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Article ; Online: Clonal haematopoiesis and cardiac arrythmias: rhythm-altering mutations.

Zuriaga, María A / Pascual-Figal, Domingo / Fuster, José J

2024 Volume 45, Issue 10, Page(s) 806–808

MeSH term(s)	Humans ; Clonal Hematopoiesis/genetics ; Mutation/genetics ; Hematopoiesis/genetics ; Cardiac Conduction System Disease ; Arrhythmias, Cardiac/genetics
Language	English
Publishing date	2024-02-06
Publishing country	England
Document type	Journal Article
ZDB-ID	603098-1
ISSN	1522-9645 ; 0195-668X
ISSN (online)	1522-9645
ISSN	0195-668X
DOI	10.1093/eurheartj/ehae052
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Article ; Online: Clonal hematopoiesis and atherosclerotic cardiovascular disease: A primer.

Zuriaga, María A / Fuster, José J

Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis

2021 Volume 35, Issue 1, Page(s) 35–41

Abstract: Despite current standards of care, a considerable risk of atherosclerotic cardiovascular disease remains in both primary and secondary prevention. In this setting, clonal hematopoiesis driven by somatic mutations has recently emerged as a relatively ... ...

Abstract	Despite current standards of care, a considerable risk of atherosclerotic cardiovascular disease remains in both primary and secondary prevention. In this setting, clonal hematopoiesis driven by somatic mutations has recently emerged as a relatively common, potent and independent risk factor for atherosclerotic cardiovascular disease and other cardiovascular conditions. Experimental studies in mice suggest that mutations in TET2 and JAK2, which are among the most common in clonal hematopoiesis, increase inflammation and are causally connected to accelerated atherosclerosis development, which may explain the link between clonal hematopoiesis and increased cardiovascular risk. In this review, we provide an overview of our current understanding of this emerging cardiovascular risk factor.
MeSH term(s)	Animals ; Mice ; Clonal Hematopoiesis/genetics ; Cardiovascular Diseases/genetics ; Atherosclerosis/genetics ; Heart Disease Risk Factors ; Inflammation ; Mutation
Language	Spanish
Publishing date	2021-12-05
Publishing country	Spain
Document type	Journal Article ; Review
ISSN	1578-1879
ISSN (online)	1578-1879
DOI	10.1016/j.arteri.2021.09.006
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Article ; Online: Emerging Role of Acquired Mutations and Clonal Hematopoiesis in Atherosclerosis　- Beyond Conventional Cardiovascular Risk Factors.

Zuriaga, María A / Fuster, José J

Circulation journal : official journal of the Japanese Circulation Society

2021 Volume 87, Issue 3, Page(s) 394–400

Abstract: Accumulating evidence suggests that conventional cardiovascular risk factors are incompletely predictive of cardiovascular disease, as a substantial risk remains even when these factors are apparently managed well. In this context, clonal hematopoiesis ... ...

Abstract	Accumulating evidence suggests that conventional cardiovascular risk factors are incompletely predictive of cardiovascular disease, as a substantial risk remains even when these factors are apparently managed well. In this context, clonal hematopoiesis has emerged as a new and potent risk factor for atherosclerotic cardiovascular disease and other cardiometabolic conditions. Clonal hematopoiesis typically arises from somatic mutations that confer a competitive advantage to a mutant hematopoietic stem cell, leading to its clonal expansion in the stem cell population and its progeny of blood leukocytes. Human sequencing studies and experiments in mice suggest that clonal hematopoiesis, at least when driven by certain mutations, contributes to accelerated atherosclerosis development. However, the epidemiology, biology and clinical implications of this phenomenon remain incompletely understood. Here, we review the current understanding of the connection between clonal hematopoiesis and atherosclerosis, and highlight knowledge gaps in this area of research.
MeSH term(s)	Humans ; Animals ; Mice ; Risk Factors ; Clonal Hematopoiesis ; Cardiovascular Diseases/etiology ; Hematopoiesis/genetics ; Atherosclerosis/genetics ; Heart Disease Risk Factors ; Mutation
Language	English
Publishing date	2021-08-25
Publishing country	Japan
Document type	Review ; Journal Article
ZDB-ID	2068090-9
ISSN	1347-4820 ; 1346-9843
ISSN (online)	1347-4820
ISSN	1346-9843
DOI	10.1253/circj.CJ-21-0505
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Article: Humans and Mice Display Opposing Patterns of "Browning" Gene Expression in Visceral and Subcutaneous White Adipose Tissue Depots.

