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  • 1
    Online Resource
    Online Resource
    Genome-wide Association Study of Lipid Traits in Youth With Type 2 Diabetes
    The Endocrine Society ; 2021
    In:  Journal of the Endocrine Society Vol. 5, No. 11 ( 2021-11-01)
    Details
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 5, No. 11 ( 2021-11-01)
    Abstract: Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood. Objective To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study. Design, Participants, and Main Outcome Measures We genotyped 206 928 variants and imputed 17 642 824 variants in 1076 youth (mean age 15.0 ± 2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-c) concentrations adjusted for the genetic relationship matrix within each substudy followed by meta-analyses for each trait. Results We identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance (P = 2.3 × 10−8) with each risk allele increasing triglycerides by 20%. We also identified a genome-wide significant signal at rs247617 (P = 5.1 × 10−9) between HERFUD1 and CETP associated with HDL-c, with carriers of 1 copy of the risk allele having twice higher HDL-c. Conclusions Our genetic analyses of lipid traits in youth with T2D have identified 1 novel and 1 previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    URL: Article
    DOI: 10.1210/jendso/bvab139
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2021
    detail.hit.zdb_id: 2881023-5
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  • 2
    Online Resource
    Online Resource
    28-OR: Identification of Ancestry-Specific Alleles in a Genome-Wide Association Study (GWAS) for Metformin (MET) Response in the Diabetes Prevention Program (DPP)
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Genome-wide significant (GWS) loci for glycemic response to MET in type 2 diabetes (T2D) reported elsewhere have not replicated in the DPP. Thus, to assess whether pharmacogenetic interactions may differ in impaired glucose tolerance (IGT), we conducted a GWAS in the DPP for MET response, defined by diabetes incidence and change in quantitative traits (fasting glucose, 2-hour glucose on oral glucose tolerance test, hemoglobin A1c [HbA1c], fasting insulin, insulin sensitivity index, and weight). Samples were genotyped on the Illumina HumanCore Exome array and imputed on the 1000 Genomes Phase3 panel. Cox proportional hazards models tested associations with diabetes incidence in MET (n=876) and placebo (PBO, n=887) arms. Multiple linear regression using an additive model evaluated for association with 1-year change in quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-environment (G×E) interaction between MET and PBO. Results were filtered to minor allele frequency (MAF) & gt;1% and imputation score & gt;0.7. We identified 3 GWS variants after correcting for correlated traits (P & lt;9×10-9). In MET, a variant near ENOSF1 was associated with an increase in % HbA1c (rs144322333, β=0.39 [95% CI 0.28, 0.50], P=2.8×10-12) and was mainly found in African ancestry participants (MAFAFR=0.07, MAFEUR=0.002). A variant near OMSR was associated with greater weight loss (kg) in MET (rs145591055, β=-7.55 [95% CI -9.88, -5.22] , P=3.2×10-10) and found in 10% of Native Americans. Neither variant had an impact in PBO; the interaction with treatment arm was significant for rs144322333 (G×E P=1.4×10-6) and rs145591055 (G×E P=1.5×10-5). No GWS associations emerged for diabetes incidence. In summary, a GWAS for MET response in participants with IGT revealed novel associations that require validation in ancestry-specific populations and may have implications for tailored therapy. Disclosure J. H. Li: None. R. L. Hanson: None. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. W. C. Knowler: None. T. I. Pollin: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. D. Research group: None. J. A. Perry: None. K. A. Jablonski: None. L. Chen: None. S. Srinivasan: None. J. N. Todd: None. M. Harden: None. J. M. Mercader: None. P. W. Franks: Advisory Panel; Self; Zoe Global Limited, Consultant; Self; Eli Lilly and Company, Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-28-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
    detail.hit.zdb_id: 1501252-9
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  • 3
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    900-P: Continuous Glucose Monitoring in Youth with Type 2 Diabetes: A Pilot and Feasibility Study
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Objective: Real-time continuous glucose monitoring (CGM) is effective for diabetes management in T1D and adults with T2D, but has not been assessed in youth with T2D. The objective of this study was to assess the feasibility and acceptability of CGM use in youth with T2D. Methods: Youth (13- 21 years old) with T2D ≥ 6 months and A1c & gt; 7%, on any FDA approved treatment regimen were included. After a blinded run-in period, participants were given a Dexcom G6 CGM system for 12 weeks. The use and acceptability of the real-time CGM were evaluated by sensor usage, surveys, and focus group qualitative data. Results: Youth (n=8) had median age 19.4 (IQR 15.5-20.6) years, were 75% female, 50% hispanic/latino ethnicity, 50% non-English speaking at home, and 91% had public insurance. Baseline A1c was 11.7 (±2.8)% with mean diabetes duration of 2.5 (IQR 1.4 - 5.1) years and 75% were on basal insulin. Of the 7 participants who have completed the CGM intervention, all reported CGM was a positive experience (50% very positive, 50% slightly positive), easy to use (50% very easy, 50% easy), and useful (83% useful, 17% useful). All participants desired to continue to use real-time CGM in the future. 85% were “extremely” likely to recommend real-time CGM to friends. 67% of participants self-reported eating fewer meals while using CGM. All participants used sensors for the duration of the study. Conclusion: Real-time CGM is feasible and acceptable for youth with type 2 diabetes. Larger randomized controlled trials are needed to assess effects on glycemic control, healthy lifestyle changes, and diabetes distress. Disclosure H. Chesser: None. S. Srinivasan: None. J. C. Wong: Advisory Panel; Self; Provention Bio, Inc., Research Support; Self; Dexcom, Inc., Tandem Diabetes Care.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-900-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 4
