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

2021 ◽  
Author(s):  
Andrea K Steck ◽  
Fran Dong ◽  
Cristy Geno Rasmussen ◽  
Kimberly Bautista ◽  
Flor Sepulveda ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
High Risk ◽  
Area Under The Curve ◽  
Glycemic Variability ◽  
Receiver Operating Curve ◽  
Clinical Diabetes ◽  
Islet Autoantibody ◽  
Sensor Glucose ◽  
Risk Of Progression

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>

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

2021 ◽  
Author(s):  
Andrea K Steck ◽  
Fran Dong ◽  
Cristy Geno Rasmussen ◽  
Kimberly Bautista ◽  
Flor Sepulveda ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
High Risk ◽  
Area Under The Curve ◽  
Glycemic Variability ◽  
Receiver Operating Curve ◽  
Clinical Diabetes ◽  
Islet Autoantibody ◽  
Sensor Glucose ◽  
Risk Of Progression

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>

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

Diabetes Care ◽  
2021 ◽  
pp. dc210878
Author(s):  
Kenney Ng ◽  
Harry Stavropoulos ◽  
Vibha Anand ◽  
Riitta Veijola ◽  
Jorma Toppari ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Autoantibody ◽  
Risk Of Progression

scholarly journals T Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

2021 ◽  
Author(s):  
Josephine M. Forbes ◽  
Domenica A. McCarthy ◽  
Andrew J. Kassianos ◽  
Tracey Baskerville ◽  
Amelia J. Fotheringham ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
High Risk ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Glycemic Variability ◽  
Low Risk ◽  
Kidney Injury Molecule 1

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of kidney disease (DKD). In Type 1 diabetes, increased uACR (urinary albumin-creatinine ratio) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule- 1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. <p>DKD risk was assigned in youth with type 1 diabetes [n=100; 20.0±2.8 yrs; M:F-54:46, HbA<sub>1C</sub>-66.1(12.3) mmol/mol; diabetes duration-10.7±5.2 yrs; BMI-24.5(5.3) kg.m<sup>-2</sup>] and 10 year historical uACR, HbA<sub>1C</sub> and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared to streptozotocin diabetes in <i>Apolipoprotein E-/-</i> mice. Kidney biopsies were used to examine infiltration of KIM-1 expressing T cells in DKD and compared with other chronic kidney disease.</p> <p>Individuals at high risk for DKD had persistent elevations in uACR (uACR<sub>AUC0-10yrs</sub>, 29.7±8.8 vs 4.5±0.5; <i>P</i><0.01 vs low risk) and early kidney dysfunction including ~8.3ml.min<sup>-1</sup>.1.73m<sup>-2</sup> higher estimated glomerular filtration rates (eGFR<sub>SCHWARTZ</sub>; <i>P<sub>adj</sub></i> <0.031 vs low risk) and plasma KIM-1 concentrations (~15% higher vs low risk;<i> P</i><0.034). High risk individuals had greater glycemic variability and increased peripheral blood T cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high risk youth with diabetes showed elevated collagen IV and SGLT2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T cell production of KIM-1.<b><br> </b></p>

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

2021 ◽  
Author(s):  
Kenney Ng ◽  
Harry Stavropoulos ◽  
Vibha Anand ◽  
Riitta Veijola ◽  
Jorma Toppari ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Familial Risk ◽  
Multivariable Analysis ◽  
Diabetes Risk ◽  
Islet Autoimmunity ◽  
Acid Decarboxylase ◽  
Islet Autoantibody ◽  
Surveillance Strategy ◽  
Risk Of Progression

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<sup>st</sup> quartile) to 60% (IA-2A 4<sup>th</sup> quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6<sup>th</sup>, 52.4<sup>th</sup> and 10.2<sup>nd</sup> 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>

scholarly journals Cord-Blood Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes

Biomolecules ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 33 ◽  
Author(s):  
Santosh Lamichhane ◽  
Linda Ahonen ◽  
Thomas Sparholt Dyrlund ◽  
Alex M. Dickens ◽  
Heli Siljander ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cord Blood ◽  
Characteristic Curve ◽  
Newborn Infants ◽  
Study Groups ◽  
Islet Autoimmunity ◽  
Molecular Profile ◽  
Islet Autoantibody ◽  
Risk Of Progression

Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.

scholarly journals T Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

2021 ◽  
Author(s):  
Josephine M. Forbes ◽  
Domenica A. McCarthy ◽  
Andrew J. Kassianos ◽  
Tracey Baskerville ◽  
Amelia J. Fotheringham ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
High Risk ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Glycemic Variability ◽  
Low Risk ◽  
Kidney Injury Molecule 1

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of kidney disease (DKD). In Type 1 diabetes, increased uACR (urinary albumin-creatinine ratio) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule- 1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. <p>DKD risk was assigned in youth with type 1 diabetes [n=100; 20.0±2.8 yrs; M:F-54:46, HbA<sub>1C</sub>-66.1(12.3) mmol/mol; diabetes duration-10.7±5.2 yrs; BMI-24.5(5.3) kg.m<sup>-2</sup>] and 10 year historical uACR, HbA<sub>1C</sub> and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared to streptozotocin diabetes in <i>Apolipoprotein E-/-</i> mice. Kidney biopsies were used to examine infiltration of KIM-1 expressing T cells in DKD and compared with other chronic kidney disease.</p> <p>Individuals at high risk for DKD had persistent elevations in uACR (uACR<sub>AUC0-10yrs</sub>, 29.7±8.8 vs 4.5±0.5; <i>P</i><0.01 vs low risk) and early kidney dysfunction including ~8.3ml.min<sup>-1</sup>.1.73m<sup>-2</sup> higher estimated glomerular filtration rates (eGFR<sub>SCHWARTZ</sub>; <i>P<sub>adj</sub></i> <0.031 vs low risk) and plasma KIM-1 concentrations (~15% higher vs low risk;<i> P</i><0.034). High risk individuals had greater glycemic variability and increased peripheral blood T cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high risk youth with diabetes showed elevated collagen IV and SGLT2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T cell production of KIM-1.<b><br> </b></p>

scholarly journals High-affinity ZnT8 autoantibodies by electrochemiluminescence assay improve risk prediction for type 1 diabetes

