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Ozkan H, Yildiz M, Ustundag A, Kara I, Guldiken B, Sut N, Sipahi T. IRS gene polymorphisms in Turkish patients with late-onset Alzheimer's disease. Mol Biol Rep 2025; 52:235. [PMID: 39954137 DOI: 10.1007/s11033-025-10352-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/10/2025] [Indexed: 02/17/2025]
Abstract
BACKGROUND Factors that cause changes in insulin signaling in the brain are thought to affect the synaptic plasticity and accelerate the process of brain aging and neurodegeneration. Insulin receptor substrate (IRS) molecules are key mediators in insulin signaling. The aim of the current study is to determine whether there is an association between IRS gene polymorphisms, which are critical for insulin signaling, and the late-onset Alzheimer's disease in Turkish patients. METHODS AND RESULTS Demographic and clinical characteristics of 115 patients with late-onset Alzheimer's disease (age of onset ≥ 65 years) and 107 age-matched control subjects were obtained. DNAs were isolated from patient and control groups, IRS-1 and IRS-2 gene polymorphisms were investigated and genotyped according to the PCR-RFLP method. No statistically significant difference was observed in the genotypes for IRS-1 Gly972Arg (rs1801278) (p = 0.499) and IRS-2 Gly1057Asp (rs1805097) polymorphism between late-onset Alzheimer's disease patients and controls (p = 0.658). However, when the compliance of IRS-2 polymorphism with Hardy- Weinberg distribution was tested, in the case-control comparison, G allele frequency of IRS-2 polymorphisms was significantly higher in the patient population than in the control group in the Turkish population of the Thrace region. CONCLUSIONS Despite the potential role of insulin resistance and hyperinsulinemia in the development of Alzheimer's disease, we did not find any association between polymorphism of the IRS-1 and IRS-2 genes and late-onset Alzheimer's disease. However, compared to the healthy subjects, Gly/Gly genotypes and the G allele in the IRS-2 were significantly more frequent in patients with late-onset Alzheimer's disease.
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Affiliation(s)
- Hulya Ozkan
- Medical Faculty, Department of Neurology, Trakya University, Edirne, 22030, Turkey
| | - Mustafa Yildiz
- Medical Faculty, Department of Biophysics, Trakya University, Edirne, 22030, Turkey.
| | - Ayten Ustundag
- Medical Faculty, Department of Internal Medicine, Trakya University, Edirne, 22030, Turkey
| | - Ismail Kara
- Medical Faculty, Department of Biophysics, Trakya University, Edirne, 22030, Turkey
| | - Baburhan Guldiken
- Medical Faculty, Department of Neurology, Trakya University, Edirne, 22030, Turkey
| | - Necdet Sut
- Medical Faculty, Department of Biostatistics and Informatics, Trakya University, Edirne, 22030, Turkey
| | - Tammam Sipahi
- Medical Faculty, Department of Biophysics, Trakya University, Edirne, 22030, Turkey
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Shen L, Liu J, Zhao X, Wang A, Hu X. Association between insulin receptor substrate 1 gene polymorphism rs1801278 and gestational diabetes mellitus: an updated meta- analysis. Diabetol Metab Syndr 2024; 16:62. [PMID: 38448958 PMCID: PMC10919047 DOI: 10.1186/s13098-024-01289-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/12/2024] [Indexed: 03/08/2024] Open
Abstract
OBJECTIVES we performed this meta- analysis to investigate the impact of insulin receptor substrate 1 (IRS1) gene rs1801278 on susceptibility to gestational diabetes mellitus (GDM). METHODS The pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated, and p value is used to determine statistical significance. Sensitivity analysis was performed under three models (dominant, recessive and allele model), and the pooled ORs and 95%CI were calculated. Funnel plots and Begger's regression test were employed to test the publication bias. RESULTS The meta-analysis included 4777 participants (2116 cases and 2661 controls). The IRS1 rs1801278 (C/T) were not significant associated with GDM risk under the dominant and allele models, OR (95%CI) = 1.22 (0.88-1.70) and 1.24 (0.91-1.68), respectively (both p values were more than 0.05). But we also found the IRS1 rs1801278 (C/T) were significant associated with GDM risk under the recessive model, OR (95%CI) = 0.37 (0.16-0.86), p = 0.030. Our results showed that none of the studies affected the quality of the pooled OR. We also found no significant publication bias existed in this meta study for three genetic models, PTT + CT vs. CC = 0.445; PCC+CT vs. TT= 0.095; PC vs. T = 0.697. CONCLUSION this meta-analysis indicated that IRS1 rs1801278 (C/T) was associated with the GDM risk under the recessive model but was not associated with the GDM risk under dominant and allele models.
