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Sayed S, Saba AA, Hasan I, Rahat R, Sayem M, Ebihara A, Nabi AN. Truncated variant rs373056577 confers increased risk of type 2 diabetes and missense variant rs121912717 is associated with hypertriglyceridemia in Bangladeshi population. Metabol Open 2025; 26:100364. [PMID: 40292074 PMCID: PMC12032864 DOI: 10.1016/j.metop.2025.100364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/29/2025] [Accepted: 04/13/2025] [Indexed: 04/30/2025] Open
Abstract
This study investigates the association of allelic and genotypic variations of rs121912717 and rs373056577 within APOA1 and APOA2 genes, respectively with the risk of type 2 diabetes (T2D). In this cross-sectional study, real-time quantitative PCR with specific Taqman probes was used to determine the genotypic and allelic frequencies of rs121912717 and rs373056577 in 300 unrelated Bangladeshi individuals (Healthy = 144, T2D patients = 156). Logistic regression analysis was performed to investigate the association of genotypic and allelic frequencies of these SNPs with respect to T2D under different inheritance models. Neither allelic nor genotypic frequencies of rs121912717 within APOA1 showed any significant association with T2D. Genotypes with respect to rs373056577 within APOA2 showed significant association with the risk of T2D under co-dominant heterozygous model (GG vs GA) [OR (95 %CI): 2.64 (1.32-5.59), p = 0.008], dominant [OR (95 %CI): 2.31 (1.24-4.49), p = 0.01] and over-dominant [OR (95 %CI): 2.62 (1.31-5.53), p = 0.008] models without adjusting for age, gender and BMI. After adjusting for age, gender and BMI, the A allele of rs373056577 showed significant association with T2D only in the dominant model [OR (95 %CI): 3.20 (1.12-10.51), p = 0.04]. Also, A allele of rs373056577 demonstrated significant association with the risk of T2D compared to allele G with [OR (95 %CI): 2.90 (1.15-8.14), p = 0.03] and without adjusting for confounders [OR (95 %CI): 1.97 (1.14-3.52), p = 0.02]. The genotypic frequency was significantly associated with T2D in codominant, dominant, and overdominant models in male participants when a gender-stratified analysis was conducted for rs373056577. However, when the logistic regression analysis was adjusted for age and BMI, the association was not significant in any of the models with respect to rs373056577 for male participants. On the other hand, gender-stratified regression analyses revealed no significant association with T2D before and after adjusting for age and BMI with respect to both allelic and genotypic frequencies of rs121912717. Individuals with CT genotype of rs121912717 had significantly higher triglyceride levels (322.2 mg/dL) compared to those harboring CC genotype (202.8 mg/dL) with or without adjusting for age, gender, BMI and disease status of the study participants. In conclusion, this study revealed that individuals harboring the allele A of rs373056577 possessed an increased risk of developing T2D and individuals having CT genotype of rs121912717 had increased triglyceride levels. The result of this study needs to be validated in a larger cohort for a more robust assessment.
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Affiliation(s)
- Shomoita Sayed
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Abdullah Al Saba
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Imrul Hasan
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Rafia Rahat
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Mohammad Sayem
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Akio Ebihara
- United Graduate School of Agricultural Science, Gifu University, 1-1 Yanagido, Gifu Shi, 501-1193, Japan
| | - A.H.M. Nurun Nabi
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
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Biegański HM, Dąbrowski KM, Różańska-Walędziak A. Omentin-General Overview of Its Role in Obesity, Metabolic Syndrome and Other Diseases; Problem of Current Research State. Biomedicines 2025; 13:632. [PMID: 40149608 PMCID: PMC11940803 DOI: 10.3390/biomedicines13030632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/02/2025] [Accepted: 03/03/2025] [Indexed: 03/29/2025] Open
Abstract
Background: Omentin (omentin-1, intelectin-1, ITLN-1) is an adipokine considered to be a novel substance. Many chronic, inflammatory, or civilization diseases are linked to obesity, in which omentin plays a significant role. Methods: MEDLINE and SCOPUS databases were searched using the keywords "omentin" or "intelectin-1". Then the most recent articles providing new perspectives on the matter and the most important studies, which revealed crucial insight, were selected to summarize the current knowledge on the role of omentin in a literature review. Results and Conclusions: The valid role of this adipokine is evident in the course of metabolic syndrome. In most cases, elevated omentin expression is correlated with the better course of diseases, including: type 2 diabetes mellitus, polycystic ovary syndrome, rheumatoid arthritis, metabolic dysfunction-associated steatotic liver disease, Crohn's disease, ulcerative colitis, atherosclerosis, or ischemic stroke, for some of which it can be a better marker than the currently used ones. However, results of omentin studies are not completely one-sided. It was proven to participate in the development of asthma and atopic dermatitis and to have different concentration dynamics in various types of tumors. All of omentin's effects and properties make it an attractive subject of research, considering still unexplored inflammation mechanisms, in which it may play an important role. Omentin was proven to prevent osteoarthritis, hepatocirrhosis, and atherosclerosis in mouse models. All of the above places omentin among potential therapeutic products, and not only as a biomarker. However, the main problems with the omentin's research state are the lack of standardization, which causes many contradictions and disagreements in this field.
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Affiliation(s)
- Hubert Mateusz Biegański
- Medical Faculty, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, 01-938 Warsaw, Poland; (H.M.B.); (K.M.D.)
| | - Krzysztof Maksymilian Dąbrowski
- Medical Faculty, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, 01-938 Warsaw, Poland; (H.M.B.); (K.M.D.)
| | - Anna Różańska-Walędziak
- Departament of Human Physiology and Pathophysiology, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, 01-938 Warsaw, Poland
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Sanz-González A, Cózar-Castellano I, Broca C, Sabatier J, Acosta GA, Royo M, Hernándo-Muñoz C, Torroba T, Perdomo G, Merino B. Pharmacological activation of insulin-degrading enzyme improves insulin secretion and glucose tolerance in diet-induced obese mice. Diabetes Obes Metab 2023; 25:3268-3278. [PMID: 37493025 DOI: 10.1111/dom.15225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 07/10/2023] [Accepted: 07/10/2023] [Indexed: 07/27/2023]
Abstract
AIM To investigate the use of synthetic preimplantation factor (sPIF) as a potential therapeutic tool for improving glucose-stimulated insulin secretion (GSIS), glucose tolerance and insulin sensitivity in the setting of diabetes. MATERIALS AND METHODS We used a preclinical murine model of type 2 diabetes (T2D) induced by high-fat diet (HFD) feeding for 12 weeks. Saline or sPIF (1 mg/kg/day) was administered to mice by subcutaneously implanted osmotic mini-pumps for 25 days. Glucose tolerance, circulating insulin and C-peptide levels, and GSIS were assessed. In addition, β-cells (Min-6) were used to test the effects of sPIF on GSIS and insulin-degrading enzyme (IDE) activity in vitro. The effect of sPIF on GSIS was also tested in human islets. RESULTS GSIS was enhanced 2-fold by sPIF in human islets ex vivo. Furthermore, continuous administration of sPIF to HFD mice increased circulating levels of insulin and improved glucose tolerance, independently of hepatic insulin clearance. Of note, islets isolated from mice treated with sPIF exhibited restored β-cell function. Finally, genetic (shRNA-IDE) or pharmacological (6bK) inactivation of IDE in Min-6 abolished sPIF-mediated effects on GSIS, showing that both the protein and its protease activity are required for its action. CONCLUSIONS We conclude that sPIF is a promising secretagogue for the treatment of T2D.
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Affiliation(s)
- Alba Sanz-González
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y Universidad de Valladolid (UVa), Valladolid, Spain
| | - Irene Cózar-Castellano
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y Universidad de Valladolid (UVa), Valladolid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Christophe Broca
- Laboratory of Cell Therapy for Diabetes (LTCDPRIMS), IRMB Hop. St Eloi, CHU Montpellier, Montpellier, France
| | - Julia Sabatier
- Laboratory of Cell Therapy for Diabetes (LTCDPRIMS), IRMB Hop. St Eloi, CHU Montpellier, Montpellier, France
| | - Gerardo A Acosta
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBERBBN), Barcelona, Spain
- Department of Surfactants and Nanobiotechnology, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
- Department of Organic Chemistry, University of Barcelona, Barcelona, Spain
| | - Miriam Royo
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBERBBN), Barcelona, Spain
- Department of Surfactants and Nanobiotechnology, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
| | - Carla Hernándo-Muñoz
- Department of Chemistry, Faculty of Science, University of Burgos, Burgos, Spain
| | - Tomás Torroba
- Department of Chemistry, Faculty of Science, University of Burgos, Burgos, Spain
| | - Germán Perdomo
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y Universidad de Valladolid (UVa), Valladolid, Spain
| | - Beatriz Merino
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y Universidad de Valladolid (UVa), Valladolid, Spain
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Leissring MA, González-Casimiro CM, Merino B, Suire CN, Perdomo G. Targeting Insulin-Degrading Enzyme in Insulin Clearance. Int J Mol Sci 2021; 22:ijms22052235. [PMID: 33668109 PMCID: PMC7956289 DOI: 10.3390/ijms22052235] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/20/2021] [Accepted: 02/21/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50–80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn2+-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky’s seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients.
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Affiliation(s)
- Malcolm A. Leissring
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI MIND), Irvine, CA 92697-4545, USA
- Correspondence: (M.A.L.); (G.P.); Tel.: +1-904-254-3050 (M.A.L.); +34-983-184-805 (G.P.)
| | - Carlos M. González-Casimiro
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), 47003 Valladolid, Spain; (C.M.G.-C.); (B.M.)
| | - Beatriz Merino
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), 47003 Valladolid, Spain; (C.M.G.-C.); (B.M.)
| | - Caitlin N. Suire
- Department of Biomedical Sciences, Florida State University, Tallahassee, FL 32306-4300, USA;
| | - Germán Perdomo
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), 47003 Valladolid, Spain; (C.M.G.-C.); (B.M.)
- Correspondence: (M.A.L.); (G.P.); Tel.: +1-904-254-3050 (M.A.L.); +34-983-184-805 (G.P.)
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Interaction between Apo A-II -265T>C polymorphism and dietary total antioxidant capacity on some anthropometric indices and serum lipid profile in patients with type 2 diabetes mellitus. J Nutr Sci 2021; 10:e9. [PMID: 33889392 PMCID: PMC8057501 DOI: 10.1017/jns.2020.61] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 12/15/2020] [Indexed: 12/22/2022] Open
Abstract
The present study aimed to investigate the interaction of Apo A-II polymorphism and dietary total antioxidant capacity (DTAC) with lipid profile and anthropometric markers in patients with type 2 diabetes (T2DM) that are at risk for atherosclerosis. This cross-sectional study was conducted on 778 patients with T2DM (35–65 years). Dietary intakes were assessed by a 147-item food frequency questionnaire. DTAC was computed using international databases. Participants were categorised into two groups based on rs5082 genotypes. The gene–diet interaction was analysed by an ANCOVA multivariate interaction model. Total cholesterol, TC; triacylglycerol, TG; high- and low-density lipoprotein, HDL and LDL; TC–HDL ratio; waist circumference, WC and body mass index, BMI were obtained according to standard protocols. Overall, the frequency of CC homozygous was 12⋅1 % among study participants. We found that a significant interaction between rs5082 variants and DTAC on mean WC (PTEAC = 0⋅044), TC concentration (PFRAP = 0⋅049 and PTEAC = 0⋅031) and TC/HDL (PFRAP = 0⋅031 and PTRAP = 0⋅040). Among patients whose DTAC was higher than the median intake, the mean of weight, WC and TC/HDL were significantly higher only in individuals with CC genotype. Also, the high DTAC was associated with a lower TC concentration only in T-allele carriers (PFRAP = 0⋅042). We found that adherence to a diet with high total antioxidant capacity can improve the complications of diabetes and atherosclerosis in the T carrier genotype more effectively than the CC genotype. These results could indicate the anti-atherogenic properties of Apo A-II. However, further studies are needed to shed light on this issue.