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    Monogenic Diabetes in Youth With Presumed Type 2 Diabetes: Results From the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 10 ( 2021-10-01), p. 2312-2319
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 10 ( 2021-10-01), p. 2312-2319
    Abstract: Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multiethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. RESULTS Of 3,333 participants, 93 (2.8%) carried an LP/P variant in HNF4A (16 participants), GCK (23), HNF1A (44), PDX1 (5), INS (4), and CEL (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 vs. 13.6 ± 2.3 years, P = 0.002) and lower fasting C-peptide levels (3.0 ± 1.7 vs. 4.7 ± 3.5 ng/mL, P & lt; 0.0001). Youth with MODY were less likely to have hypertension (6.9% vs. 19.5%, P = 0.007) and had higher HDL cholesterol (43.8 vs. 39.7 mg/dL, P = 0.006). CONCLUSIONS By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n = 83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria for selection of individuals for genetic testing.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc21-0491
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
    detail.hit.zdb_id: 1490520-6
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  • 5
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    249-OR: Type 2 Diabetes (T2D) Genetic Clusters for Association with Glycemic Responses to Intervention for Diabetes Prevention
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Polygenic scores (PS) of T2D genetic variants based on pathophysiologic mechanisms underlying diabetes have been developed. We investigated whether T2D cluster PS influences response to interventions for diabetes prevention. We examined 2,647 DPP participants with impaired glucose tolerance and genetic data randomized to intensive lifestyle, metformin or placebo arms for diabetes prevention. We generated five PS clusters including β-cell related clusters (β-cell, proinsulin) and insulin resistance clusters (liver/lipid, obesity, lipodystrophy). We examined associations of PS with baseline and 1-year glycemic traits after intervention derived from oral glucose tolerance tests using general linear models, and with diabetes incidence over an average period of 3 years using Cox Regression Models. Models were adjusted for sex, age, and 10 principal components, respective baseline trait, and treatment group. At one-year follow-up, β-cell PS was associated with reduction in the insulinogenic index and corrected insulin response, in each treatment group and, statistically significant, in all combined (P & lt;0.001), with no statistically significant interaction term between treatment groups, a finding consistent with a slightly increased diabetes incidence (HR 1.02 per weighted allele [CI 95% 1.00, 1.03]). The remaining PS were associated with baseline participant features, but not with diabetes incidence or change in glycemic parameters from baseline. We conclude that high genetic burden in β-cell cluster PS is associated with greater risk of diabetes and a decrease in insulin secretion, seen across all treatment groups. Despite interventions with intensive lifestyle and metformin, participants with high β-cell cluster genetic burden had an increased risk of diabetes and worsening in insulin secretion similar to placebo group. These data suggest that alternate therapies may be needed to prevent β-cell decline in this subset of prediabetes patients. Disclosure L. K. Billings: Advisory Panel; Self; Bayer Inc., Lilly Diabetes, Novo Nordisk, Sanofi. S. Raghavan: None. S. Srinivasan: None. J. Xu: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. M. Udler: None. D. Research group: None. K. A. Jablonski: None. P. W. Franks: Advisory Panel; Self; Zoe Global Limited, Consultant; Self; Eli Lilly and Company, Novo Nordisk. R. B. Goldberg: None. M. Hivert: None. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. W. C. Knowler: None. C. Lee: None. J. Merino: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-249-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
    detail.hit.zdb_id: 1501252-9
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  • 6
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    Online Resource
    Adjunctive Therapies to Optimize Closed-loop Glucose Control
    SAGE Publications ; 2021
    In:  Journal of Diabetes Science and Technology Vol. 15, No. 6 ( 2021-11), p. 1243-1251
    Details
    In: Journal of Diabetes Science and Technology, SAGE Publications, Vol. 15, No. 6 ( 2021-11), p. 1243-1251
    Abstract: Closed-loop insulin delivery systems are fast becoming the standard of care in the management of type 1 diabetes and have led to significant improvements in diabetes management. Nevertheless, there is still room for improvement for the closed-loop systems to optimize treatment and meet target glycemic control. Adjunct treatments have been introduced as an alternative method to insulin-only treatment methods to overcome diabetes treatment challenges and improve clinical and patient reported outcomes during closed-loop treatment. The adjunct treatment agents mostly consist of medications that are already approved for type 2 diabetes treatment and aim to complete the missing physiologic factors, such as the entero-endocrine system, that regulate glycemia in addition to insulin. This paper will review many of these adjunct therapies, including the basic mechanisms of action, potential benefits, side effects, and the evidence supporting their use during closed-loop treatment.