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Affiliation(s)
- Lili Shen
- Department of Obstetrics and Gynecology, Heping Hospital Affiliated to Changzhi Medical College, 110 South Yan'an Road, 046000, Changzhi, Shanxi Province, China.
| | - Junli Liu
- Department of Obstetrics and Gynecology, Heping Hospital Affiliated to Changzhi Medical College, 110 South Yan'an Road, 046000, Changzhi, Shanxi Province, China
| | - Xiaolei Zhao
- Department of Obstetrics and Gynecology, Heping Hospital Affiliated to Changzhi Medical College, 110 South Yan'an Road, 046000, Changzhi, Shanxi Province, China
| | - Aiqin Wang
- Department of Obstetrics and Gynecology, Heping Hospital Affiliated to Changzhi Medical College, 110 South Yan'an Road, 046000, Changzhi, Shanxi Province, China
| | - Xiaomei Hu
- Department of Obstetrics and Gynecology, Heping Hospital Affiliated to Changzhi Medical College, 110 South Yan'an Road, 046000, Changzhi, Shanxi Province, China
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Rohini HN, Punita P, Santhekadur PK, Ravishankar MV. Gestational Diabetes Mellitus - The Modern Indian Perspective. Indian J Endocrinol Metab 2023; 27:387-393. [PMID: 38107727 PMCID: PMC10723610 DOI: 10.4103/ijem.ijem_147_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/08/2023] [Accepted: 04/22/2023] [Indexed: 12/19/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is a serious and most frequent health complication during pregnancy which is associated with a significant increase in the risk of maternal and neonatal outcomes. GDM is usually the result of β-cell dysfunction along with chronic insulin resistance during pregnancy. Seshiah et al. pioneer work led to the adoption of Diabetes in Pregnancy Study Group in India criteria as the norm to diagnose GDM, especially in the community setting. In 2014, the Maternal Health Division of the Ministry of Health and Family Welfare, Government of India, updated guidelines and stressed upon the proper use of guidelines such as using a glucometer for self-monitoring and the use of oral hypoglycaemic agents. The 2018 Government of India guidelines stress the importance of counselling about lifestyle modifications, weight control, exercise, and family planning.