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Merino B, Fernández-Díaz CM, Parrado-Fernández C, González-Casimiro CM, Postigo-Casado T, Lobatón CD, Leissring MA, Cózar-Castellano I, Perdomo G. Hepatic insulin-degrading enzyme regulates glucose and insulin homeostasis in diet-induced obese mice. Metabolism 2020; 113:154352. [PMID: 32916153 PMCID: PMC8616598 DOI: 10.1016/j.metabol.2020.154352] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/20/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023]
Abstract
UNLABELLED The insulin-degrading enzyme (IDE) is a metalloendopeptidase with a high affinity for insulin. Human genetic polymorphisms in Ide have been linked to increased risk for T2DM. In mice, hepatic Ide ablation causes glucose intolerance and insulin resistance when mice are fed a regular diet. OBJECTIVE These studies were undertaken to further investigate its regulatory role in glucose homeostasis and insulin sensitivity in diet-induced obesity. METHODS To this end, we have compared the metabolic effects of loss versus gain of IDE function in mice fed a high-fat diet (HFD). RESULTS We demonstrate that loss of IDE function in liver (L-IDE-KO mouse) exacerbates hyperinsulinemia and insulin resistance without changes in insulin clearance but in parallel to an increase in pancreatic β-cell function. Insulin resistance was associated with increased FoxO1 activation and a ~2-fold increase of GLUT2 protein levels in the liver of HFD-fed mice in response to an intraperitoneal injection of insulin. Conversely, gain of IDE function (adenoviral delivery) improves glucose tolerance and insulin sensitivity, in parallel to a reciprocal ~2-fold reduction in hepatic GLUT2 protein levels. Furthermore, in response to insulin, IDE co-immunoprecipitates with the insulin receptor in liver lysates of mice with adenoviral-mediated liver overexpression of IDE. CONCLUSIONS We conclude that IDE regulates hepatic insulin action and whole-body glucose metabolism in diet-induced obesity via insulin receptor levels.
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Affiliation(s)
- Beatriz Merino
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), Valladolid, Spain
| | | | - Cristina Parrado-Fernández
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), Valladolid, Spain; AlzeCure Pharma AB, Huddinge, Sweden
| | | | - Tamara Postigo-Casado
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), Valladolid, Spain.
| | - Carmen D Lobatón
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), Valladolid, Spain.
| | - Malcolm A Leissring
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI MIND), Irvine, CA, USA.
| | - Irene Cózar-Castellano
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), Valladolid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
| | - Germán Perdomo
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), Valladolid, Spain; Departamento de Ciencias de la Salud, Universidad de Burgos, Burgos, Spain.
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Liang T, Wu Z, Du S, Hu L. TXNIP Gene Single Nucleotide Polymorphisms Associated with the Risk of Type 2 Diabetes Mellitus in a Chinese Han Population. DNA Cell Biol 2020; 39:1513-1520. [PMID: 32522049 DOI: 10.1089/dna.2020.5592] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Affiliation(s)
- Tao Liang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zubo Wu
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuaixian Du
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lihua Hu
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Catalina MOS, Redondo PC, Granados MP, Cantonero C, Sanchez-Collado J, Albarran L, Lopez JJ. New Insights into Adipokines as Potential Biomarkers for Type-2 Diabetes Mellitus. Curr Med Chem 2019; 26:4119-4144. [PMID: 29210636 DOI: 10.2174/0929867325666171205162248] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 10/30/2017] [Accepted: 10/30/2017] [Indexed: 02/06/2023]
Abstract
A large number of studies have been focused on investigating serum biomarkers associated with risk or diagnosis of type-2 diabetes mellitus. In the last decade, promising studies have shown that circulating levels of adipokines could be used as a relevant biomarker for diabetes mellitus progression as well as therapeutic future targets. Here, we discuss the possible use of recently described adipokines, including apelin, omentin-1, resistin, FGF-21, neuregulin-4 and visfatin, as early biomarkers for diabetes. In addition, we also include recent findings of other well known adipokines such as leptin and adiponectin. In conclusion, further studies are needed to clarify the pathophysiological significance and clinical value of these biological factors as potential biomarkers in type-2 diabetes and related dysfunctions.
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Affiliation(s)
| | - Pedro C Redondo
- Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Maria P Granados
- Aldea Moret's Medical Center, Extremadura Health Service, 10195-Caceres, Spain
| | - Carlos Cantonero
- Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Jose Sanchez-Collado
- Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Letizia Albarran
- Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Jose J Lopez
- Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
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Aguayo-Mazzucato C, Diaque P, Hernandez S, Rosas S, Kostic A, Caballero AE. Understanding the growing epidemic of type 2 diabetes in the Hispanic population living in the United States. Diabetes Metab Res Rev 2019; 35:e3097. [PMID: 30445663 PMCID: PMC6953173 DOI: 10.1002/dmrr.3097] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 11/12/2018] [Accepted: 11/13/2018] [Indexed: 12/15/2022]
Abstract
The prevalence and incidence of type 2 diabetes (T2D) among the Hispanic population in the United States are higher than the national average. This is partly due to sociocultural factors, such as lower income and decreased access to education and health care, as well as a genetic susceptibility to obesity and higher insulin resistance. This review focuses on understanding the Hispanic population living in the United States from a multidisciplinary approach and underlines the importance of cultural, social, and biological factors in determining the increased risk of T2D in this population. An overview of the acute and chronic complications of T2D upon this population is included, which is of paramount importance to understand the toll that diabetes has upon this population, the health system, and society as a whole. Specific interventions directed to the Hispanic populations are needed to prevent and alleviate some of the burdens of T2D. Different prevention strategies based on medications, lifestyle modifications, and educational programmes are discussed herein. Diabetes self-management education (DSME) is a critical element of care of all people with diabetes and is considered necessary to improve patient outcomes. To be more effective, programmes should take into consideration cultural factors that influence the development and progression of diabetes. These interventions aim to enhance long-term effects by reducing the incidence, morbidity, and mortality of T2D in the Hispanic population of the United States.
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Affiliation(s)
| | - Paula Diaque
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Sonia Hernandez
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
- Surgery Department, University of Chicago, Chicago, Illinois, USA
| | - Silvia Rosas
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Aleksandar Kostic
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
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Johnson MP, Keyho R, Blackburn NB, Laston S, Kumar S, Peralta J, Thapa SS, Towne B, Subedi J, Blangero J, Williams-Blangero S. Glycated Serum Protein Genetics and Pleiotropy with Cardiometabolic Risk Factors. J Diabetes Res 2019; 2019:2310235. [PMID: 31089471 PMCID: PMC6476113 DOI: 10.1155/2019/2310235] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 12/20/2018] [Accepted: 01/12/2019] [Indexed: 01/08/2023] Open
Abstract
Measurements of fasting glucose (FG) or glycated hemoglobin A1c (HbA1c) are two clinically approved approaches commonly used to determine glycemia, both of which are influenced by genetic factors. Obtaining accurate measurements of FG or HbA1c is not without its challenges, though. Measuring glycated serum protein (GSP) offers an alternative approach for assessing glycemia. The aim of this study was to estimate the heritability of GSP and GSP expressed as a percentage of total serum albumin (%GA) using a variance component approach and localize genomic regions (QTLs) that harbor genes likely to influence GSP and %GA trait variation in a large extended multigenerational pedigree from Jiri, Nepal (n = 1,800). We also performed quantitative bivariate analyses to assess the relationship between GSP or %GA and several cardiometabolic traits. Additive genetic effects significantly influence variation in GSP and %GA levels (p values: 1.15 × 10-5 and 3.39 × 10-5, respectively). We localized a significant (LOD score = 3.18) and novel GSP QTL on chromosome 11q, which has been previously linked to type 2 diabetes. Two common (MAF > 0.4) SNPs within the chromosome 11 QTL were associated with GSP (adjusted pvalue < 5.87 × 10-5): an intronic variant (rs10790184) in the DSCAML1 gene and a 3'UTR variant (rs8258) in the CEP164 gene. Significant positive correlations were observed between GSP or %GA and blood pressure, and lipid traits (p values: 0.0062 to 1.78 × 10-9). A significant negative correlation was observed between %GA and HDL cholesterol (p = 1.12 × 10-5). GSP is influenced by genetic factors and can be used to assess glycemia and diabetes risk. Thus, GSP measurements can facilitate glycemic studies when accurate FG and/or HbA1c measurements are difficult to obtain. GSP can also be measured from frozen blood (serum) samples, which allows the prospect of retrospective glycemic studies using archived samples.
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Affiliation(s)
- Matthew P. Johnson
- South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
| | - Ryan Keyho
- The University of Texas at Austin, Austin, Texas 78705, USA
| | - Nicholas B. Blackburn
- South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
| | - Sandra Laston
- South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
| | - Satish Kumar
- South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
| | - Juan Peralta
- South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
- Menzies Institute for Medical Research, University of Tasmania, Hobart 7000, Australia
| | - Suman S. Thapa
- Tilganga Institute of Ophthalmology, Gaushala, Bagmati Bridge, P.O. Box 561, Kathmandu, Nepal
| | - Bradford Towne
- Department of Population Health and Public Health Sciences, Boonshoft School of Medicine, Wright State University, Kettering, Ohio 45435, USA
| | - Janardan Subedi
- Department of Sociology and Gerontology, College of Arts and Science, Miami University, Oxford, Ohio 45056, USA
| | - John Blangero
- South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
| | - Sarah Williams-Blangero
- South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas 78520, USA
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11
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Villa-Pérez P, Merino B, Fernández-Díaz CM, Cidad P, Lobatón CD, Moreno A, Muturi HT, Ghadieh HE, Najjar SM, Leissring MA, Cózar-Castellano I, Perdomo G. Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice. Metabolism 2018; 88:1-11. [PMID: 30098324 PMCID: PMC6185772 DOI: 10.1016/j.metabol.2018.08.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 07/24/2018] [Accepted: 08/06/2018] [Indexed: 11/23/2022]
Abstract
UNLABELLED The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood. OBJECTIVE This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance. METHODS We generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action. RESULTS L-IDE-KO mice exhibited higher (~20%) fasting and non-fasting plasma glucose levels, glucose intolerance and insulin resistance. This phenotype was associated with ~30% lower plasma membrane insulin receptor levels in liver, as well as ~55% reduction in insulin-stimulated phosphorylation of the insulin receptor, and its downstream signaling molecules, AKT1 and AKT2 (reduced by ~40%). In addition, FoxO1 was aberrantly distributed in cellular nuclei, in parallel with up-regulation of the gluconeogenic genes Pck1 and G6pc. Surprisingly, L-IDE-KO mice showed similar plasma insulin levels and hepatic insulin clearance as control mice, despite reduced phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1, which upon its insulin-stimulated phosphorylation, promotes receptor-mediated insulin uptake to be degraded. CONCLUSION IDE is not a rate-limiting regulator of plasma insulin levels in vivo.
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Affiliation(s)
- Pablo Villa-Pérez
- Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain
| | - Beatriz Merino
- Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain
| | | | - Pilar Cidad
- Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain
| | - Carmen D Lobatón
- Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain
| | - Alfredo Moreno
- Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain
| | - Harrison T Muturi
- Department of Biomedical Sciences, Ohio University, USA; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, USA
| | - Hilda E Ghadieh
- Department of Biomedical Sciences, Ohio University, USA; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, USA
| | - Sonia M Najjar
- Department of Biomedical Sciences, Ohio University, USA; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, USA
| | - Malcolm A Leissring
- Institute for Memory Impairments and Neurological Disorders, University of California, UCI MIND, Irvine, CA, USA
| | - Irene Cózar-Castellano
- Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain
| | - Germán Perdomo
- Departamento de Ciencias de la Salud, Universidad de Burgos, Burgos, Spain.
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12
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Kim Y, Bayona PW, Kim M, Chang J, Hong S, Park Y, Budiman A, Kim YJ, Choi CY, Kim WS, Lee J, Cho KW. Macrophage Lamin A/C Regulates Inflammation and the Development of Obesity-Induced Insulin Resistance. Front Immunol 2018; 9:696. [PMID: 29731750 PMCID: PMC5920030 DOI: 10.3389/fimmu.2018.00696] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 03/21/2018] [Indexed: 01/28/2023] Open
Abstract
Obesity-induced chronic low-grade inflammation, in particular in adipose tissue, contributes to the development of insulin resistance and type 2 diabetes. However, the mechanism by which obesity induces adipose tissue inflammation has not been completely elucidated. Recent studies suggest that alteration of the nuclear lamina is associated with age-associated chronic inflammation in humans and fly. These findings led us to investigate whether the nuclear lamina regulates obesity-mediated chronic inflammation. In this study, we show that lamin A/C mediates inflammation in macrophages. The gene and protein expression levels of lamin A/C are significantly increased in epididymal adipose tissues from obese rodent models and omental fat from obese human subjects compared to their lean controls. Flow cytometry and gene expression analyses reveal that the protein and gene expression levels of lamin A/C are increased in adipose tissue macrophages (ATMs) by obesity. We further show that ectopic overexpression of lamin A/C in macrophages spontaneously activates NF-κB, and increases the gene expression levels of proinflammatory genes, such as Il6, Tnf, Ccl2, and Nos2. Conversely, deletion of lamin A/C in macrophages reduces LPS-induced expression of these proinflammatory genes. Importantly, we find that myeloid cell-specific lamin A/C deficiency ameliorates obesity-induced insulin resistance and adipose tissue inflammation. Thus, our data suggest that lamin A/C mediates the activation of ATM inflammation by regulating NF-κB, thereby contributing to the development of obesity-induced insulin resistance.