Zuriaga, Maria A / Fuster, Jose J / Gokce, Noyan / Walsh, Kenneth

Frontiers in cardiovascular medicine

2017 Volume 4, Page(s) 27

Abstract: Visceral adiposity is much more strongly associated with cardiometabolic disease in humans than subcutaneous adiposity. Browning, the appearance of brown-like adipocytes in the white adipose tissue (WAT), has been shown to protect mice against metabolic ... ...

Abstract	Visceral adiposity is much more strongly associated with cardiometabolic disease in humans than subcutaneous adiposity. Browning, the appearance of brown-like adipocytes in the white adipose tissue (WAT), has been shown to protect mice against metabolic dysfunction, suggesting the possibility of new therapeutic approaches to treat obesity and type 2 diabetes. In mice, subcutaneous WAT depots express higher levels of browning genes when compared with visceral WAT, further suggesting that differences in WAT browning could contribute to the differences in the pathogenicity of the two depots. However, the expression of browning genes in different WAT depots of human has not been characterized. Here, it is shown that the expression of browning genes is higher in visceral than in subcutaneous WAT in humans, a pattern that is opposite to what is observed in mice. These results suggest that caution should be applied in extrapolating the results of murine browning gene expression studies to human pathophysiology.
Language	English
Publishing date	2017-05-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2017.00027
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Article ; Online: Clonal Hematopoiesis and Risk of Progression of Heart Failure With Reduced Left Ventricular Ejection Fraction.

Pascual-Figal, Domingo A / Bayes-Genis, Antoni / Díez-Díez, Miriam / Hernández-Vicente, Álvaro / Vázquez-Andrés, David / de la Barrera, Jorge / Vazquez, Enrique / Quintas, Ana / Zuriaga, María A / Asensio-López, Mari C / Dopazo, Ana / Sánchez-Cabo, Fátima / Fuster, José J

Journal of the American College of Cardiology

2021 Volume 77, Issue 14, Page(s) 1747–1759

Abstract: Background: Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in ... ...

Abstract	Background: Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown. Objectives: The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology. Methods: The study cohort comprised 62 patients with HF and LVEF <45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization. Results: CHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology. Conclusions: Somatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology.
MeSH term(s)	Aged ; Cause of Death ; Clonal Hematopoiesis/genetics ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA-Binding Proteins/genetics ; Disease Progression ; Female ; Heart Failure/diagnosis ; Heart Failure/genetics ; Heart Failure/mortality ; Heart Failure/physiopathology ; Hospitalization/statistics & numerical data ; Humans ; Male ; Mortality ; Mutation ; Prognosis ; Prospective Studies ; Proto-Oncogene Proteins/genetics ; Spain/epidemiology ; Ventricular Dysfunction, Left/etiology ; Ventricular Dysfunction, Left/physiopathology
Chemical Substances	DNA-Binding Proteins ; Proto-Oncogene Proteins ; TET2 protein, human (EC 1.13.11.-) ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA methyltransferase 3A (EC 2.1.1.37)
Language	English
Publishing date	2021-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605507-2
ISSN	1558-3597 ; 0735-1097
ISSN (online)	1558-3597
ISSN	0735-1097
DOI	10.1016/j.jacc.2021.02.028
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Article ; Online: TP53-

Zekavat, Seyedeh M / Viana-Huete, Vanesa / Matesanz, Nuria / Jorshery, Saman Doroodgar / Zuriaga, María A / Uddin, Md Mesbah / Trinder, Mark / Paruchuri, Kaavya / Zorita, Virginia / Ferrer-Pérez, Alba / Amorós-Pérez, Marta / Kunderfranco, Paolo / Carriero, Roberta / Greco, Carolina M / Aroca-Crevillen, Alejandra / Hidalgo, Andrés / Damrauer, Scott M / Ballantyne, Christie M / Niroula, Abhishek /

Gibson, Christopher J / Pirruccello, James / Griffin, Gabriel / Ebert, Benjamin L / Libby, Peter / Fuster, Valentín / Zhao, Hongyu / Ghassemi, Marzyeh / Natarajan, Pradeep / Bick, Alexander G / Fuster, José J / Klarin, Derek

Nature cardiovascular research

2023 Volume 2, Page(s) 144–158

Abstract: Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP ... ...

Abstract	Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as
Language	English
Publishing date	2023-04-14
Publishing country	England
Document type	Journal Article
ISSN	2731-0590
ISSN (online)	2731-0590
DOI	10.1038/s44161-022-00206-6
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Article ; Online: TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity.

Fuster, José J / Zuriaga, María A / Zorita, Virginia / MacLauchlan, Susan / Polackal, Maya N / Viana-Huete, Vanesa / Ferrer-Pérez, Alba / Matesanz, Nuria / Herrero-Cervera, Andrea / Sano, Soichi / Cooper, Matthew A / González-Navarro, Herminia / Walsh, Kenneth

Cell reports

2020 Volume 33, Issue 4, Page(s) 108326

Abstract: Human aging is frequently accompanied by the acquisition of somatic mutations in the hematopoietic system that induce clonal hematopoiesis, leading to the development of a mutant clone of hematopoietic progenitors and leukocytes. This somatic-mutation- ... ...