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Affiliation(s)
- H N Rohini
- Department of Physiology, Meeankshi Medical College and Research Institute, Affiliated to Meenakshi Academy of Higher Education and Research, Mysore, India
| | - Pushpanathan Punita
- Department of Physiology, Meeankshi Medical College and Research Institute, Affiliated to Meenakshi Academy of Higher Education and Research, Mysore, India
| | - Prasanna Kumar Santhekadur
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, Mysore, India
| | - MV Ravishankar
- Department of Anatomy, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
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Luo Q, Ling Z, Huang X, Zuo Y. Association of IRS-1 and IRS-2 polymorphisms with predisposition to type-2 diabetes (T2D): a meta-analysis and trial sequential analysis. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2023; 42:837-851. [PMID: 37173295 DOI: 10.1080/15257770.2023.2211122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 04/24/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023]
Abstract
Background: Insulin Receptor Substrate (IRS) molecules play a major role in insulin signalling, and single nucleotide polymorphisms in the IRS-1 (rs1801278) and IRS-2 (rs1805097) gene has been associated with the predisposition to the development of type-2 diabetes (T2D) in some population. However, the observations remain contradictory. Discrepancies in the results have been attributed to several factors, and consideration of a smaller sample size is one of them. To reach a valid conclusion, we performed a meta-analysis of the genetic association between IRS-1 (rs1801278) and IRS-2 (rs1805097) polymorphism with a predisposition to T2D. Materials and Methods: The literature search was performed in different databases such as PubMed, Science Direct, and Scopus. All relevant articles were screened and based in inclusion and exclusion criteria eligible reports were identified. Baseline characteristics, genotype and allele frequencies were extracted from the eligible reports. The meta-analysis was performed by comprehensive meta-analysis software v3.3.070 and odds ratios, 95% confidence interval and probability values were calculated to find out association of IRS-1 and IRS-2 polymorphisms with rhinitis. Results: A total of seven studies comprising 1287 cases and 1638 control were considered for the present meta-analysis for the association of IRS-1 (rs1801278) polymorphism with T2D, and no significant association was observed. For IRS-2 (rs1805097) polymorphism, data from eight cohorts (cases: 1824, controls: 1786) were considered. The heterozygous genetic comparison models revealed a significant protective association against T2D predisposition (p = 0.017, OR = 0.841, 95% CI = 0.729 to 0.970). The trial sequential analysis revealed the requirement of additional case-control studies to draw a definitive conclusion for IRS-1 polymorphism. Conclusions: IRS-2 rs1805097 heterozygotes are protected from T2D development. However, IRS-1 (rs1801278) is not associated with a subject's proclivity for T2D.
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Affiliation(s)
- Qiaoyan Luo
- Department of Endocrinology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, China
| | - Zhifa Ling
- Department of Blood Transfusion, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, China
| | - Xiaojia Huang
- Department of Endocrinology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, China
| | - Ying Zuo
- Department of Endocrinology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, China
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Wei W, He Y, Wang X, Tan G, Zhou F, Zheng G, Tian D, Ma X, Yu H. Gestational Diabetes Mellitus: The Genetic Susceptibility Behind the Disease. Horm Metab Res 2021; 53:489-498. [PMID: 34384105 DOI: 10.1055/a-1546-1652] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Gestational diabetes mellitus (GDM), a type of pregnancy-specific glucose intolerance or hyperglycemia, is one of the most common metabolic disorders in pregnant women with 16.9% of the global prevalence of gestational hyperglycemia. Not only are women with GDM likely to develop T2DM, but their children are also at risk for birth complications or metabolic disease in adulthood. Therefore, identifying the potential risk factors for GDM is very important in the prevention and treatment of GDM. Previous studies have shown that genetic predisposition is an essential component in the occurrence of GDM. In this narrative review, we describe the role of polymorphisms in different functional genes associated with increased risk for GDM, and available evidence on genetic factors in the risk of GDM is summarized and discussed.