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Affiliation(s)
- Youngjo Kim
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheon-an, South Korea
| | - Princess Wendy Bayona
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheon-an, South Korea
| | - Miri Kim
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheon-an, South Korea
| | - Jiyeon Chang
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheon-an, South Korea
| | - Sunmin Hong
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheon-an, South Korea
| | - Yoona Park
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheon-an, South Korea
| | - Andrea Budiman
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheon-an, South Korea
| | - Yong-Jin Kim
- Department of Surgery, Soonchunhyang University Hospital, Seoul, South Korea
| | - Chang Yong Choi
- Department of Plastic and Reconstructive Surgery, Soonchunhyang University Hospital, Gumi, South Korea
| | - Woo Seok Kim
- Department of Surgery, Soonchunhyang University Gumi Hospital, Gumi, South Korea
| | - Jongsoon Lee
- The Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Kae Won Cho
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheon-an, South Korea
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13
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Thioredoxin-Interacting Protein (TXNIP) in Cerebrovascular and Neurodegenerative Diseases: Regulation and Implication. Mol Neurobiol 2018; 55:7900-7920. [PMID: 29488135 DOI: 10.1007/s12035-018-0917-z] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Accepted: 01/21/2018] [Indexed: 02/07/2023]
Abstract
Neurological diseases, including acute attacks (e.g., ischemic stroke) and chronic neurodegenerative diseases (e.g., Alzheimer's disease), have always been one of the leading cause of morbidity and mortality worldwide. These debilitating diseases represent an enormous disease burden, not only in terms of health suffering but also in economic costs. Although the clinical presentations differ for these diseases, a growing body of evidence suggests that oxidative stress and inflammatory responses in brain tissue significantly contribute to their pathology. However, therapies attempting to prevent oxidative damage or inhibiting inflammation have shown little success. Identification and targeting endogenous "upstream" mediators that normalize such processes will lead to improve therapeutic strategy of these diseases. Thioredoxin-interacting protein (TXNIP) is an endogenous inhibitor of the thioredoxin (TRX) system, a major cellular thiol-reducing and antioxidant system. TXNIP regulating redox/glucose-induced stress and inflammation, now is known to get upregulated in stroke and other brain diseases, and represents a promising therapeutic target. In particular, there is growing evidence that glucose strongly induces TXNIP in multiple cell types, suggesting possible physiological roles of TXNIP in glucose metabolism. Recently, a significant body of literature has supported an essential role of TXNIP in the activation of the NOD-like receptor protein (NLRP3)-inflammasome, a well-established multi-molecular protein complex and a pivotal mediator of sterile inflammation. Accordingly, TXNIP has been postulated to reside centrally in detecting cellular damage and mediating inflammatory responses to tissue injury. The majority of recent studies have shown that pharmacological inhibition or genetic deletion of TXNIP is neuroprotective and able to reduce detrimental aspects of pathology following cerebrovascular and neurodegenerative diseases. Conspicuously, the mainstream of the emerging evidences is highlighting TXNIP link to damaging signals in endothelial cells. Thereby, here, we keep the trend to present the accumulative data on CNS diseases dealing with vascular integrity. This review aims to summarize evidence supporting the significant contribution of regulatory mechanisms of TXNIP with the development of brain diseases, explore pharmacological strategies of targeting TXNIP, and outline obstacles to be considered for efficient clinical translation.
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14
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Blanco-Rojo R, Delgado-Lista J, Lee YC, Lai CQ, Perez-Martinez P, Rangel-Zuñiga O, Smith CE, Hidalgo B, Alcala-Diaz JF, Gomez-Delgado F, Parnell LD, Arnett DK, Tucker KL, Lopez-Miranda J, Ordovas JM. Interaction of an S100A9 gene variant with saturated fat and carbohydrates to modulate insulin resistance in 3 populations of different ancestries. Am J Clin Nutr 2016; 104:508-17. [PMID: 27440084 PMCID: PMC4962160 DOI: 10.3945/ajcn.116.130898] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 05/19/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND S100 calcium-binding protein A9 (S100A9) has previously been identified as a type 2 diabetes (T2D) gene. However, this finding requires independent validation and more in-depth analyses in other populations and ancestries. OBJECTIVES We aimed to replicate the associations between an S100A9 variant and insulin resistance and T2D and to initiate an investigation of potential interactions with the habitual diet in several independent populations. DESIGN We investigated the association of the S100A9 variant rs3014866 with insulin resistance and T2D risk and its interactions with diet in 3 diverse populations as follows: the CORDIOPREV (Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; n = 711), which consisted of Spanish white adults; the GOLDN (Genetics of Lipids Lowering Drugs and Diet Network; n = 818), which involved North American non-Hispanic white adults; and Hispanic adults who participated in the BPRHS (Boston Puerto Rican Health Study; n = 1155). RESULTS Meta-analysis indicated that T carriers presented a lower risk of T2D than CC carriers (pooled OR: 0.714; 95% CI: 0.584, 0.845; P = 0.002). In all 3 populations (CORDIOPREV, GOLDN, and BPRHS), we showed a significant interaction between the rs3014866 single nucleotide polymorphism and dietary SFA:carbohydrate ratio intake for the homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.028, P = 0.017, and P = 0.026, respectively). CC carriers had a significantly higher HOMA-IR only when SFA:carbohydrate intake was high (P = 0.045 for the CORDIOPREV, P = 0.033 for the GOLDN, and P = 0.046 for the BPRHS) but not when SFA:carbohydrate ratio intake was low. CONCLUSIONS The minor allele (T) of the S100A9 variant rs3014866 is associated with lower T2D risk in 3 populations of different ancestries. Note that individuals with the high-risk CC genotype may be more likely to benefit from a low SFA:carbohydrate ratio intake to improve insulin resistance as evaluated with the use of the HOMA-IR. These trials were registered at clinicaltrials.gov as NCT00924937 (CORDIOPREV), NCT00083369 (GOLDN), and NCT01231958 (BPRHS).
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Affiliation(s)
- Ruth Blanco-Rojo
- Lipids and Atherosclerosis Unit, Reina Sofia University Hospital, Maimonides Institute for Biomedical Research at Cordoba, University of Cordoba, Cordoba, Spain; Centro de Investigación Biomédica en Red (CIBER) Fisiopatologia Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Nutrition and Genomics Laboratory and
| | - Javier Delgado-Lista
- Lipids and Atherosclerosis Unit, Reina Sofia University Hospital, Maimonides Institute for Biomedical Research at Cordoba, University of Cordoba, Cordoba, Spain; Centro de Investigación Biomédica en Red (CIBER) Fisiopatologia Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Chao-Qiang Lai
- Agricultural Research Service, USDA, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA
| | - Pablo Perez-Martinez
- Lipids and Atherosclerosis Unit, Reina Sofia University Hospital, Maimonides Institute for Biomedical Research at Cordoba, University of Cordoba, Cordoba, Spain; Centro de Investigación Biomédica en Red (CIBER) Fisiopatologia Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Oriol Rangel-Zuñiga
- Lipids and Atherosclerosis Unit, Reina Sofia University Hospital, Maimonides Institute for Biomedical Research at Cordoba, University of Cordoba, Cordoba, Spain; Centro de Investigación Biomédica en Red (CIBER) Fisiopatologia Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Bertha Hidalgo
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL
| | - Juan F Alcala-Diaz
- Lipids and Atherosclerosis Unit, Reina Sofia University Hospital, Maimonides Institute for Biomedical Research at Cordoba, University of Cordoba, Cordoba, Spain; Centro de Investigación Biomédica en Red (CIBER) Fisiopatologia Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco Gomez-Delgado
- Lipids and Atherosclerosis Unit, Reina Sofia University Hospital, Maimonides Institute for Biomedical Research at Cordoba, University of Cordoba, Cordoba, Spain; Centro de Investigación Biomédica en Red (CIBER) Fisiopatologia Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Laurence D Parnell
- Agricultural Research Service, USDA, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA
| | - Donna K Arnett
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL
| | - Katherine L Tucker
- Department of Clinical Laboratory and Nutritional Sciences, University of Massachusetts, Lowell, MA
| | - Jose Lopez-Miranda
- Lipids and Atherosclerosis Unit, Reina Sofia University Hospital, Maimonides Institute for Biomedical Research at Cordoba, University of Cordoba, Cordoba, Spain; Centro de Investigación Biomédica en Red (CIBER) Fisiopatologia Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain;
| | - Jose M Ordovas
- Nutrition and Genomics Laboratory and Department of Epidemiology, Spanish National Center for Cardiovascular Research (CNIC), Madrid, Spain; and Madrid Institute for Advanced Studies (IMDEA) Food Institute, Madrid, Spain
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15
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Senemar S, Edraki MR, Toosi S. Association between type 2 diabetes mellitus, biochemical factors and UCSNP-43 polymorphisms of CALPIN-10 gene in patients with atherosclerosis of coronary artery disease in Southern Iran population. J Cardiovasc Thorac Res 2016; 8:13-9. [PMID: 27069562 PMCID: PMC4827134 DOI: 10.15171/jcvtr.2016.03] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 01/16/2016] [Indexed: 11/09/2022] Open
Abstract
Introduction: Genetic variations in the calpain 10 gene (CALPIN-10), single nucleotide polymorphisms-43 (SNP-43), have increased the risk of type 2 diabete mellitus (T2DM) and coronary artery disease (CAD).
Methods: We studied the control and CAD groups for association of association of SNP-43 in the CALPIN-10 gene with T2DM and other risk factors of its complications. Overall, we examined 452 individuals, 224 patients with CAD and 228 healthy subjects for CAD in Iranian population. All the subjects were genotyped for the CALPIN-10, SNP-43 by polymorphism chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods, using biochemical methods to detect fasting glucose and other biochemical factors in the blood sample. We assessed frequencies of SNP-43 alleles between CAD and normal population groups.
Results: In CAD patients, the GG allele was significantly associated with T2DM and GG allele was causing high level of glucose. But in control group, there was no relationship between them. Between clinical and biochemical risk factors with different genotypes there was no significant difference in the compared group.
Conclusion: The results of our study suggest no significant association between SNP-43 and the risk of T2DM. In other words, CALPIN-10 did not show a major diabetes gene pool capacity in normal southern Iranian population.
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Affiliation(s)
- Sara Senemar
- Human Genetics Research Group, Iranian Academic Center for Education & Research (ACECR), Fars Branch, Shiraz, Iran
| | - Mohammad Reza Edraki
- Institute for Pediatric Cardiologist, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samane Toosi
- Human Genetics Research Group, Iranian Academic Center for Education & Research (ACECR), Fars Branch, Shiraz, Iran
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16
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Abstract
Adhesion G protein-coupled receptors (aGPCRs) have a long evolutionary history dating back to very basal unicellular eukaryotes. Almost every vertebrate is equipped with a set of different aGPCRs. Genomic sequence data of several hundred extinct and extant species allows for reconstruction of aGPCR phylogeny in vertebrates and non-vertebrates in general but also provides a detailed view into the recent evolutionary history of human aGPCRs. Mining these sequence sources with bioinformatic tools can unveil many facets of formerly unappreciated aGPCR functions. In this review, we extracted such information from the literature and open public sources and provide insights into the history of aGPCR in humans. This includes comprehensive analyses of signatures of selection, variability of human aGPCR genes, and quantitative traits at human aGPCR loci. As indicated by a large number of genome-wide genotype-phenotype association studies, variations in aGPCR contribute to specific human phenotypes. Our survey demonstrates that aGPCRs are significantly involved in adaptation processes, phenotype variations, and diseases in humans.
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Affiliation(s)
- Peter Kovacs
- Integrated Research and Treatment Center (IFB) AdiposityDiseases, Medical Faculty, University of Leipzig, Liebigstr. 21, Leipzig, 04103, Germany.
| | - Torsten Schöneberg
- Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, Leipzig, 04103, Germany.
