist, HbA1c improved from 8.8 to 6.8% and body mass index (BMI) also improved from 31.0 to 29.2 kg/m2. Conclusions It may be worth investigating genetic etiology in early-onset autoantibody-negative DM for specific genetic diagnosis and better management.

Comparison of Demographic and Diagnostic Markers in New Onset Pediatric Type 1 and Type 2 Diabetes

Purpose Type 1 diabetes (T1D) is the most common type of diabetes in children, but the frequency of type 2 diabetes (T2D) is increasing rapidly. Classification of diabetes is based on a constellation of features that are typical of each type. We aimed to compare demographic, clinical and laboratory characteristics at diabetes diagnosis in pediatric T1D and T2D. Methods We studied children who attended a large academic hospital in Houston, Texas (USA) with a new diagnosis of T2D (n=753) or T1D (n=758). We compared age, sex, race/ethnicity, presence of obesity, glucose, hemoglobin A1c, islet autoantibody positivity, C-peptide, and presence of diabetic ketoacidosis (DKA) at diabetes diagnosis. Results At diagnosis of diabetes, children with T2D, compared with those with T1D, were older (13.6 vs 9.7% years old), more likely females (63.2% vs 47.8%), of racial/ethnic minority (91.1%% versus 42.3%) and obese (90.9% vs 19.4%), and were less likely to have DKA (7.8% vs 35.0%) and diabetes autoantibodies (5.5% vs 95.4%). Children with T2D also had significantly less marked elevation of glucose and hemoglobin A1c, and lower C-peptide levels (all comparisons, p<0.0001). In multiple logistic regression analysis, older age, racial/ethnic minority, obesity, higher C-peptide and negative islet autoantibodies were independently associated with T2D (all, p<0.05) while sex, glucose, hemoglobin A1c and DKA were not (model p<0.0001). Conclusions There are important demographic, clinical and laboratory differences between T1D and T2D in children with T1D. However, none of the characteristics was unique to either diabetes type, which poses challenges to diabetes classification at diagnosis.

Islet autoantibody level distributions in type 1 diabetes and their association with genetic and clinical characteristics

Positivity for islet autoantibodies is used for diagnosis of type 1 diabetes. However, the importance of the autoantibody level at diagnosis of type 1 diabetes is not clear. Here, we assessed the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) autoantibody levels, measured using radiobinding assays, on genetic and clinical characteristics at diagnosis of 1536 participants with diabetes who were positive for these autoantibodies. We show that GADA and IA-2A levels had bimodal distributions, but ZnT8A level did not. The comparison of genetic and clinical characteristics between high and low level categories showed high GADA level was associated with older age at diagnosis, female sex and HLA-DR3-DQ2, whereas high IA-2A level was associated with younger age of diagnosis, ZnT8A positivity and HLA-DR4-DQ8. We replicated our findings in an independent cohort of 427 people with type 1 diabetes where autoantibodies were measured using enzyme-linked immunosorbent assays. In conclusion, Islet autoantibody levels provide additional information over positivity in type 1 diabetes at diagnosis. The bimodality of islet autoantibody levels highlights the novel aspect of heterogeneity of type 1 diabetes which may have implications on prediction, treatment and prognosis.