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Affiliation(s)
- Wenwen Wei
- School of Basic Medical Science, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Guizhou, Zunyi, China
| | - Yuejuan He
- School of Basic Medical Science, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Guizhou, Zunyi, China
| | - Xin Wang
- School of Basic Medical Science, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Guizhou, Zunyi, China
| | - Guiqin Tan
- School of Basic Medical Science, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Guizhou, Zunyi, China
| | - Fangyu Zhou
- School of Basic Medical Science, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Guizhou, Zunyi, China
| | - Guangbing Zheng
- School of Basic Medical Science, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Guizhou, Zunyi, China
| | - Dan Tian
- School of Basic Medical Science, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Guizhou, Zunyi, China
| | - Xiaomin Ma
- School of Basic Medical Science, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Guizhou, Zunyi, China
| | - Hongsong Yu
- School of Basic Medical Science, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Guizhou, Zunyi, China
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Wu L, Fang C, Zhang J, Ye Y, Zhao H. The Association between Maternal/Fetal Insulin Receptor Substrate 1 Gene Polymorphism rs1801278 and Gestational Diabetes Mellitus in a Chinese Population. Gynecol Obstet Invest 2021; 86:177-184. [PMID: 33895751 DOI: 10.1159/000514971] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 01/04/2021] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Insulin receptor substrate 1 (IRS1) is a crucial factor in the insulin signaling pathway. IRS1 gene polymorphism rs1801278 in mothers has been reported to be associated with gestational diabetes mellitus (GDM). However, it is not clear whether IRS1 gene polymorphism rs1801278 in fetuses is associated with their mothers' GDM morbidity. The purpose of this study is to analyze the association between maternal, fetal, or maternal/fetal IRS1 gene polymorphism rs1801278 and GDM risk. DESIGN The study was a single-center, prospective cohort study. In total, 213 pairs of GDM mothers/fetuses and 191 pairs of control mothers/fetuses were included in this study. They were recruited after they underwent oral glucose tolerance test during 24-28 weeks of gestation and followed up until delivery. All participants received the conventional interventions (diet and exercise), and no special therapy except routine treatment. METHODS A total of 213 pairs of GDM mothers/fetuses and 191 pairs of normal blood glucose pregnant mothers/fetuses were ge-notyped using PCR and DNA sequencing from January 2015 to September 2016. Maternal/fetal IRS1 gene polymorphism rs1801278 was analyzed and compared between 2 groups. RESULTS There were no significant differences in the frequency of individual mothers' or fetuses' IRS1 rs1801278 polymorphisms between 2 groups; if both the mothers and fetuses carried A allele, significantly lower GDM morbidity was observed in the mothers. LIMITATIONS The sample size was relatively small as a single-center study. CONCLUSIONS Our study suggested that maternal/fetal rs1801278 polymorphism of IRS1 is a modulating factor in GDM; both mothers/fetuses carrying the A allele of rs1801278 may protect the mothers against the development of GDM.
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Affiliation(s)
- Lingling Wu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Changping Fang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jun Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanchou Ye
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Haiyan Zhao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Yahaya TO, Salisu T, Abdulrahman YB, Umar AK. Update on the genetic and epigenetic etiology of gestational diabetes mellitus: a review. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2020; 21:13. [DOI: 10.1186/s43042-020-00054-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 02/11/2020] [Indexed: 02/08/2023] Open
Abstract
Abstract
Background
Many studies have been conducted on the genetic and epigenetic etiology of gestational diabetes mellitus (GDM) in the last two decades because of the disease’s increasing prevalence and role in global diabetes mellitus (DM) explosion. An update on the genetic and epigenetic etiology of GDM then becomes imperative to better understand and stem the rising incidence of the disease. This review, therefore, articulated GDM candidate genes and their pathophysiology for the awareness of stakeholders.
Main body (genetic and epigenetic etiology, GDM)
The search discovered 83 GDM candidate genes, of which TCF7L2, MTNR1B, CDKAL1, IRS1, and KCNQ1 are the most prevalent. Certain polymorphisms of these genes can modulate beta-cell dysfunction, adiposity, obesity, and insulin resistance through several mechanisms. Environmental triggers such as diets, pollutants, and microbes may also cause epigenetic changes in these genes, resulting in a loss of insulin-boosting and glucose metabolism functions. Early detection and adequate management may resolve the condition after delivery; otherwise, it will progress to maternal type 2 diabetes mellitus (T2DM) and fetal configuration to future obesity and DM. This shows that GDM is a strong risk factor for T2DM and, in rare cases, type 1 diabetes mellitus (T1DM) and maturity-onset diabetes of the young (MODY). This further shows that GDM significantly contributes to the rising incidence and burden of DM worldwide and its prevention may reverse the trend.
Conclusion
Mutations and epigenetic changes in certain genes are strong risk factors for GDM. For affected individuals with such etiologies, medical practitioners should formulate drugs and treatment procedures that target these genes and their pathophysiology.