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17
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Khodaeian M, Enayati S, Tabatabaei-Malazy O, Amoli MM. Association between Genetic Variants and Diabetes Mellitus in Iranian Populations: A Systematic Review of Observational Studies. J Diabetes Res 2015; 2015:585917. [PMID: 26587547 PMCID: PMC4637497 DOI: 10.1155/2015/585917] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 01/15/2015] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Diabetes mellitus as the most prevalent metabolic disease is a multifactorial disease which is influenced by environmental and genetic factors. In this systematic review, we assessed the association between genetic variants and diabetes/its complications in studies with Iranian populations. METHODS Google Scholar, PubMed, Scopus, and Persian web databases were systematically searched up to January 2014. The search terms were "gene," "polymorphism," "diabetes," and "diabetic complications"; nephropathy, retinopathy, neuropathy, foot ulcer, and CAD (coronary artery diseases); and Persian equivalents. Animal studies, letters to editor, and in vitro studies were excluded. RESULTS Out of overall 3029 eligible articles, 88 articles were included. We found significant association between CTLA-4, IL-18, VDR, TAP2, IL-12, and CD4 genes and T1DM, HNFα and MODY, haptoglobin, paraoxonase, leptin, TCF7L2, calreticulin, ERα, PPAR-γ2, CXCL5, calpain-10, IRS-1 and 2, GSTM1, KCNJ11, eNOS, VDR, INSR, ACE, apoA-I, apo E, adiponectin, PTPN1, CETP, AT1R, resistin, MMP-3, BChE K, AT2R, SUMO4, IL-10, VEGF, MTHFR, and GSTM1 with T2DM or its complications. DISCUSSION We found some controversial results due to heterogeneity in ethnicity and genetic background. We thought genome wide association studies on large number of samples will be helpful in identifying diabetes susceptible genes as an alternative to studying individual candidate genes in Iranian populations.
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Affiliation(s)
- Mehrnoosh Khodaeian
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Enayati
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ozra Tabatabaei-Malazy
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa M. Amoli
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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18
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Gu N, Ma X, Zhang J, Dong A, Jin M, Feng N, Zhang H, Guo X. Obesity has an interactive effect with genetic variation in the activating transcription factor 6 gene on the risk of pre-diabetes in individuals of Chinese Han descent. PLoS One 2014; 9:e109805. [PMID: 25302688 PMCID: PMC4193822 DOI: 10.1371/journal.pone.0109805] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 09/13/2014] [Indexed: 11/19/2022] Open
Abstract
Endoplasmic reticulum (ER) stress is one of the contributing factors to the development of β-cell failure in type 2 diabetes. ER stress response through ATF6 has been shown to play an important role in insulin resistance and pancreatic β-cell function. We investigated whether genetic polymorphisms in ATF6 were associated with the risk of pre-diabetes in a Chinese Han population, and whether they had a synergistic effect with obesity. Our samples included 828 individuals who were diagnosed as pre-diabetic, and 620 controls. The minor allele A at rs2340721 was associated with increased risk for pre-diabetes(p = 0.013), and this association was still significant after adjusting for gender, age, body mass index (BMI), and waist-hip ratio(p' = 0.011). BMI, treated as a continuous variable, and rs2340721 had an interactive effect on pre-diabetic risk(p for interaction = 0.003, β = 0.106). Carriers of GG at rs7522210 were also at a higher risk compared to non-carriers (OR = 1.390, 95%CI:1.206-1.818, p = 0.013, adjusted OR' = 1.516, 95%CI:1.101-2.006, p' = 0.006). GG homozygotes had increased fasting blood glucose (FBG) levels(GG vs CX: 5.6 ± 0.52 vs 5.5 ± 0.57 mmol/L, p = 0.016), lower insulin levels (0,30,120 minutes after glucose load) (p < 0.05), and reduced areas under the insulin curve than non-carriers(GG vs CX:67.3(44.2-102.3) vs 73.1(49.4-111.4), p = 0.014). rs10918270 was associated with FBG, and rs4657103 with 2 hour glucose levels after a 75 g glucose load. We also identified a haplotype of TTAG composed of rs4657103, rs2134697, rs2340721, and rs12079579, which was associated with pre-diabetes. The genetic variation in ATF6 is associated with pre-diabetes and has interactive effects with BMI on pre-diabetes in the Chinese Han population.
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Affiliation(s)
- Nan Gu
- Endocrinology Department, First Hospital, Peking University, Beijing, China
| | - Xiaowei Ma
- Endocrinology Department, First Hospital, Peking University, Beijing, China
| | - Junqing Zhang
- Endocrinology Department, First Hospital, Peking University, Beijing, China
| | - Aimei Dong
- Endocrinology Department, First Hospital, Peking University, Beijing, China
| | - Mengmeng Jin
- Endocrinology Department, First Hospital, Peking University, Beijing, China
| | - Nan Feng
- Endocrinology Department, First Hospital, Peking University, Beijing, China
| | - Hong Zhang
- Endocrinology Department, First Hospital, Peking University, Beijing, China
| | - Xiaohui Guo
- Endocrinology Department, First Hospital, Peking University, Beijing, China
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Kebede MA, Attie AD. Insights into obesity and diabetes at the intersection of mouse and human genetics. Trends Endocrinol Metab 2014; 25:493-501. [PMID: 25034129 PMCID: PMC4177963 DOI: 10.1016/j.tem.2014.06.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 06/06/2014] [Accepted: 06/06/2014] [Indexed: 11/25/2022]
Abstract
Many of our insights into obesity and diabetes come from studies in mice carrying natural or induced mutations. In parallel, genome-wide association studies (GWAS) in humans have identified numerous genes that are causally associated with obesity and diabetes, but discovering the underlying mechanisms required in-depth studies in mice. We discuss the advantages of studying natural variation in mice and summarize several examples where the combination of human and mouse genetics opened windows into fundamental physiological pathways. A noteworthy example is the melanocortin-4 receptor (MC4R) and its role in energy balance. The pathway was delineated by discovering the gene responsible for the Agouti mutation in mice. With more targeted phenotyping, we predict that additional pathways relevant to human pathophysiology will be discovered.
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Affiliation(s)
- Melkam A Kebede
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Alan D Attie
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
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20
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Tawfeek HM, Maghrapy HM, Elsaid FM, Eliazeed HA. Relationship between omentin-1 and carotid intima thickness in type 2 diabetes mellitus. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2014. [DOI: 10.4103/1110-7782.139547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Zaki ME, Amr KS, Abdel-Hamid M. Evaluating the association of APOA2 polymorphism with insulin resistance in adolescents. Meta Gene 2014; 2:366-73. [PMID: 25606421 PMCID: PMC4287816 DOI: 10.1016/j.mgene.2014.04.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 04/21/2014] [Accepted: 04/22/2014] [Indexed: 12/26/2022] Open
Abstract
Background 265T>C SNP in the APOA-II gene promoter may be associated with obesity risk and insulin resistance (IR). This study aims to analyze the association between the APOA2 − 265T>C SNP and risk for obesity and IR in adolescents. Material and methods The study was conducted on 500 adolescents. They were 240 obese and 260 non-obese individuals, aged 16–21 years old. Their mean age was 18.25 ± 2.54 years. Variables examined body weight, height, waist circumference (WC), systolic and diastolic blood pressure (BP), body fat percentage (BF%), and abdominal visceral fat layer. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was used as a biomarker for IR. BF% was assessed by body composition analyzer and abdominal visceral fat thickness was determined by ultrasonography. The APOA2 − 265T>C polymorphism genotype was analyzed by PCR amplification of a 273-bp fragment. Results Genotype frequencies were in Hardy–Weinberg equilibrium. The frequency of the mutant C allele was significantly higher in obese cases than non-obese cases. After multivariate adjustment, waist, BF%, visceral adipose layer and HOMA-IR were significantly higher in homozygous allele CC carriers than TT + TC carriers. Homozygous individuals for the CC allele had statistically higher values of energy intake, total fat (g/day) and saturated fat (SATFAT) than carriers of the T allele. Conclusions Homozygous individuals for the C allele had higher obesity risk than carriers of the T allele and had elevated levels of visceral adipose tissue. Moreover, the present study shows that the CC polymorphism is associated with the development of IR [OR 1.89 (1.35–2.91), P = .012] and remains significant after adjusting for gender, age and body mass index.
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Affiliation(s)
- Moushira Erfan Zaki
- Biological Anthropology Department, Medical Research Division, National Research Centre, Egypt
| | - Khalda Sayed Amr
- Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Egypt
| | - Mohamed Abdel-Hamid
- Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Egypt
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Moreno-Navarrete JM, Fernández-Real JM. The possible role of antimicrobial proteins in obesity-associated immunologic alterations. Expert Rev Clin Immunol 2014; 10:855-66. [DOI: 10.1586/1744666x.2014.911088] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Splichal Z, Bienertova-Vasku J, Novak J, Zlamal F, Tomandl J, Tomandlova M, Forejt M, Havlenova S, Jackowska A, Vasku A. The common polymorphism Val109Asp in the omentin gene is associated with daily energy intake in the Central-European population. Nutr Neurosci 2014; 18:41-8. [DOI: 10.1179/1476830513y.0000000100] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Hoteit M, Arabi A, Habib R, Mahfouz R, Baddoura R, Halaby G, El-Hajj Fuleihan G. Estrogen receptor α is not a candidate gene for metabolic syndrome in Caucasian elderly subjects. Metabolism 2014; 63:50-60. [PMID: 24140101 DOI: 10.1016/j.metabol.2013.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Revised: 07/22/2013] [Accepted: 08/09/2013] [Indexed: 11/21/2022]
Abstract
OBJECTIVE Variants of estrogen receptor α (ERα) have been associated with obesity, dyslipidemia, diabetes and blood pressure. The Middle East registers some of the highest rate of metabolic syndrome worldwide. The aim of this study is to investigate the relationship between metabolic syndrome, a clustered combination of these metabolic factors, and polymorphisms PvuII and XbaI of ERα in Lebanese Caucasian elderly overweight subjects. MATERIAL/METHODS 250 Caucasian Lebanese unrelated elderly men and women, median age 71 years, were studied. ERα intronic polymorphisms variants, PvuII and XbaI diplotypes and genotypes, were examined. Associations with metabolic syndrome, defined by the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI), and its components, namely high density lipoprotein (HDL), fasting glucose levels, blood pressure, and waist circumference were evaluated in regression models. RESULTS ER α diplotypes and genotypes distributions were similar between participants with and without metabolic syndrome, in the overall group of subjects, and by gender. No consistent associations between the diplotypes and genotypes tested and metabolic syndrome, or its components, could be detected. CONCLUSIONS Genetic variants in ERα were not associated with metabolic syndrome or its components, in a group of 250 Lebanese Caucasian elderly participants, a group with a high prevalence of metabolic syndrome.
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Affiliation(s)
- Maha Hoteit
- Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, American University of Beirut Medical Center, Beirut, Lebanon
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Karadeniz M, Erdogan M, Berdeli A, Yilmaz C. Association of interleukin-6 -174 G>C promoter polymorphism with increased risk of type 2 diabetes mellitus patients with diabetic nephropathy in Turkey. Genet Test Mol Biomarkers 2013; 18:62-5. [PMID: 24102240 DOI: 10.1089/gtmb.2013.0357] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. We aimed to evaluate the interleukin (IL)-6 gene polymorphisms in type 2 DN and control subjects. MATERIALS AND METHODS The patients selected from the Department of Endocrinology and Metabolism Diseases included 43 type 2 diabetes mellitus patients without DN and 43 type 2 diabetes mellitus patients with DN and 340 healthy normal controls. All subjects underwent venous blood drawing for complete hormonal assays, lipid profile, glucose, and insulin and Il-6 gene polymorphism genetic analysis. RESULTS IL-6 -174 G>C genotype distribution was different between the control group and the type 2 diabetes mellitus patients (p=0.004). The higher frequency of the polymorphic G allele was also similar for the group with type 2 diabetes mellitus as for the control group. The frequency of the polymorphic G allele was 83.9% in diabetic patients with nephropathy versus 70.9% in those without nephropathy (p=0.039). CONCLUSION We suggest that the -174 G>C polymorphism of the IL-6 gene is an independent risk factor for DN in Turkish type 2 diabetes mellitus patients.
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Affiliation(s)
- Muammer Karadeniz
- 1 Department of Endocrinology and Metabolism, Sifa University Medical School , Izmir, Turkey
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26
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Mondal AK, Sharma NK, Elbein SC, Das SK. Allelic expression imbalance screening of genes in chromosome 1q21-24 region to identify functional variants for Type 2 diabetes susceptibility. Physiol Genomics 2013; 45:509-20. [PMID: 23673729 DOI: 10.1152/physiolgenomics.00048.2013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes (T2D)-associated SNPs are more likely to be expression quantitative trait loci (eQTLs). The allelic expression imbalance (AEI) analysis is the measure of relative expression between two allelic transcripts and is the most sensitive measurement to detect cis-regulatory effects. We performed AEI screening to detect cis-regulators for genes expressed in transformed lymphocytes of 190 Caucasian (CA) and African American (AA) subjects to identify functional variants for T2D susceptibility in the chromosome 1q21-24 region of linkage. Among transcribed SNPs studied in 115 genes, significant AEI (P < 0.001) occurred in 28 and 30 genes in CA and AA subjects, respectively. Analysis of the effect of selected AEI-SNPs (≥10% mean AEI) on total gene expression further established the cis-eQTLs in thioesterase superfamily member-4 (THEM4) (rs13320, P = 0.027), and IGSF8 (rs1131891, P = 0.02). Examination of published genome-wide association data identified significant associations (P < 0.01) of three AEI-SNPs with T2D in the DIAGRAM-v3 dataset. Six AEI single nucleotide polymorphisms, including rs13320 (P = 1.35E-04) in THEM4, were associated with glucose homeostasis traits in the MAGIC dataset. Evaluation of AEI-SNPs for association with glucose homeostasis traits in 611 nondiabetic subjects showed lower AIRG (P = 0.005) in those with TT/TC genotype for rs13320. THEM4 expression in adipose was higher (P = 0.005) in subjects carrying the T allele; in vitro analysis with luciferase construct confirmed the higher expression of the T allele. Resequencing of THEM4 exons in 192 CA subjects revealed four coding nonsynonymous variants, but did not explain transmission of T2D in 718 subjects from 67 Caucasian pedigrees. Our study indicates the role of a cis-regulatory SNP in THEM4 that may influence T2D predisposition by modulating glucose homeostasis.