Abstract	Human aging is frequently accompanied by the acquisition of somatic mutations in the hematopoietic system that induce clonal hematopoiesis, leading to the development of a mutant clone of hematopoietic progenitors and leukocytes. This somatic-mutation-driven clonal hematopoiesis has been associated with an increased incidence of cardiovascular disease and type 2 diabetes, but whether this epidemiological association reflects a direct, causal contribution of mutant hematopoietic and immune cells to age-related metabolic abnormalities remains unexplored. Here, we show that inactivating mutations in the epigenetic regulator TET2, which lead to clonal hematopoiesis, aggravate age- and obesity-related insulin resistance in mice. This metabolic dysfunction is paralleled by increased expression of the pro-inflammatory cytokine IL-1β in white adipose tissue, and it is suppressed by pharmacological inhibition of NLRP3 inflammasome-mediated IL-1β production. These findings support a causal contribution of somatic TET2 mutations to insulin resistance and type 2 diabetes.
MeSH term(s)	Aging ; Animals ; Clonal Hematopoiesis/genetics ; DNA-Binding Proteins/metabolism ; Dioxygenases/metabolism ; Humans ; Insulin Resistance/genetics ; Mice ; Obesity/genetics
Chemical Substances	DNA-Binding Proteins ; Dioxygenases (EC 1.13.11.-) ; TET2 protein, human (EC 1.13.11.-)
Language	English
Publishing date	2020-11-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.108326
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Article ; Online: Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction.

Wang, Ying / Sano, Soichi / Yura, Yoshimitsu / Ke, Zhonghe / Sano, Miho / Oshima, Kosei / Ogawa, Hayato / Horitani, Keita / Min, Kyung-Duk / Miura-Yura, Emiri / Kour, Anupreet / Evans, Megan A / Zuriaga, Maria A / Hirschi, Karen K / Fuster, Jose J / Pietras, Eric M / Walsh, Kenneth

JCI insight

2020 Volume 5, Issue 6

Abstract: Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its ... ...

Abstract	Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We developed a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR2+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac-resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2-mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.
MeSH term(s)	Adoptive Transfer ; Aging/pathology ; Animals ; Clonal Hematopoiesis/physiology ; DNA-Binding Proteins/metabolism ; Dioxygenases ; Disease Models, Animal ; Heart Diseases ; Hematopoietic Stem Cells ; Macrophages ; Mice ; Proto-Oncogene Proteins/metabolism
Chemical Substances	DNA-Binding Proteins ; Proto-Oncogene Proteins ; Dioxygenases (EC 1.13.11.-) ; Tet2 protein, mouse (EC 1.13.11.-)
Language	English
Publishing date	2020-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.135204
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Article ; Online: Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome.

Sano, Soichi / Oshima, Kosei / Wang, Ying / MacLauchlan, Susan / Katanasaka, Yasufumi / Sano, Miho / Zuriaga, María A / Yoshiyama, Minoru / Goukassian, David / Cooper, Matthew A / Fuster, José J / Walsh, Kenneth

Journal of the American College of Cardiology

2018 Volume 71, Issue 8, Page(s) 875–886

Abstract: Background: Recent studies have shown that hematopoietic stem cells can undergo clonal expansion secondary to somatic mutations in leukemia-related genes, thus leading to an age-dependent accumulation of mutant leukocytes in the blood. This somatic ... ...