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Dalfrà MG, Burlina S, Del Vescovo GG, Lapolla A. Genetics and Epigenetics: New Insight on Gestational Diabetes Mellitus. Front Endocrinol (Lausanne) 2020; 11:602477. [PMID: 33335512 PMCID: PMC7736606 DOI: 10.3389/fendo.2020.602477] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy, with a prevalence that has increased significantly in the last decade, coming to affect 12-18% of all pregnancies. GDM is believed to be the result of a combination of genetic, epigenetic and environmental factors. Following the identification of susceptibility genes for type 2 diabetes by means of genome-wide association studies, an association has also been demonstrated between some type 2 diabetes susceptibility genes and GDM, suggesting a partial similarity of the genetic architecture behind the two forms of diabetes. More recent genome-wide association studies, focusing on maternal metabolism during pregnancy, have demonstrated an overlap in the genes associated with metabolic traits in gravid and non-gravid populations, as well as in genes apparently unique to pregnancy. Epigenetic changes-such as DNA methylation, histone modifications and microRNA gene silencing-have also been identified in GDM patients. Metabolomics has been used to profile the metabolic state of women during pregnancy, based on the measurement of numerous low-molecular-weight metabolites. Measuring amino acids and conventional metabolites has revealed changes in pregnant women with a higher insulin resistance and high blood glucose levels that resemble the changes seen in non-gravid, insulin-resistant populations. This would suggest similarities in the metabolic profiles typical of insulin resistance and hyperglycemia whether individuals are pregnant or not. Future studies combining data obtained using multiple technologies will enable an integrated systems biology approach to maternal metabolism during a pregnancy complicated by GDM. This review highlights the recent knowledge on the impact of genetics and epigenetics in the pathophysiology of GDM and the maternal and fetal complications associated with this pathology condition.
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Jia H, Pan Y, Wang Y, Yin FL, Xu N. β-3 adrenergic receptor gene polymorphisms are associated with gestational diabetes mellitus in a Chinese population. Medicine (Baltimore) 2019; 98:e17258. [PMID: 31651836 PMCID: PMC6824659 DOI: 10.1097/md.0000000000017258] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Increasing studies demonstrated that genetic susceptibility attributes to the development of gestational diabetes mellitus (GDM). The polymorphisms of the β-3 adrenergic receptor(β-3AR) gene have been found to be of great importance in bodyweight elevation and dyslipidaemias. We aimed to determine the influence of β-3AR polymorphisms on the GDM risk. Thus, we performed a case-control study including 136 GDM cases and 138 controls to evaluate the relation between the rs201607471 and susceptibility to GDM. Likelihood ratios X analysis showed the distribution of the genotype frequency (rs201607471 in β-3AR gene) was accorded with the Hardy-Weinberg genetic equilibrium. Although no significant association between rs201607471 alleles and GDM susceptibility (Chi-square test, P > .05), we observed that β-3AR gene rs201607471 CT genotype was significantly prevalent in GDM (Chi-square test, P < .05). Moreover, we observed that β-3AR gene rs201607471 C > T was significantly associated with an increased risk of GDM using the recessive model (CC vs CT/TT: P = .026) and the additive model (CC vs CT vs TT: P = .038). These data indicate that β-3AR rs201607471 may be a helpful susceptibility marker for GDM in Chinese pregnant women.