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Affiliation(s)
- Ashis K Mondal
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
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Chen X, Jia X, Qiao J, Guan Y, Kang J. Adipokines in reproductive function: a link between obesity and polycystic ovary syndrome. J Mol Endocrinol 2013; 50:R21-37. [PMID: 23335807 DOI: 10.1530/jme-12-0247] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy associated with infertility and metabolic disorder in women of reproductive age. Dysfunction of adipose tissue has been implicated in the pathophysiology of PCOS. Increasing evidence shows that the dysregulated expression of adipokines, the secreted products of adipose tissue, plays an important role in the pathology of PCOS. Here, we review the role of several identified adipokines that may act as a link between obesity and PCOS. PCOS also reciprocally influences the profile of adipokines. Insight into the underlying mechanisms will help better understand the pathology of PCOS and identify new therapeutic targets of this syndrome.
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Affiliation(s)
- Xinwang Chen
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
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Muller YL, Hanson RL, Knowler WC, Fleming J, Goswami J, Huang K, Traurig M, Sutherland J, Wiedrich C, Wiedrich K, Mahkee D, Ossowski V, Kobes S, Bogardus C, Baier LJ. Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes. Hum Genet 2013; 132:697-707. [PMID: 23468175 PMCID: PMC3654185 DOI: 10.1007/s00439-013-1278-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Accepted: 02/16/2013] [Indexed: 11/28/2022]
Abstract
A prior linkage scan in Pima Indians identified a putative locus for type two diabetes (T2D) and body mass index (BMI) on chromosome 11q23-25. Association mapping across this region identified single nucleotide polymorphisms (SNPs) in the trehalase gene (TREH) that were associated with T2D. To assess the putative connection between trehalase activity and T2D, we performed a linkage study for trehalase activity in 570 Pima Indians who had measures of trehalase activity. Strong evidence of linkage of plasma trehalase activity (LOD = 7.0) was observed in the TREH locus. Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907 (p = 2.2 × 10−11–1.4 × 10−23), and the fourth SNP, rs10790256, was associated conditionally on these three (p = 2.9 × 10−7). Together, the four tag SNPs explained 51 % of the variance in plasma trehalase activity and 79 % of the variance attributed to the linked locus. These four tag SNPs were further genotyped in 828 subjects used for association mapping of T2D, and rs558907 was associated with T2D (odds ratio (OR) 1.94, p = 0.002). To assess replication of the T2D association, all four tag SNPs were additionally genotyped in two non-overlapping samples of Native Americans. Rs558907 was reproducibly associated with T2D in 2,942 full-heritage Pima Indians (OR 1.27 p = 0.03) and 3,897 “mixed” heritage Native Americans (OR 1.21, p = 0.03), and the strongest evidence for association came from combining all samples (OR 1.27 p = 1.6 × 10−4, n = 7,667). However, among 320 longitudinally studied subjects, measures of trehalase activity from a non-diabetic exam did not predict those who would eventually develop diabetes versus those who would remain non-diabetic (hazard ratio 0.94 per SD of trehalase activity, p = 0.29). We conclude that variants in TREH control trehalase activity, and although one of these variants is also reproducibly associated with T2D, it is likely that the effect of the SNP on risk of T2D occurs by a mechanism different than affecting trehalase activity. Alternatively, TREH variants may be tagging a nearby T2D locus.
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Affiliation(s)
- Yunhua L. Muller
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Robert L. Hanson
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - William C. Knowler
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Jamie Fleming
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Jayita Goswami
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Ke Huang
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Michael Traurig
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Jeff Sutherland
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Chris Wiedrich
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Kim Wiedrich
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Darin Mahkee
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Vicky Ossowski
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Sayuko Kobes
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Clifton Bogardus
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
| | - Leslie J. Baier
- Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 455 North 5th Street, Phoenix, AZ 85004 USA
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Ortega FJ, Mercader JM, Moreno-Navarrete JM, Sabater M, Pueyo N, Valdés S, Ruiz B, Luche E, Serino M, Naon D, Ricart W, Botas P, Delgado E, Burcelin R, Frühbeck G, Bosch F, Mingrone G, Zorzano A, Fernández-Real JM. Targeting the association of calgranulin B (S100A9) with insulin resistance and type 2 diabetes. J Mol Med (Berl) 2012. [PMID: 23207880 DOI: 10.1007/s00109-012-0979-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Calgranulin B (S100A9) was recognized as a candidate type 2 diabetes (T2D) gene in the genomic profiling of muscle from a rodent model of T2D and identifying the human orthologs of genes localized in T2D susceptibility regions. Circulating and S100A9 expressions in muscle and adipose tissue, isolated fat cells, and mouse models were evaluated. A common 5'-upstream single-nucleotide polymorphism (SNP; rs3014866) for S100A9 was analyzed, as well as the effects of weight loss and treatments in vitro with recombinant S100A9. S100a9 expression was increased in muscle of diabetic mice (1.6-fold, p = 0.002), and in muscle from subjects with impaired glucose tolerance (∼4-fold, p = 0.028; n = 34). The rs3014866 SNP was associated with circulating S100A9 and the risk of T2D, having TT carriers at 28 % (p = 0.03) lower risk (n = 1,450). Indeed, increased circulating S100A9 (∼4-fold, p = 0.03; n = 206) and subcutaneous (2-fold, p = 0.01) and omental (1.4-fold, p = 0.04) S100A9 gene expressions (n = 83) in TT carriers run in parallel to decreased fasting glucose and glycated hemoglobin. Accordingly, metformin led to increased S100A9 mRNA in ex vivo-treated adipose tissue explants (n = 5/treatment). Otherwise, obese subjects showed a compensatory increase in circulating and S100A9 expressions in adipose (n = 126), as further demonstrated by decreased levels after diet- (-34 %, p = 0.002; n = 20) and surgery-induced (-58 %, p = 0.02; n = 8) weight loss. Lipopolysaccharide led to increased S100A9 in adipose from mice (n = 5/treatment) while recombinant S100A9 downregulated inflammation in adipocytes (n = 3/treatment). Current findings support the strategy of testing differentially expressed genes in mice and human orthologs associated with T2D. The increased S100A9 reported for obesity and insulin resistance may be envisioned as a compensatory mechanism for inflammation.
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Affiliation(s)
- Francisco J Ortega
- Department of Diabetes, Endocrinology and Nutrition (UDEN), Institut d'Investigació Biomédica de Girona (IdIBGi), CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBERobn, CB06/03/0010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
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Hsieh CH, Hung YJ, Wu LI, He CT, Lee CH, Hsiao FC, Chu NF. Interleukin-6 receptor gene 48892 A/C polymorphism is associated with metabolic syndrome in female Taiwanese adolescents. Genet Test Mol Biomarkers 2012; 16:1376-81. [PMID: 23094986 DOI: 10.1089/gtmb.2012.0188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND This study was to evaluate the relationship between the interleukin-6 receptor (IL-6R) 48892 A/C single-nucleotide polymorphism (SNP) (rs8192284) and the metabolic syndrome (MetS) and its components among young adolescents in Taiwan. METHODS We enrolled 925 adolescents (451 boys and 474 girls). Modified National Cholesterol Education Program Adult Treatment Panel-III (NCEP ATP-III) criteria were applied to define MetS (with age- and gender-specific 90th percentile cutoff point of variables). Subjects had three or more of the following cardiometabolic abnormalities that occur in MetS: high blood pressure, high fasting glucose, high triglyceride (TG), low high-density lipoprotein cholesterol (HDL-C), and obesity. The characteristics of the MetS components associated with different alleles and genotypes of the IL-6R rs8192284 SNP were compared. RESULTS Frequencies of alleles and genotypes of the IL-6R 48892 polymorphism were similar in both sexes. Boys with C-alleles had borderline lower TG levels than A-allele carriers (66.0±30.1 vs. 70.3±34.6 mg/dL, p=0.07). However, girls with C-alleles had higher waist circumference (WC) (68.0±7.9 vs. 67.0±7.7 cm) and lower HDL-C levels (50.7±11.1 vs. 52.2±11.7 g/dL) than A-allele carriers (p=0.05). The prevalence of MetS and its components, high WC and low HDL-C level, were higher in female C-allele carriers (all p<0.05) but not in boys. The odds ratios for high WC, low HDL-C levels, and MetS for female C-allele carriers were 1.54 (95% confidence interval [CI]: 1.01-2.34), 1.49 (95% CI: 1.01-2.18), and 2.19-2.39 (95% CI: 1.15-4.51), respectively, when compared with A-allele carriers. CONCLUSIONS The IL-6R 48892 A/C polymorphism is associated with high TG and WC, and low HDL-C levels in adolescents. Additionally, there is a gender difference in the incidence of MetS, indicating a possible gene-gender interaction of the IL-6R 48892 A/C polymorphism in MetS among Taiwanese adolescents.
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Affiliation(s)
- Chang-Hsun Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
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Mahde A, Shaker M, Al-Mashhadani Z. Study of Omentin1 and Other Adipokines and Hormones in PCOS Patients. Oman Med J 2012; 24:108-18. [PMID: 22334855 DOI: 10.5001/omj.2009.25] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2009] [Accepted: 02/27/2009] [Indexed: 11/03/2022] Open
Abstract
OBJECTIVES Polycystic ovary syndrome (PCOS) is associated with insulin resistance and obesity. Recent studies have shown that plasma omentin-1 levels decrease with obesity. Currently, no data exists on the relative correlation between omentin-1 with other adipokines or the expression and regulation of omentin-1 in the serum of women with PCOS. The objective of this study is to evaluate the role of omentin-1 levels or omentin-1 /adipokines ratio in the serum of women with PCOS compared with matched control subjects. METHODS The study involved 60 patients with PCOS and 30 women without PCOS who were used as controls. To examine the relationship between fasting serum omentin-1 and serum interleukin-6 (IL-6), interleukin-8 (IL-8), resistin, ghrelin, leptin RBP-4 and tumor necrosis factor-a (TNF-a) levels in infertile PCOS and non-PCOS subjects. Also, insulin and other hormones were measured in both groups. All these factors were measured by enzyme-linked immunosorbent assays. RESULTS From the total of 60 cases, there was a significant increase (p<0.001) in PCOS patients when compared to the control group in fasting serum, serum interleukin-6 (IL-6), interleukin-8 (IL-8), resistin, leptin RBP-4, tumor necrosis factor-a (TNF-a) levels and insulin. A significant decrease in omentin-1 and ghrelin (p<0.001) was observed. The results also showed that 93.33% and 98.30% in PCOS patients had abnormal omentin1: Insulin ratio and omentin1: Resistin ratio respectively according to the cut off values ≤27.42 and ≤31.35. Moreover, 81.67% of PCOS patients had abnormal omentin1:IL-6 ratio according to the cut of value (≤66.09). CONCLUSION This is the first time the role of plasma omentin1 has been investigated with respect to its implication in PCOS. Usually, LH/FSH ratio and FAI (ratio of total testosterone to SHBG) are the important factors used for the diagnosis of PCOS in all previous literature, but none of them referred to the parameters discussed in this report. Also, the percentage of sensitivity and the difference between range of these parameters in PCOS patients and the controls may give a different perspective in trying to understand the etiology of PCOS. Therefore, these parameters may be used for future diagnosis of PCOS. This study also suggested that omentin/resistin ratio may play a crucial paracrine or endocrine role in modulating insulin sensitivity.