Abstract	Background: Recent studies have shown that hematopoietic stem cells can undergo clonal expansion secondary to somatic mutations in leukemia-related genes, thus leading to an age-dependent accumulation of mutant leukocytes in the blood. This somatic mutation-related clonal hematopoiesis is common in healthy older individuals, but it has been associated with an increased incidence of future cardiovascular disease. The epigenetic regulator TET2 is frequently mutated in blood cells of individuals exhibiting clonal hematopoiesis. Objectives: This study investigated whether Tet2 mutations within hematopoietic cells can contribute to heart failure in 2 models of cardiac injury. Methods: Heart failure was induced in mice by pressure overload, achieved by transverse aortic constriction or chronic ischemia induced by the permanent ligation of the left anterior descending artery. Competitive bone marrow transplantation strategies with Tet2-deficient cells were used to mimic TET2 mutation-driven clonal hematopoiesis. Alternatively, Tet2 was specifically ablated in myeloid cells using Cre recombinase expressed from the LysM promoter. Results: In both experimental heart failure models, hematopoietic or myeloid Tet2 deficiency worsened cardiac remodeling and function, in parallel with increased interleukin-1beta (IL-1β) expression. Treatment with a selective NLRP3 inflammasome inhibitor protected against the development of heart failure and eliminated the differences in cardiac parameters between Tet2-deficient and wild-type mice. Conclusions: Tet2 deficiency in hematopoietic cells is associated with greater cardiac dysfunction in murine models of heart failure as a result of elevated IL-1β signaling. These data suggest that individuals with TET2-mediated clonal hematopoiesis may be at greater risk of developing heart failure and respond better to IL-1β-NLRP3 inflammasome inhibition.
MeSH term(s)	Animals ; Cells, Cultured ; DNA-Binding Proteins/deficiency ; DNA-Binding Proteins/genetics ; Dioxygenases ; Furans ; Heart Failure/genetics ; Heart Failure/metabolism ; Heart Failure/prevention & control ; Hematopoiesis/drug effects ; Hematopoiesis/physiology ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Heterocyclic Compounds, 4 or More Rings/therapeutic use ; Indenes ; Inflammasomes/antagonists & inhibitors ; Inflammasomes/metabolism ; Interleukin-1beta/antagonists & inhibitors ; Interleukin-1beta/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Proto-Oncogene Proteins/deficiency ; Proto-Oncogene Proteins/genetics ; Sulfonamides ; Sulfones/pharmacology ; Sulfones/therapeutic use
Chemical Substances	DNA-Binding Proteins ; Furans ; Heterocyclic Compounds, 4 or More Rings ; Indenes ; Inflammasomes ; Interleukin-1beta ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nlrp3 protein, mouse ; Proto-Oncogene Proteins ; Sulfonamides ; Sulfones ; N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide (6RS86E2BWQ) ; Dioxygenases (EC 1.13.11.-) ; Tet2 protein, mouse (EC 1.13.11.-)
Language	English
Publishing date	2018-02-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605507-2
ISSN	1558-3597 ; 0735-1097
ISSN (online)	1558-3597
ISSN	0735-1097
DOI	10.1016/j.jacc.2017.12.037
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Article ; Online: Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion.

Fuster, José J / Zuriaga, María A / Ngo, Doan Thi-Minh / Farb, Melissa G / Aprahamian, Tamar / Yamaguchi, Terry P / Gokce, Noyan / Walsh, Kenneth

Diabetes

2015 Volume 64, Issue 4, Page(s) 1235–1248

Abstract: Adipose tissue dysfunction plays a pivotal role in the development of insulin resistance in obese individuals. Cell culture studies and gain-of-function mouse models suggest that canonical Wnt proteins modulate adipose tissue expansion. However, no ... ...

Abstract	Adipose tissue dysfunction plays a pivotal role in the development of insulin resistance in obese individuals. Cell culture studies and gain-of-function mouse models suggest that canonical Wnt proteins modulate adipose tissue expansion. However, no genetic evidence supports a role for endogenous Wnt proteins in adipose tissue dysfunction, and the role of noncanonical Wnt signaling remains largely unexplored. Here we provide evidence from human, mouse, and cell culture studies showing that Wnt5a-mediated, noncanonical Wnt signaling contributes to obesity-associated metabolic dysfunction by increasing adipose tissue inflammation. Wnt5a expression is significantly upregulated in human visceral fat compared with subcutaneous fat in obese individuals. In obese mice, Wnt5a ablation ameliorates insulin resistance, in parallel with reductions in adipose tissue inflammation. Conversely, Wnt5a overexpression in myeloid cells augments adipose tissue inflammation and leads to greater impairments in glucose homeostasis. Wnt5a ablation or overexpression did not affect fat mass or adipocyte size. Mechanistically, Wnt5a promotes the expression of proinflammatory cytokines by macrophages in a Jun NH2-terminal kinase-dependent manner, leading to defective insulin signaling in adipocytes. Exogenous interleukin-6 administration restores insulin resistance in obese Wnt5a-deficient mice, suggesting a central role for this cytokine in Wnt5a-mediated metabolic dysfunction. Taken together, these results demonstrate that noncanonical Wnt signaling contributes to obesity-induced insulin resistance independent of adipose tissue expansion.
MeSH term(s)	Animals ; Glucose/metabolism ; Humans ; Inflammation/metabolism ; Insulin Resistance ; Intra-Abdominal Fat/metabolism ; Macrophages/metabolism ; Mice ; Obesity/metabolism ; Phosphorylation ; Subcutaneous Fat/metabolism ; Wnt Signaling Pathway/physiology
Chemical Substances	Glucose (IY9XDZ35W2)
Language	English
Publishing date	2015-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db14-1164
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