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Affiliation(s)
- He Jia
- Department of Obstetrics and Gynecology, the 940th Hospital of Lianqin Security Force, Lanzhou
| | - Yuan Pan
- Center for Reproductive Medicine and Center for Prenatal Diagnosis, First Hospital, Jilin University, Changchun, 130021, China
| | - Yun Wang
- Department of Obstetrics and Gynecology, the 940th Hospital of Lianqin Security Force, Lanzhou
| | - Feng-Ling Yin
- Department of Obstetrics and Gynecology, Xuzhou central hospital, Xuzhou
| | - Na Xu
- Department of Obstetrics, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
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Mirghani Dirar A, Doupis J. Gestational diabetes from A to Z. World J Diabetes 2017; 8:489-511. [PMID: 29290922 PMCID: PMC5740094 DOI: 10.4239/wjd.v8.i12.489] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 10/24/2017] [Accepted: 10/30/2017] [Indexed: 02/05/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is defined as any degree of hyperglycaemia that is recognized for the first time during pregnancy. This definition includes cases of undiagnosed type 2 diabetes mellitus (T2DM) identified early in pregnancy and true GDM which develops later. GDM constitutes a greater impact on diabetes epidemic as it carries a major risk of developing T2DM to the mother and foetus later in life. In addition, GDM has also been linked with cardiometabolic risk factors such as lipid abnormalities, hypertensive disorders and hyperinsulinemia. These might result in later development of cardiovascular disease and metabolic syndrome. The understanding of the different risk factors, the pathophysiological mechanisms and the genetic factors of GDM, will help us to identify the women at risk, to develop effective preventive measures and to provide adequate management of the disease. Clinical trials have shown that T2DM can be prevented in women with prior GDM, by intensive lifestyle modification and by using pioglitazone and metformin. However, a matter of controversy surrounding both screening and management of GDM continues to emerge, despite several recent well-designed clinical trials tackling these issues. The aim of this manuscript is to critically review GDM in a detailed and comprehensive manner, in order to provide a scientific analysis and updated write-up of different related aspects.
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Affiliation(s)
- AbdelHameed Mirghani Dirar
- Prince Abdel Aziz Bin Musaad Hospital, Diabetes and Endocrinology Center, Arar 91421, North Zone Province, Saudi Arabia
| | - John Doupis
- Iatriko Paleou Falirou Medical Center, Division of Diabetes and Clinical Research Center, Athens 17562, Greece
- Postgraduate Diabetes Education, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom
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Guan L, Cui X, Zhou H. Meta-analysis of the association between the Trp64Arg polymorphism of the beta-3 adrenergic receptor and susceptibility to gestational diabetes mellitus. J OBSTET GYNAECOL 2017; 38:172-176. [PMID: 28783993 DOI: 10.1080/01443615.2017.1331339] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Lianyue Guan
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Xiaofeng Cui
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Hui Zhou
- Department of Anesthesiology, China-Japan Union Hospital, Jilin University, Changchun, China
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Association of Perilipin and Insulin Receptor Substrate-1 Genes Polymorphism with Lipid Profiles, Central Obesity, and Type 2 Diabetes in a Sample of an Iranian Population. IRANIAN RED CRESCENT MEDICAL JOURNAL 2017. [DOI: 10.5812/ircmj.55100] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Zhang B, Jin Z, Sun L, Zheng Y, Jiang J, Feng C, Wang Y. Expression and correlation of sex hormone-binding globulin and insulin signal transduction and glucose transporter proteins in gestational diabetes mellitus placental tissue. Diabetes Res Clin Pract 2016; 119:106-17. [PMID: 27497146 DOI: 10.1016/j.diabres.2016.07.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 06/30/2016] [Accepted: 07/16/2016] [Indexed: 01/11/2023]
Abstract