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Affiliation(s)
- Atheer Mahde
- Department of Acceptable Analysis, Health and Medical Technical College, Baghdad, Iraq
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van Tilburg JHO, Sandkuijl LA, Strengman E, Pearson PL, van Haeften TW, Wijmenga C. Variance-Component Analysis of Obesity in Type 2 Diabetes Confirms Loci on Chromosomes 1q and 11q. ACTA ACUST UNITED AC 2012; 11:1290-4. [PMID: 14627748 DOI: 10.1038/oby.2003.175] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
To study genetic loci influencing obesity in nuclear families with type 2 diabetes, we performed a genome-wide screen with 325 microsatellite markers that had an average spacing of 11 cM and a mean heterozygosity of approximately 75% covering all 22 autosomes. Genotype data were obtained from 562 individuals from 178 families from the Breda Study Cohort. These families were determined to have at least two members with type 2 diabetes. As a measure of obesity, the BMI of each diabetes patient was determined. The genotypes were analyzed using variance components (VCs) analysis implemented in GENEHUNTER 2 to determine quantitative trait loci influencing BMI. The VC analysis revealed two genomic regions showing VC logarithm of odds (LOD) scores > or =1.0 on chromosome 1 and chromosome 11. The regions of interest on both chromosomes were further investigated by fine-mapping with additional markers, resulting in a VC LOD score of 1.5 on chromosome 1q and a VC LOD of 2.4 on chromosome 11q. The locus on chromosome 1 has been implicated previously in diabetes. The locus on chromosome 11 has been implicated previously in diabetes and obesity. Our study to determine linkage for BMI confirms the presence of quantitative trait loci influencing obesity in subjects with type 2 diabetes on chromosomes 1q31-q42 and 11q14-q24.
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Affiliation(s)
- Jonathan H O van Tilburg
- Department of Biomedical Genetics, University Medical Center Utrecht, Stratenum 2.117, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
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Abstract
In recent decades, the prevalence of type 2 diabetes in China has increased significantly, underscoring the importance of investigating the etiological mechanisms, including genetic determinants, of the disease in Chinese populations. Numerous loci conferring susceptibility to type 2 diabetes (T2D) have been identified worldwide, with most having been identified in European populations. In terms of ethnic heterogeneity in pathogenesis as well as disease predisposition, it is imperative to explore the specific genetic architecture of T2D in Han Chinese. Replication studies of European-derived susceptibility loci have been performed, validating 11 of 32 loci in Chinese populations. Genetic investigations into heritable traits related to glucose metabolism are expected to provide new insights into the pathogenesis of T2D, and such studies have already inferred some new susceptibility loci. Other than replication studies of European-derived loci, efforts have been made to identify specific susceptibility loci in Chinese populations using methods such as genome-wide association studies. These efforts have identified additional new loci for the disease. Genetic studies can facilitate the prediction of risk for T2D and also promote individualized anti-diabetic treatment. Despite many advances in the field of risk prediction and pharmacogenetics, the pace of clinical application of these findings is rather slow. As a result, more studies into the practical utility of these findings remain necessary.
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Affiliation(s)
- Weihui Yu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University, Shanghai, China
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Chan DC, Ng TWK, Watts GF. Apolipoprotein A-II: evaluating its significance in dyslipidaemia, insulin resistance, and atherosclerosis. Ann Med 2012; 44:313-24. [PMID: 21501035 DOI: 10.3109/07853890.2011.573498] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Reduced HDL cholesterol, commonly found in subjects with obesity and type 2 diabetes, is associated with increased risk of cardiovascular disease (CVD). ApoA-II, a constituent apolipoprotein of certain HDL particles, plays an important role in the regulation of cholesterol efflux, HDL remodelling, and cholesteryl ester uptake via its interactions with lipid transfer proteins, lipases, and cellular HDL receptors. Recent studies have linked apoA-II directly with triglyceride and glucose metabolism. Most of the data are, however, derived from cellular systems and transgenic animal models. Direct evidence from human studies is scarce. Clinical studies demonstrate that apoA-II is a strong predictor of risk for CVD. There is no evidence, however, that selective therapeutic modification of apoA-II impacts on atherosclerosis and clinical outcomes. More research is required to investigate further the significance of apoA-II in clinical medicine.
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Affiliation(s)
- Dick C Chan
- Metabolic Research Centre, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
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Li J, Lu Z, Wang Q, Su Z, Bao Y, Shi W. Characterization of Bglu3, a mouse fasting glucose locus, and identification of Apcs as an underlying candidate gene. Physiol Genomics 2012; 44:345-51. [PMID: 22274563 DOI: 10.1152/physiolgenomics.00087.2011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Bglu3 is a quantitative trait locus for fasting glucose on distal chromosome 1 identified in an intercross between C57BL/6 (B6) and C3H/HeJ (C3H) apolipoprotein E-deficient (apoE(-/-)) mice. This locus was subsequently replicated in two separate mouse intercrosses. The objective of this study was to characterize Bglu3 through construction and analysis of a congenic strain and identify underlying candidate genes. Congenic mice were constructed by introgressing a genomic region harboring Bglu3 from C3H.apoE(-/-) into B6.apoE(-/-) mice. Mice were started with a Western diet at 6 wk of age and maintained on the diet for 12 wk. Gene expression in the liver was analyzed by microarrays. Congenic mice had significantly higher fasting glucose levels and developed more significant glucose intolerance compared with B6.apoE(-/-) mice on the Western diet. Microarray analysis revealed 336 genes to be differentially expressed in the liver of congenic mice. Further pathway analysis suggested a role for acute phase response signaling in regulating glucose intolerance. Apcs, encoding an acute phase response protein serum amyloid P (SAP), is located underneath the linkage peak of Bglu3. Multiple single nucleotide polymorphisms between B6 and C3H mice were detected within and surrounding Apcs. Apcs expression in the liver was significantly higher in congenic and C3H mice compared with B6 mice. The Western diet consumption led to a gradual rise in plasma SAP levels, which was accompanied by rising fasting glucose in both B6 and C3H apoE(-/-) mice. Expression of C3H Apcs in B6.apoE(-/-) mice aggravated glucose intolerance. Bglu3 is confirmed to be a locus affecting diabetes susceptibility, and Apcs is a probable candidate gene.
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Affiliation(s)
- Jing Li
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, USA
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Tanaka T, Kono T, Terasaki F, Yasui K, Soyama A, Otsuka K, Fujita S, Yamane K, Manabe M, Usui K, Kohda Y. Thiamine prevents obesity and obesity-associated metabolic disorders in OLETF rats. J Nutr Sci Vitaminol (Tokyo) 2011; 56:335-46. [PMID: 21422702 DOI: 10.3177/jnsv.56.335] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
We previously found that thiamine mitigates metabolic disorders in spontaneously hypertensive rats, harboring defects in glucose and fatty acid metabolism. Mutation of thiamine transporter gene SLC19A2 is linked to type 2 diabetes mellitus. The current study extends our hypothesis that thiamine intervention may impact metabolic abnormalities in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, exhibiting obesity and metabolic disorders similar to human metabolic syndrome. Male OLETF rats (4 wk old) were given free access to water containing either 0.2% or 0% of thiamine for 21 and 51 wk. At the end of treatment, blood parameters and cardiac functions were analyzed. After sacrifice, organs weights, histological findings, and hepatic pyruvate dehydrogenase (PDH) activity in the liver were evaluated. Thiamine intervention averted obesity and prevented metabolic disorders in OLETF rats which accompanied mitigation of reduced lipid oxidation and increased hepatic PDH activity. Histological evaluation revealed that thiamine alleviated adipocyte hypertrophy, steatosis in the liver, heart, and skeletal muscle, sinusoidal fibrosis with formation of basement membranes (called pseudocapillarization) which accompanied significantly reduced expression of laminin β1 and nidogen-1 mRNA, interstitial fibrosis in the heart and kidney, fatty degeneration in the pancreas, thickening of the basement membrane of the vasculature, and glomerulopathy and mononuclear cell infiltration in the kidney. Cardiac and renal functions were preserved in thiamine treatment. Thiamine has a potential to prevent obesity and metabolic disorders in OLETF rats.
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Affiliation(s)
- Takao Tanaka
- Laboratory of Pharmacotherapy, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan
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Edwards KL, Wan JY, Hutter CM, Fong PY, Santorico SA. Multivariate linkage scan for metabolic syndrome traits in families with type 2 diabetes. Obesity (Silver Spring) 2011; 19:1235-43. [PMID: 21183932 DOI: 10.1038/oby.2010.299] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The purpose of this study was to evaluate evidence for linkage to interrelated quantitative features of the metabolic syndrome (MetS). Data on eight quantitative MetS traits (body weight, waist circumference, systolic and diastolic blood pressure, high-density lipoprotein (HDL) cholesterol, triglycerides (TGs), and fasting glucose and insulin measurements) and a 10 cM genome scan were available for 78 white families (n = 532 subjects). These data were used to conduct multipoint, multivariate linkage analyses, including tests for coincident linkage and complete pleiotropy. The strongest evidence for linkage from the bivariate analyses was observed on chromosome 1 (1p22.2) (HDL-TG; univariate lod score equivalent (lod(eq) = 3.99)) with stronger results from the trivariate analysis at the same location (HDL-TG-Insulin; lod(eq) = 4.32). Seven additional susceptibility regions (lod(eq) scores >1.9) were observed (1p36, 1q23, 2q21.2, 8q23.3, 14q23.2, 14q32.11, and 20p11.21). The results from this study indicate that several correlated traits of the MetS are influenced by the same gene(s) that account for some of the clustering of the MetS features.
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Affiliation(s)
- Karen L Edwards
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.
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Hu C, Zhang R, Wang C, Ma X, Wang J, Bao Y, Xiang K, Jia W. Lack of association between genetic polymorphisms within DUSP12 - ATF6 locus and glucose metabolism related traits in a Chinese population. BMC MEDICAL GENETICS 2011; 12:3. [PMID: 21211013 PMCID: PMC3022799 DOI: 10.1186/1471-2350-12-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2010] [Accepted: 01/06/2011] [Indexed: 11/10/2022]
Abstract
Background Genome-wide linkage studies in multiple ethnic populations found chromosome 1q21-q25 was the strongest and most replicable linkage signal in the human chromosome. Studies in Pima Indian, Caucasians and African Americans identified several SNPs in DUSP12 and ATF6, located in chromosome 1q21-q23, were associated with type 2 diabetes. Methods We selected 19 single nucleotide polymorphisms (SNPs) that could tag 98% of the SNPs with minor allele frequencies over 0.1 within DUSP12-ATF6 region. These SNPs were genotyped in a total of 3,700 Chinese Han subjects comprising 1,892 type 2 diabetes patients and 1,808 controls with normal glucose regulation. Results None of the SNPs and haplotypes showed significant association to type 2 diabetes in our samples. No association between the SNPs and quantitative traits was observed either. Conclusions Our data suggests common SNPs within DUSP12-ATF6 locus may not play a major role in glucose metabolism in the Chinese.
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Affiliation(s)
- Cheng Hu
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China
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Jin QS, Kim SH, Piao SJ, Lim HA, Lee SY, Hong SB, Kim YS, Lee HJ, Nam M. R1467H Variants of Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) are Associated with Type 2 Diabetes Mellitus in Koreans. KOREAN DIABETES JOURNAL 2010; 34:368-73. [PMID: 21246010 PMCID: PMC3021113 DOI: 10.4093/kdj.2010.34.6.368] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2010] [Accepted: 09/28/2010] [Indexed: 01/22/2023]
Abstract
Background The human Rho guanine nucleotide exchange factor 11 (ARHGEF11) functions as an activator of Rho GTPases and is thought to influence insulin signaling. The R1467H variant of ARHGEF11 has been reported to be associated with susceptibility to type 2 diabetes mellitus (T2DM) in Western populations. Methods We investigated the effects of the R1467H variant on susceptibility to T2DM as well as related traits in a Korean population. We genotyped the R1467H (rs945508) of ARHGEF11 in 689 unrelated T2DM patients and 249 non-diabetic individuals and compared the clinical and biochemical characteristics according to different alleles. Results The H allele was significantly more frequent in T2DM cases than in controls (P = 0.037, 17.1% and 13.1%; respectively). H homozygocity was associated with a higher risk of T2DM compared to those with R/R or R/H genotype (odds ratio, 5.24; 95% confidence interval, 1.06 to 25.83; P = 0.042). The fasting plasma glucose, HbA1c, fasting insulin, HOMA2-IR and HOMA2-%β levels did not differ significantly between different genotypes. Conclusion Our study replicated associations of the ARHGEF11 polymorphism with increased risk of T2DM in a Korean population and thus supports previous data implicating a potential role of ARHGEF11 in the etiology of T2DM. Further studies revealing the underlying mechanism for this association are needed.
