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  • American Diabetes Association  (6)
  • 1
    Online-Ressource
    Online-Ressource
    A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
    American Diabetes Association ; 2017
    In:  Diabetes Vol. 66, No. 7 ( 2017-07-01), p. 2019-2032
    Details
    In: Diabetes, American Diabetes Association, Vol. 66, No. 7 ( 2017-07-01), p. 2019-2032
    Kurzfassung: To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
    Materialart: Online-Ressource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db16-1329
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2017
    ZDB Id: 1501252-9
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk
    American Diabetes Association ; 2018
    In:  Diabetes Care Vol. 41, No. 9 ( 2018-09-01), p. 1887-1894
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 9 ( 2018-09-01), p. 1887-1894
    Kurzfassung: We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals. RESEARCH DESIGN AND METHODS We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients’ relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2–51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial–Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables. RESULTS Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06–1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS & gt;0.295, 95% CI 1.47–3.51; P = 0.0002). CONCLUSIONS The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
    Materialart: Online-Ressource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0087
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2018
    ZDB Id: 1490520-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes
    American Diabetes Association ; 2019
    In:  Diabetes Care Vol. 42, No. 2 ( 2019-02-01), p. 192-199
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 42, No. 2 ( 2019-02-01), p. 192-199
    Kurzfassung: There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A] , and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P & lt; 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody–positive, 13% for single autoantibody–positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody–positive, 12% for single autoantibody–positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody–positive identical twins and multiple autoantibody–positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.
    Materialart: Online-Ressource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0288
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2019
    ZDB Id: 1490520-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 4
    Online-Ressource
    Online-Ressource
    Weight Change During the Postintervention Follow-up of Look AHEAD
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 6 ( 2022-06-02), p. 1306-1314
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 6 ( 2022-06-02), p. 1306-1314
    Kurzfassung: Patients with type 2 diabetes are encouraged to lose weight, but excessive weight loss in older adults may be a marker of poor health and subsequent mortality. We examined weight change during the postintervention period of Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) with diabetes support and education (DSE) (control) in overweight/obese individuals with type 2 diabetes and sought to identify predictors of excessive postintervention weight loss and its association with mortality. RESEARCH DESIGN AND METHODS These secondary analyses compared postintervention weight change (year 8 to final visit; median 16 years) in ILI and DSE in 3,999 Look AHEAD participants. Using empirically derived trajectory categories, we compared four subgroups: weight gainers (n = 307), weight stable (n = 1,561), steady losers (n = 1,731), and steep losers (n = 380), on postintervention mortality, demographic variables, and health status at randomization and year 8. RESULTS Postintervention weight change averaged −3.7 ± 9.5%, with greater weight loss in the DSE than the ILI group. The steep weight loss trajectory subgroup lost on average 17.7 ± 6.6%; 30% of steep losers died during postintervention follow-up versus 10–18% in other trajectories (P & lt; 0001). The following variables distinguished steep losers from weight stable: baseline, older, longer diabetes duration, higher BMI, and greater multimorbidity; intervention, randomization to control group and less weight loss in years 1–8; and year 8, higher prevalence of frailty, multimorbidity, and depressive symptoms and lower use of weight control strategies. CONCLUSIONS Steep weight loss postintervention was associated with increased risk of mortality. Older individuals with longer duration of diabetes and multimorbidity should be monitored for excessive unintentional weight loss.
    Materialart: Online-Ressource
    ISSN: 0149-5992
    URL: Article
    DOI: 10.2337/dc21-1990
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2022
    ZDB Id: 1490520-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 5
    Online-Ressource
    Online-Ressource
    Effects of Intensive Lifestyle Intervention on All-Cause Mortality in Older Adults With Type 2 Diabetes and Overweight/Obesity: Results From the Look AHEAD Study
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 5 ( 2022-05-01), p. 1252-1259
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 5 ( 2022-05-01), p. 1252-1259
    Kurzfassung: Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) and diabetes support and education (DSE) (control) in 5,145 individuals with overweight/obesity and type 2 diabetes, found no significant differences in all-cause or cardiovascular mortality or morbidity during 9.6 (median) years of intervention. Participants in ILI who lost ≥10% at 1 year had lower risk of composite cardiovascular outcomes relative to DSE. Since effects of ILI may take many years to emerge, we conducted intent-to-treat analyses comparing mortality in ILI over 16.7 years (9.6 years of intervention and then observation) to DSE. In a secondary exploratory analysis, we compared mortality by magnitude of weight loss in ILI relative to DSE. RESEARCH DESIGN AND METHODS Primary outcome was all-cause mortality from randomization to 16.7 years. Other outcomes included cause-specific mortality, interactions by subgroups (age, sex, race/ethnicity, and cardiovascular disease history), and an exploratory analysis by magnitude of weight loss in ILI versus DSE as reference. Analyses used proportional hazards regression and likelihood ratio. RESULTS The incidence of all-cause mortality did not differ significantly in ILI and DSE (549 and 589 participants, respectively) (hazard ratio [HR] 0.91 [95% CI 0.81, 1.02] ; P = 0.11). There were no significant differences between treatments in cause-specific mortality or within prespecified subgroups. ILI participants who lost ≥10% at 1 year had a 21% reduced risk of mortality (HR 0.79 [95% CI 0.67, 0.94]; P = 0.007) relative to DSE. CONCLUSIONS ILI focused on weight loss did not significantly affect mortality risk. However, ILI participants who lost ≥10% had reduced mortality relative to DSE.
    Materialart: Online-Ressource
    ISSN: 0149-5992
    URL: Article
    DOI: 10.2337/dc21-1805
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2022
    ZDB Id: 1490520-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 6
    Online-Ressource
    Online-Ressource
    Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes
    American Diabetes Association ; 2020
    In:  Diabetes Care Vol. 43, No. 1 ( 2020-01-01), p. 5-12
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 43, No. 1 ( 2020-01-01), p. 5-12
    Kurzfassung: The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the “single disease” approach appears untenable, as does the notion of individualizing each single patient’s care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.
    Materialart: Online-Ressource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc19-0880
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2020
    ZDB Id: 1490520-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
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