OBJECTIVE The aim of the present study was to investigate the probable pathogenesis of gestational diabetes mellitus (GDM) by analyzing the correlation between sex hormone-binding globulin (SHBG) secreted by the placenta during pregnancy and insulin signaling components and glucose transporter proteins (GLUTs) in the placental tissue. DESIGN AND METHODS Placental tissue was collected from full-term and non-obese [body mass index <25kg/m(2)] pregnant women; 10 diagnosed with GDM and 10 with normal pregnancy. We used real-time polymerase chain reaction (PCR), immunohistochemistry and western blotting to detect expression of protein and mRNA of SHBG and insulin signaling components and GLUTs in placental tissue. RESULTS In the placental tissue of non-obese women, there was a decrease in expression of SHBG protein and mRNA, with a concurrent decrease in expression of GLUT-4 protein and mRNA in women with GDM compared with normal controls. There was a decrease in GLUT-3 and insulin receptor substrate (IRS)-1 protein expression and lower IRS-2 mRNA expression was also observed in GDM placental tissue. Linear correlation analyses showed a positive correlation between SHBG and IRS-2 mRNA (P=0.038, R(2)=0.2178, y=0.249x+1.4208); positive correlation between SHBG and phosphatidylinositol 3-kinase (PI3K) p85α mRNA (P=0.035, R(2)=0.224, y=0.3506x+0.7433); positive correlation between SHBG and GLUT-4 mRNA (P=0.000, R(2)=0.5174, y=1.3822+1.7811x); positive correlation between IRS-2 and GLUT-4 mRNA (P=0.002, R(2)=0.4064, y=-0.8272+2.9592x); negative correlation between IRS-1 and PI3K p85α mRNA (P=0.005, R(2)=0.366, y=2.4492-0.1929x); negative correlation between IRS-1 and GLUT-3 mRNA (P=0.027, R(2)=0.243, y=0.9254-0.0714x); and positive correlation between IRS-2 and GLUT-1 mRNA (P=0.004, R(2)=0.3794, y=0.0225+0.6298x). CONCLUSION The results confirm that defective receptors for insulin signal transduction and GLUT proteins are present in GDM placental tissue. Decreasing expression of SHBG may participate in regulation of insulin signaling, leading to a concomitant decrease in expression of relevant insulin signaling components in placental tissue, implying insulin resistance and eventual development of GDM.
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Affiliation(s)
- Bao Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, No. 36, Sanhao Street, Heping District, Shenyang 110004, China
| | - Zhen Jin
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, No. 36, Sanhao Street, Heping District, Shenyang 110004, China.
| | - Lei Sun
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, No. 36, Sanhao Street, Heping District, Shenyang 110004, China
| | - Yang Zheng
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, No. 36, Sanhao Street, Heping District, Shenyang 110004, China
| | - Jiexuan Jiang
- Department of Obstetrics and Gynecology, Qingdao Women and Children's Hospital, No. 217, Liao Yang West Road, Shi Bei District, Qingdao 266000, China
| | - Chong Feng
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, No. 36, Sanhao Street, Heping District, Shenyang 110004, China
| | - Yue Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, No. 36, Sanhao Street, Heping District, Shenyang 110004, China
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Angiotensin converting enzyme gene polymorphism studies: A case-control study. Saudi J Biol Sci 2015; 22:327-31. [PMID: 25972755 PMCID: PMC4423719 DOI: 10.1016/j.sjbs.2014.11.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 10/27/2014] [Accepted: 11/11/2014] [Indexed: 11/23/2022] Open
Abstract
Mild gestational hyperglycemia (MGH) is a very common complication of pregnancy that is characterized by intolerance to glucose. The association of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism to MGH has been previously reported. In this study, we evaluated the association between ACE polymorphism and the risk of MGH in a Saudi population. We conducted a case-control study in a population of 100 MGH patients and 100 control subjects. ACE gene polymorphism was analyzed by the novel approach of tetraprimer amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR). The frequency of ACE polymorphism was not associated with either alleles or genotypes in MGH patients. Glucose concentration was found to be significantly associated with the MGH group. Our study suggests that ACE genotypes were not associated with ACE polymorphism in a Saudi population.