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Affiliation(s)
- Qing Song Jin
- Diabetes Clinical Research Center, Inha University Hospital, Incheon, Korea
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Corella D, Tai ES, Sorlí JV, Chew SK, Coltell O, Sotos-Prieto M, García-Rios A, Estruch R, Ordovas JM. Association between the APOA2 promoter polymorphism and body weight in Mediterranean and Asian populations: replication of a gene-saturated fat interaction. Int J Obes (Lond) 2010; 35:666-75. [PMID: 20975728 PMCID: PMC3030929 DOI: 10.1038/ijo.2010.187] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE The APOA2 gene has been associated with obesity and insulin resistance (IR) in animal and human studies with controversial results. We have reported an APOA2-saturated fat interaction determining body mass index (BMI) and obesity in American populations. This work aims to extend our findings to European and Asian populations. METHODS Cross-sectional study in 4602 subjects from two independent populations: a high-cardiovascular risk Mediterranean population (n = 907 men and women; aged 67 ± 6 years) and a multiethnic Asian population (n = 2506 Chinese, n = 605 Malays and n = 494 Asian Indians; aged 39 ± 12 years) participating in a Singapore National Health Survey. Anthropometric, clinical, biochemical, lifestyle and dietary variables were determined. Homeostasis model assessment of insulin resistance was used in Asians. We analyzed gene-diet interactions between the APOA2 -265T>C polymorphism and saturated fat intake (<or ≥ 22 g per day) on anthropometric measures and IR. RESULTS Frequency of CC (homozygous for the minor allele) subjects differed among populations (1-15%). We confirmed a recessive effect of the APOA2 polymorphism and replicated the APOA2-saturated fat interaction on body weight. In Mediterranean individuals, the CC genotype was associated with a 6.8% greater BMI in those consuming a high (P = 0.018), but not a low (P = 0.316) saturated fat diet. Likewise, the CC genotype was significantly associated with higher obesity prevalence in Chinese and Asian Indians only, with a high-saturated fat intake (P = 0.036). We also found a significant APOA2-saturated fat interaction in determining IR in Chinese and Asian Indians (P = 0.026). CONCLUSION The influence of the APOA2 -265T>C polymorphism on body-weight-related measures was modulated by saturated fat in Mediterranean and Asian populations.
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Affiliation(s)
- D Corella
- Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111-1524, USA
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Wegner L, Anthonsen S, Bork-Jensen J, Dalgaard L, Hansen T, Pedersen O, Poulsen P, Vaag A. LMNA rs4641 and the muscle lamin A and C isoforms in twins--metabolic implications and transcriptional regulation. J Clin Endocrinol Metab 2010; 95:3884-92. [PMID: 20501691 DOI: 10.1210/jc.2009-2675] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Lamins are essential for nuclear shape and function. Polymorphisms in LMNA may associate with fat and muscle development and aging. OBJECTIVE Our aim was to determine the influence of LMNA rs4641 on lean body mass (LBM) and fat mass (FM), in vivo metabolism, and expression of LMNA transcripts in human skeletal muscle. DESIGN We genotyped LMNA rs4641 in 196 Danish twins who were extensively phenotypically characterized. We measured mRNA levels of LMNA transcripts, lamin A and C, in basal and insulin-stimulated skeletal muscle biopsies. RESULTS The rs4641 T-allele was associated with increased weight and body mass index (P=0.02), including increased FM (P=0.03) and LBM (P=0.004). Impact of rs4641 on FM was seen primarily among elderly twins. The T-allele was associated with elevated fasting plasma insulin levels (P=0.01) and homeostasis model of insulin resistance (P=0.02) in young twins. T-allele carriers did not exhibit consistent changes of first phase insulin secretion, nor did they exhibit significant peripheral or hepatic insulin resistance, and rs4641 did not influence muscle lamin A or C mRNA levels. The lamin A-to-C mRNA ratio was increased with acute insulin stimulation (P<0.0005), and the lamin A and C mRNA levels were diminished in young compared to elderly twins (P<0.001). CONCLUSIONS The LMNA rs4641 T-allele is associated with increased LBM and FM with more fat relative to muscle in elderly twins, which may impact risk of type 2 diabetes. Increased mRNA levels of lamins with age may counteract muscle wasting, and influence of insulin on lamin A-to-C ratio suggests a role in cytoskeletal muscle protein regulation.
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Affiliation(s)
- L Wegner
- Hagedorn Research Institute, Niels Steensens Vej 1, DK-2820 Gentofte, Denmark.
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Chu AY, Coresh J, Arking DE, Pankow JS, Tomaselli GF, Chakravarti A, Post WS, Spooner PH, Boerwinkle E, Kao WHL. NOS1AP variant associated with incidence of type 2 diabetes in calcium channel blocker users in the Atherosclerosis Risk in Communities (ARIC) study. Diabetologia 2010; 53:510-6. [PMID: 19943157 PMCID: PMC3039128 DOI: 10.1007/s00125-009-1608-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2009] [Accepted: 10/26/2009] [Indexed: 01/04/2023]
Abstract
AIMS/HYPOTHESIS To validate the reported association between rs10494366 in NOS1AP (the gene encoding nitric oxide synthase-1 adaptor protein) and the incidence of type 2 diabetes in calcium channel blocker (CCB) users and to identify additional NOS1AP variants associated with type 2 diabetes risk. METHODS Data from 9 years of follow-up in 9,221 middle-aged white and 2,724 African-American adults free of diabetes at baseline from the Atherosclerosis Risk in Communities study were analysed. Nineteen NOS1AP variants were examined for associations with incident diabetes and fasting glucose levels stratified by baseline CCB use. RESULTS Prevalence of CCB use at baseline was 2.7% (n = 247) in whites and 2.3% (n = 72) in African-Americans. Among white CCB users, the G allele of rs10494366 was associated with lower diabetes incidence (HR 0.57, 95% CI 0.35-0.92, p = 0.016). The association was marginally significant after adjusting for age, sex, obesity, smoking, alcohol use, physical activity, hypertension, heart rate and electrocardiographic QT interval (HR 0.63, 95% CI 0.38-1.04, p = 0.052). rs10494366 was associated with lower average fasting glucose during follow-up (p = 0.037). No other variants were associated with diabetes risk in CCB users after multiple-testing correction. No associations were observed between any NOS1AP variant and diabetes development in non-CCB users. NOS1AP variants were not associated with diabetes risk in either African-American CCB users or non-CCB users. CONCLUSIONS/INTERPRETATION We have independently replicated the association between rs10494366 in NOS1AP and incident diabetes among white CCB users. Further exploration of NOS1AP variants and type 2 diabetes and functional studies of NOS1AP in type 2 diabetes pathology is warranted.
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Affiliation(s)
- A Y Chu
- Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, USA.
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Tsai FJ, Yang CF, Chen CC, Chuang LM, Lu CH, Chang CT, Wang TY, Chen RH, Shiu CF, Liu YM, Chang CC, Chen P, Chen CH, Fann CSJ, Chen YT, Wu JY. A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 2010; 6:e1000847. [PMID: 20174558 PMCID: PMC2824763 DOI: 10.1371/journal.pgen.1000847] [Citation(s) in RCA: 263] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Accepted: 01/18/2010] [Indexed: 12/16/2022] Open
Abstract
To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54×10−10; odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36–1.82), and serine racemase (SRR) (P = 3.06×10−9; OR = 1.28; 95% CI = 1.18–1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65×10−10; OR = 1.29, 95% CI = 1.19–1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations. Type 2 diabetes (T2D) is a complex disease that involves many genes and environmental factors. Genome-wide and candidate-gene association studies have thus far identified at least 19 regions containing genes that may confer a risk for T2D. However, most of these studies were conducted with patients of European descent. We studied Chinese patients with T2D and identified two genes, PTPRD and SRR, that were not previously known to be involved in diabetes and are involved in biological pathways different from those implicated in T2D by previous association reports. PTPRD is a protein tyrosine phosphatase and may affect insulin signaling on its target cells. SRR encodes a serine racemase that synthesizes D-serine from L-serine. Both D-serine (coagonist) and the neurotransmitter glutamate bind to NMDA receptors and trigger excitatory neurotransmission in the brain. Glutamate signaling also regulates insulin and glucagon secretion in pancreatic islets. Thus, SRR and D-serine, in addition to regulating insulin and glucagon secretion, may play a role in the etiology of T2D. Our study suggests that, in different patient populations, different genes may confer risks for diabetes. Our findings may lead to a better understanding of the molecular pathogenesis of T2D.
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Affiliation(s)
- Fuu-Jen Tsai
- School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Medical Genetics, Pediatrics and Medical Research, China Medical University Hospital, Taichung, Taiwan
- Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan
| | - Chi-Fan Yang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- National Genotyping Center, Academia Sinica, Taipei, Taiwan
| | - Ching-Chu Chen
- Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Lee-Ming Chuang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chieh-Hsiang Lu
- Department of Internal Medicine, Endocrinology and Metabolism, Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Chwen-Tzuei Chang
- Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Tzu-Yuan Wang
- Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Rong-Hsing Chen
- Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Chiung-Fang Shiu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yi-Min Liu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chih-Chun Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Pei Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chien-Hsiun Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- National Genotyping Center, Academia Sinica, Taipei, Taiwan
| | - Cathy S. J. Fann
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yuan-Tsong Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- National Genotyping Center, Academia Sinica, Taipei, Taiwan
- Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States of America
- * E-mail: (Y-TC); (J-YW)
| | - Jer-Yuarn Wu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- National Genotyping Center, Academia Sinica, Taipei, Taiwan
- Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan
- * E-mail: (Y-TC); (J-YW)
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Hu C, Wang C, Zhang R, Ng MC, Bao Y, Wang C, So WY, Ma RC, Ma X, Chan JC, Xiang K, Jia W. Association of genetic variants of NOS1AP with type 2 diabetes in a Chinese population. Diabetologia 2010; 53:290-8. [PMID: 19937226 DOI: 10.1007/s00125-009-1594-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2009] [Accepted: 10/20/2009] [Indexed: 10/20/2022]
Abstract
AIMS/HYPOTHESIS Chromosome 1q21-q24 has been shown to be linked to type 2 diabetes. The International Type 2 Diabetes 1q Consortium showed that one of the nominal associations was located in the NOS1AP gene. Although this association was not replicated in additional samples of European descent, it remains unknown whether NOS1AP plays a role in Chinese individuals. METHODS In stage 1 analyses, 79 single nucleotide polymorphisms (SNPs) of the NOS1AP gene were successfully genotyped in a group of Shanghai Chinese individuals, comprising 1,691 type 2 diabetes patients and 1,720 control participants. In stage 2 analyses, the SNP showing the strongest association was genotyped in additional Chinese individuals, including 1,663 type 2 diabetes patients and 1,408 control participants. RESULTS In stage 1 analyses, 20 SNPs were nominally associated with type 2 diabetes (p < 0.05), with SNP rs12742393 showing the strongest association (OR 1.24 [95% CI 1.11-1.38]; p = 0.0002, empirical p = 0.019). Haplotype analysis also confirmed the association between rs12742393 and type 2 diabetes. In stage 2 analyses, the difference in allele frequency distribution of rs12742393 did not reach statistical significance (p = 0.254). However, the meta-analysis showed a significant association between rs12742393 and type 2 diabetes with an OR of 1.17 (95% CI 1.07-1.26; p = 0.0005). CONCLUSIONS/INTERPRETATION Our data suggest that NOS1AP variants may not play a dominant role in susceptibility to type 2 diabetes, but a minor effect cannot be excluded.
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Affiliation(s)
- C Hu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, People's Republic of China
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Malhotra A, Igo RP, Thameem F, Kao WL, Abboud HE, Adler SG, Arar NH, Bowden DW, Duggirala R, Freedman BI, Goddard KA, Ipp E, Iyengar SK, Kimmel PL, Knowler WC, Kohn O, Leehey D, Meoni LA, Nelson RG, Nicholas SB, Parekh RS, Rich SS, Chen YDI, Saad MF, Scavini M, Schelling JR, Sedor JR, Shah VO, Taylor KD, Thornley-Brown D, Zager PG, Horvath A, Hanson RL. Genome-wide linkage scans for type 2 diabetes mellitus in four ethnically diverse populations-significant evidence for linkage on chromosome 4q in African Americans: the Family Investigation of Nephropathy and Diabetes Research Group. Diabetes Metab Res Rev 2009; 25:740-7. [PMID: 19795399 PMCID: PMC2783577 DOI: 10.1002/dmrr.1031] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Previous studies have shown that in addition to environmental influences, type 2 diabetes mellitus (T2DM) has a strong genetic component. The goal of the current study is to identify regions of linkage for T2DM in ethnically diverse populations. METHODS Phenotypic and genotypic data were obtained from African American (AA; total number of individuals [N] = 1004), American Indian (AI; N = 883), European American (EA; N = 537), and Mexican American (MA; N = 1634) individuals from the Family Investigation of Nephropathy and Diabetes. Non-parametric linkage analysis, using an average of 4404 SNPs, was performed in relative pairs affected with T2DM in each ethnic group. In addition, family-based tests were performed to detect association with T2DM. RESULTS Statistically significant evidence for linkage was observed on chromosome 4q21.1 (LOD = 3.13; genome-wide p = 0.04) in AA. In addition, a total of 11 regions showed suggestive evidence for linkage (estimated at LOD > 1.71), with the highest LOD scores on chromosomes 12q21.31 (LOD = 2.02) and 22q12.3 (LOD = 2.38) in AA, 2p11.1 (LOD = 2.23) in AI, 6p12.3 (LOD = 2.77) in EA, and 13q21.1 (LOD = . 2.24) in MA. While no region overlapped across all ethnic groups, at least five loci showing LOD > 1.71 have been identified in previously published studies. CONCLUSIONS The results from this study provide evidence for the presence of genes affecting T2DM on chromosomes 4q, 12q, and 22q in AA; 6p in EA; 2p in AI; and 13q in MA. The strong evidence for linkage on chromosome 4q in AA provides important information given the paucity of diabetes genetic studies in this population.