    Type of Medium: Online Resource
    ISSN: 1932-2968 , 1932-2968
    URL: Article
    DOI: 10.1177/19322968211032701
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2467312-2
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  • 7
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    23-OR: ADA Presidents’ Select Abstract: Genetic Architecture and Novel Genes Implicated in Youth-Onset Type 2 Diabetes
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Youth-onset type 2 diabetes (T2D) has a strong genetic predisposition and is regarded as a phenotypic extreme of adult-onset T2D. In this study, we aimed to investigate the contribution of rare coding variants to the genetic basis of youth-onset T2D by analyzing whole-exome sequences of 3,005 persons with youth-onset T2D (diagnosed before 20 years of age) from the Progress in Diabetes Genetics in Youth (ProDiGY) consortium and 9,777 ancestry matched adult controls. We identified three genes with aggregate rare variant associations reaching exome-wide significance (P & lt;2.6×10-6). In addition, we were able to identify eight genes previously linked to diabetes that were included in the top 20 (P & lt;2.0×10-6) overlapping biologically characterized gene sets. These 11 genes were classified into three groups: 1) monogenic diabetes-related genes (HNF1A, GCK, and RFX6), 2) obesity-related genes (MC4R, ATXN2L, GHRL, and CPQ), and 3) β-cell function related genes (SLC30A8, ABCC8, PAM, and SIX3). A novel exome-wide significant gene burden association was observed for ATXN2L with odds ratio (OR) 1.26, P=1.1×10-6. For known diabetes genes, the effect sizes of gene burden analysis in youth-onset T2D were much larger than that of adult-onset T2D: examples include MC4R (OR 3.5, P=1.7×10-11 vs. OR 2.1, P=2.7×10-10 in adults) and HNF1A (OR 7.5, P=1.2×10-10 vs. OR 1.2, P=0.022). In terms of liability variance explained, both common and rare variants contributed more to youth-onset T2D than they did to adult-onset T2D (3.1-fold enrichment for common variants, 5.3-fold enrichment for rare variants). However, greater enrichment of rare variants in youth-onset T2D caused the liability variance explained by rare variants to approach 28% of that explained by common variants, in contrast to 17% for adult-onset T2D. These data paint a picture of youth-onset T2D as a disease intermediate in extremity between monogenic diabetes and T2D, in which genetic variants in both insulin secretion and insulin response pathways are implicated. Disclosure S. Kwak: None. L. M. Laffel: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompe, Insulogic LLC, Janssen Pharmaceuticals, Inc., Laxmi Therapeutic Devices, LifeScan, Lilly Diabetes, Medtronic, Provention Bio, Inc. E. M. Isganaitis: None. M. W. Haymond: Advisory Panel; Self; Daiichi Sankyo, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. L. L. Levitsky: Consultant; Self; Eli Lilly and Company. T. I. Pollin: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. J. Flannick: None. On behalf of the prodigy consortium: n/a. S. Srinivasan: None. L. Chen: None. J. Todd: None. E. T. Jensen: None. J. Divers: None. A. K. Mottl: Advisory Panel; Self; Bayer U. S. C. Pihoker: None. R. Gandica: None. Funding National Institutes of Health (1R01DK125490-01)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-23-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 8
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    The First Genome-Wide Association Study for Type 2 Diabetes in Youth: The Progress in Diabetes Genetics in Youth (ProDiGY) Consortium
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. 4 ( 2021-04-01), p. 996-1005
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. 4 ( 2021-04-01), p. 996-1005
    Abstract: The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component–clustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P = 3.2 × 10−8; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P = 8.0 × 10−20; OR 1.58), rs72982988 near MC4R (P = 4.4 × 10−14; OR 1.53), rs200893788 in CDC123 (P = 1.1 × 10−12; OR 1.32), rs2237892 in KCNQ1 (P = 4.8 × 10−11; OR 1.59), rs937589119 in IGF2BP2 (P = 3.1 × 10−9; OR 1.34), and rs113748381 in SLC16A11 (P = 4.1 × 10−8; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in CPEB2 (P = 3.2 × 10−8; OR 2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome-wide association study of youth-onset type 2 diabetes.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-0443
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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