2021 ◽  
Author(s):  
Xiaofan Jia ◽  
Ling He ◽  
Dongmei Miao ◽  
Kathleen Waugh ◽  
Cristy Geno Rasmussen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Binding Assay ◽  
Islet Autoantibody ◽  
Newly Diagnosed ◽  
High Affinity ◽  
Diabetic Children ◽  
Risk Of Progression ◽  
High Prediction ◽  
Znt8 Autoantibodies

Abstract Background The risk of progression to type 1 diabetes (T1D) in subjects positive only for ZnT8 autoantibody (ZnT8A) is currently not known. Methods We developed an electrochemiluminescence (ECL) assay to detect high-affinity ZnT8A and validated it in three populations: 302 patients newly diagnosed with T1D, 135 non-diabetic children positive for ZnT8A by standard radio-binding assay (RBA) among 23400 children screened by the Autoimmunity Screening for Kids (ASK), and 123 non-diabetic children multiple autoantibody positive or single ZnT8A positive by RBA participating in the Diabetes Autoimmunity Study in the Young (DAISY). Results In 302 patients with T1D at diagnosis, the positivity for ZnT8A was 62% in both RBA and ECL. Among ASK 135 participants positive for RBA-ZnT8A, 64 were detected ZnT8A as the only islet autoantibody. Of these 64, only 9 were confirmed by ECL-ZnT8A, found to be of high affinity with increased T1D risk. Overall positive predictive value of ECL-ZnT8A for T1D risk was 87.1%, significantly higher than that of RBA-ZnT8A (53.5%, P&lt;0.0001). In DAISY, 11/2547 children who had no positivity previously detected for other islet autoantibodies were identified as single ZnT8A by RBA; of these, three were confirmed positive by ECL-ZnT8A and all three progressed to clinical T1D. Conclusions Large proportion of ZnT8A by RBA are single ZnT8A with low T1D risk while ZnT8A by ECL were of high-affinity and high prediction for T1D development.

scholarly journals Glycemic Variability and Hypoglycemic Excursions With Continuous Glucose Monitoring Compared to Intermittently Scanned Continuous Glucose Monitoring in Adults With Highest Risk Type 1 Diabetes

2019 ◽  
Vol 14 (3) ◽  
pp. 567-574 ◽  
Author(s):  
Parizad Avari ◽  
Vanessa Moscardo ◽  
Narvada Jugnee ◽  
Nick Oliver ◽  
Monika Reddy
Keyword(s):  
Type 1 Diabetes ◽  
High Risk ◽  
Continuous Glucose Monitoring ◽  
Glucose Monitoring ◽  
Severe Hypoglycemia ◽  
Glycemic Variability ◽  
Clinical Trial Registration ◽  
Freestyle Libre ◽  
The Impact

Background: The I-HART CGM study has shown that real-time continuous glucose monitoring (rtCGM) has greater beneficial impact on hypoglycemia than intermittently scanned continuous glucose monitoring (iscCGM) in adults with type 1 diabetes at high risk (Gold score ≥4 or recent severe hypoglycemia using insulin injections). In this subanalysis, we present the impact of rtCGM and iscCGM on glycemic variability (GV). Methods: Forty participants were recruited to this parallel group study. Following two weeks of blinded rtCGM (DexcomG4), participants were randomized to rtCGM (Dexcom G5; n = 20) or iscCGM (Freestyle Libre; n = 20) for eight weeks. An open-extension phase enabled participants on rtCGM to continue for a further eight weeks and those on iscCGM to switch to rtCGM over this period. Glycemic variability measures at baseline, 8- and 16-week endpoints were compared between groups. Results: At the eight-week endpoint, between-group differences demonstrated significant reduction in several GV measures with rtCGM compared to iscCGM (GRADE%hypoglycemia, index of glycemic control [IGC], and average daily risk range [ADRR]; P < .05). Intermittently scanned continuous glucose monitoring reduced mean average glucose and glycemic variability percentage and GRADE%hyperglycemia compared with rtCGM ( P < .05). At 16 weeks, the iscCGM group switching to rtCGM showed significant improvement in GRADE%hypoglycemia, personal glycemic status, IGC, and ADRR. Conclusion: Our data suggest most, but not all, GV measures improve with rtCGM compared with iscCGM, particularly those measures associated with the risk of hypoglycemia. Selecting appropriate glucose monitoring technology to address GV in this high-risk cohort is important to minimize the risk of glucose extremes and severe hypoglycemia. Clinical trial registration: ClinicalTrials.gov NCT03028220

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

2021 ◽  
Author(s):  
Kenney Ng ◽  
Harry Stavropoulos ◽  
Vibha Anand ◽  
Riitta Veijola ◽  
Jorma Toppari ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Familial Risk ◽  
Multivariable Analysis ◽  
Diabetes Risk ◽  
Islet Autoimmunity ◽  
Acid Decarboxylase ◽  
Islet Autoantibody ◽  
Surveillance Strategy ◽  
Risk Of Progression

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<sup>st</sup> quartile) to 60% (IA-2A 4<sup>th</sup> quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6<sup>th</sup>, 52.4<sup>th</sup> and 10.2<sup>nd</sup> 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>

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