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Affiliation(s)
- Alka Malhotra
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
| | | | - Farook Thameem
- University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | | | - Hanna E. Abboud
- University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Sharon G. Adler
- Harbor-University of California Los Angeles Medical Center, Torrance, California
| | - Nedal H. Arar
- University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | | | | | | | | | - Eli Ipp
- Harbor-University of California Los Angeles Medical Center, Torrance, California
| | | | - Paul L. Kimmel
- National Institute of Diabetes and Digestive and Kidney Diseases Program Office, Bethesda, Maryland
| | - William C. Knowler
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
| | - Orly Kohn
- University of Chicago, Chicago, Illinois
| | | | | | - Robert G. Nelson
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
| | | | | | | | - Yii-Der I. Chen
- University of California Los Angeles, Los Angeles, California
| | | | - Marina Scavini
- University of New Mexico, Albuquerque, New Mexico
- San Raffaele Scientific Institute, Milan (Italy)
| | | | | | | | - Kent D. Taylor
- University of California Los Angeles, Los Angeles, California
| | | | | | | | - Robert L. Hanson
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
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Lillioja S, Wilton A. Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies. Diabetologia 2009; 52:1061-74. [PMID: 19296077 DOI: 10.1007/s00125-009-1324-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2008] [Accepted: 02/13/2009] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies. METHODS We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic 'hot spots'. RESULTS Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result. CONCLUSIONS/INTERPRETATION Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.
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Affiliation(s)
- S Lillioja
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
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Duesing K, Charpentier G, Marre M, Tichet J, Hercberg S, Balkau B, Froguel P, Gibson F. Evaluating the association of common APOA2 variants with type 2 diabetes. BMC MEDICAL GENETICS 2009; 10:13. [PMID: 19216768 PMCID: PMC2650681 DOI: 10.1186/1471-2350-10-13] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/10/2008] [Accepted: 02/13/2009] [Indexed: 01/14/2023]
Abstract
BACKGROUND APOA2 is a positional and biological candidate gene for type 2 diabetes at the chromosome 1q21-q24 susceptibility locus. The aim of this study was to examine if HapMap phase II tag SNPs in APOA2 are associated with type 2 diabetes and quantitative traits in French Caucasian subjects. METHODS We genotyped the three HapMap phase II tagging SNPs (rs6413453, rs5085 and rs5082) required to capture the common variation spanning the APOA2 locus in our type 2 diabetes case-control cohort comprising 3,093 French Caucasian subjects. The association between these variants and quantitative traits was also examined in the normoglycaemic adults of the control cohort. In addition, meta-analysis of publicly available whole genome association data was performed. RESULTS None of the APOA2 tag SNPs were associated with type 2 diabetes in the French Caucasian case-control cohort (rs6413453, P = 0.619; rs5085, P = 0.245; rs5082, P = 0.591). However, rs5082 was marginally associated with total cholesterol levels (P = 0.026) and waist-to-hip ratio (P = 0.029). The meta-analysis of data from 12,387 subjects confirmed our finding that common variation at the APOA2 locus is not associated with type 2 diabetes. CONCLUSION The available data does not support a role for common variants in APOA2 on type 2 diabetes susceptibility or related quantitative traits in Northern Europeans.
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Affiliation(s)
- Konsta Duesing
- Genomic Medicine, Imperial College London, Hammersmith Campus, Du Cane Rd, London, W12 0NN, UK
| | | | - Michel Marre
- Endocrinology-Diabetology, Bichat Hospital, Paris, France
- INSERM U695, Paris, France
| | - Jean Tichet
- Institut Régional Pour la Santé, Tours, France
| | - Serge Hercberg
- Scientific and Technical Institute of Nutrition and Food (ISTNA-CNAM), Institut National de la Santé et de la Recherche Médicale (INSERM) U557, INRA U1125, Paris, France
| | | | - Philippe Froguel
- Genomic Medicine, Imperial College London, Hammersmith Campus, Du Cane Rd, London, W12 0NN, UK
- CNRS 8090, Institut de Biologie de Lille, Institut Pasteur, CHU Lille, France
| | - Fernando Gibson
- Genomic Medicine, Imperial College London, Hammersmith Campus, Du Cane Rd, London, W12 0NN, UK
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Ban JY, Kang SA, Jung KH, Kim HJ, Uhm YK, Kim SK, Yim SV, Choe BK, Hong SJ, Seong YH, Koh IS, Chung JH. The association of PBX1 polymorphisms with overweight/obesity and metabolic alterations in the Korean population. Nutr Res Pract 2008; 2:289-94. [PMID: 20016732 PMCID: PMC2788201 DOI: 10.4162/nrp.2008.2.4.289] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2008] [Revised: 10/22/2008] [Accepted: 11/12/2008] [Indexed: 12/12/2022] Open
Abstract
Pre-B-cell leukemia transcription factor 1 (PBX1), which is located on chromosome 1q23, was recently reported to be associated with type 2 diabetes mellitus. We examined whether single nucleotide polymorphisms (SNPs) of the PBX1 gene are associated with overweight/obesity in a Korean population. We genotyped 66 SNPs in the PBX1 gene and investigated their association with clinical phenotypes found in 214 overweight/obese subjects and 160 control subjects using the Affymetrix Targeted Genotyping chip array. Seven SNPs (g.+75186C>T, g.+78350C>A, g.+80646C>T, g.+138004C>T, g.+185219G>A, g.+191272A>C, and g.+265317T>A) were associated with the risk of obesity in three models (codominant, dominant, and recessive) (P=0.007-0.05). Haplotype 1 (CAC) and 3 (TAC) of block 3 and haplotype 2 (GGAAT) of block 10 were also strongly associated with the risk of obesity. In the control group, subjects that had homozygote for the major allele for both g.+185219G>A and g.+191272A>C showed lower high density lipoprotein-cholesterol (HDL-C) level compared to those possessing the minor allele, suggesting that the association between the homozygote for the major allele for both g.+185219G>A and g.+191272A>C and HDL-C is attributable to the increased risk of obesity. This study suggests that the PBX1 gene is a possible risk factor in overweight/obese patients.
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Affiliation(s)
- Ju Yeon Ban
- Brain Korea 21 Project Center, Kyung Hee University, Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Korea
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Andreasen CH, Mogensen MS, Borch-Johnsen K, Sandbaek A, Lauritzen T, Almind K, Hansen L, Jørgensen T, Pedersen O, Hansen T. Lack of association between PKLR rs3020781 and NOS1AP rs7538490 and type 2 diabetes, overweight, obesity and related metabolic phenotypes in a Danish large-scale study: case-control studies and analyses of quantitative traits. BMC MEDICAL GENETICS 2008; 9:118. [PMID: 19111066 PMCID: PMC2654670 DOI: 10.1186/1471-2350-9-118] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/24/2008] [Accepted: 12/26/2008] [Indexed: 12/21/2022]
Abstract
Background Several studies in multiple ethnicities have reported linkage to type 2 diabetes on chromosome 1q21-25. Both PKLR encoding the liver pyruvate kinase and NOS1AP encoding the nitric oxide synthase 1 (neuronal) adaptor protein (CAPON) are positioned within this chromosomal region and are thus positional candidates for the observed linkage peak. The C-allele of PKLR rs3020781 and the T-allele of NOS1AP rs7538490 are reported to strongly associate with type 2 diabetes in various European-descent populations comprising a total of 2,198 individuals with a combined odds ratio (OR) of 1.33 [1.16–1.54] and 1.53 [1.28–1.81], respectively. Our aim was to validate these findings by investigating the impact of the two variants on type 2 diabetes and related quantitative metabolic phenotypes in a large study sample of Danes. Further, we intended to expand the analyses by examining the effect of the variants in relation to overweight and obesity. Methods PKLR rs3020781 and NOS1AP rs7538490 were genotyped, using TaqMan allelic discrimination, in a combined study sample comprising a total of 16,801 and 16,913 individuals, respectively. The participants were ascertained from four different study groups; the population-based Inter99 cohort (nPKLR = 5,962, nNOS1AP = 6,008), a type 2 diabetic patient group (nPKLR = 1,873, nNOS1AP = 1,874) from Steno Diabetes Center, a population-based study sample (nPKLR = 599, nNOS1AP = 596) from Steno Diabetes Center and the ADDITION Denmark screening study cohort (nPKLR = 8,367, nNOS1AP = 8,435). Results In case-control studies we evaluated the potential association between rs3020781 and rs7538490 and type 2 diabetes and obesity. No significant associations were observed for type 2 diabetes (rs3020781: pAF = 0.49, OR = 1.02 [0.96–1.10]; rs7538490: pAF = 0.84, OR = 0.99 [0.93–1.06]). Neither did we show association with overweight or obesity. Additionally, the PKLR and the NOS1AP genotypes were demonstrated not to have a major influence on diabetes-related quantitative metabolic phenotypes. Conclusion We failed to provide evidence of an association between PKLR rs3020781 and NOS1AP rs7538490 and type 2 diabetes, overweight, obesity or related quantitative metabolic phenotypes in large-scale studies of Danes.
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Hellgren G, Andersson B, Nierop AF, Dahlgren J, Hochberg Z, Albertsson-Wikland K. A proteomic approach identified growth hormone-dependent nutrition markers in children with idiopathic short stature. Proteome Sci 2008; 6:35. [PMID: 19077222 PMCID: PMC2621149 DOI: 10.1186/1477-5956-6-35] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2008] [Accepted: 12/11/2008] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The broad range in growth observed in short prepubertal children receiving the same growth hormone (GH) dose is due to individual variation in GH responsiveness. This study used a pharmaco-proteomic approach in order to identify novel biomarkers that discriminate between short non-GH-deficient (GHD) children who show a good or poor growth response to GH treatment.A group of 32 prepubertal children with idiopathic short stature (ISS) were included in the study. Children were classified on the basis of their first year growth velocity as either good (high responders, n = 13; range, 0.9-1.3 standard deviation score (SDS) or poor (low responders, n = 19; range, 0.3-0.5 SDS) responders to GH treatment (33 microg/kg daily).Serum protein expression profiles before, and after 1 year of GH treatment, were analyzed on a weak cationic exchange array (CM10) using surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS). RESULTS Changes in the intensity of two protein peaks (13.788 kDa and 17.139 kD) during the study period allowed the correct classification of 82% of children as high and low responders, respectively. The 13.788 kD peak, transthyretin, decreased in the high-responder group and increased in the low-responder group during 1 year of GH treatment, whereas the 17.139 kDa peak, apolipoprotein A-II (Apo A-II) decreased in the high-responder group and remained unchanged in the low-responder group. These peaks were identified by the consistency of peak pattern in the spectra, serum depletion experiments using specific antibodies and mass spectrometry. CONCLUSION Our results suggest that transthyretin and apolipoprotein A-II may have a role in GH sensitivity and could be used as markers to predict which short prepubertal children with ISS will show a good or poor response to GH treatment.
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Affiliation(s)
- Gunnel Hellgren
- Göteborg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, The Queen Silvia Children's Hospital, SE-416 85 Göteborg, Sweden
| | - Björn Andersson
- Göteborg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, The Queen Silvia Children's Hospital, SE-416 85 Göteborg, Sweden
| | | | - Jovanna Dahlgren
- Göteborg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, The Queen Silvia Children's Hospital, SE-416 85 Göteborg, Sweden
| | - Ze'ev Hochberg
- Göteborg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, The Queen Silvia Children's Hospital, SE-416 85 Göteborg, Sweden.,Meyer Children's Hospital, Rambam Medical Center, and Technion - Israel Institute of Technology, Haifa, Israel
| | - Kerstin Albertsson-Wikland
- Göteborg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, The Queen Silvia Children's Hospital, SE-416 85 Göteborg, Sweden
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