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Huang C, Li G, Dong H, Sun S, Chen H, Luo D, Sun L, Li X, Chen Z, Yang H, Wei S, Zhou Y. Arg⁹⁷² insulin receptor substrate-1 inhibits endothelial nitric oxide synthase expression in human endothelial cells by upregulating microRNA-155. Int J Mol Med 2015; 36:239-48. [PMID: 25902041 DOI: 10.3892/ijmm.2015.2192] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 03/20/2015] [Indexed: 11/06/2022] Open
Abstract
The dysregulation of nitric oxide (NO) synthesis attributable to the abnormal expression/activity of endothelial NO synthase (eNOS) is considered to be a major characteristic of insulin-resistant states, as well as an essential contributor to the pathogenesis of cardiovascular diseases. The Arg972 insulin receptor substrate-1 (IRS-1) is associated with insulin resistance. In the present study, we investigated the association between Arg972 IRS-1 and eNOS expression/activity in human subjects and in primary cultures of human endothelial cells. Data from 832 human subjects revealed that heterozygous and homozygous Arg972 IRS-1 carriers had significantly lower levels of plasma eNOS and nitrite/nitrate than the homozygous wild-type (WT) IRS-1 carriers. Human umbilical vein endothelial cells (HUVECs) established from delivering mothers expressing heterozygous Arg972 IRS-1 had significantly lower eNOS expression/activity and higher miR-155 levels than those expressing WT homozygous IRS-1. The overexpression of IRS-1 and Arg972 IRS-1 in the HUVECs, respectively, decreased and increased the miR-155 expression level. In addition, the overexpression of IRS-1 in the HUVECs significantly increased eNOS expression; this effect was reversed by transfection with mature miR-155 mimic or treatment with the selective phosphatidylinositol-3 kinase (PI3K) inhibitor, BKM120. On the other hand, the overexpression of Arg972 IRS-1 markedly decreased eNOS expression and this effect was reversed by transfection with antagomir-155. On the whole, our in vivo data demonstrate that Arg972 IRS-1 is associated with decreased plasma eNOS and nitrite/nitrate levels in human subjects. Our in vitro data demonstrate that Arg972 IRS-1 inhibits eNOS expression in human endothelial cells by upregulating miR-155 expression through the impairment of PI3K signaling. The present study provides new insight into the pathophysiological role of Arg972 IRS-1 in cardiovascular diseases.
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Affiliation(s)
- Cheng Huang
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Guang Li
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Haojian Dong
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Shuo Sun
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Haimin Chen
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Demou Luo
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Ling Sun
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Xida Li
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Zhujun Chen
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Huijian Yang
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Shuisheng Wei
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Yingling Zhou
- Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
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You Y, Liu S, Peng L, Long M, Deng H, Zhao H. Arg972 insulin receptor substrate-1 enhances tumor necrosis factor-α-induced apoptosis in osteoblasts. Mol Med Rep 2015; 12:255-60. [PMID: 25760103 DOI: 10.3892/mmr.2015.3457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Accepted: 12/02/2014] [Indexed: 11/05/2022] Open
Abstract
The presence of Arg972 insulin receptor substrate-1 (IRS-1) is associated with impaired insulin/IRS-1 signaling to activate phosphatidylinositol-3 kinase (PI3K). Tumor necrosis factor-α (TNF-α), an inflammatory cytokine with a central role in the pathogenesis of rheumatoid arthritis (RA), induces apoptosis in osteoblasts, which are the principal cell type responsible for bone loss in RA. In our previous study, an association between Arg972 IRS-1 and a high risk and severity of RA was identified. In the present study, the effects of Arg972 IRS-1 and IRS-1 on TNF-α-induced apoptosis in human osteoblasts were examined. Normal and RA osteoblasts were stably transfected with Arg972 IRS-1 and IRS-1. In addition, cells were stably transduced with IRS-1-shRNA to knock down IRS1. Following stimulation with 10 nM insulin for 30 min, the stable overexpression of Arg972 IRS-1 and knock down of IRS-1 significantly decreased IRS-1-associated PI3K activity and Akt activation/phosphorylation at serine 473 (ser473) and enhanced TNF-α-induced apoptosis in normal and in RA osteoblasts. By contrast, the stable overexpression of IRS-1 significantly increased the levels of IRS-1-associated PI3K activity and Akt phosphorylation (ser473) and inhibited TNF-α-induced apoptosis, which was eliminated by pretreatment with 50 µn BJM120, a selective PI3K inhibitor, for 30 min. In conclusion, the present study provided the first evidence, to the best of our knowledge, that insulin stimulation of Arg972 IRS-1 and IRS-1 enhanced and inhibited TNF-α-induced apoptosis, respectively in normal and RA osteoblasts by a PI3K‑dependent mechanism. These findings suggest that insulin/IRS-1 signaling is important in the pathogenesis of RA.
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Affiliation(s)
- Yunhui You
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Shiqing Liu
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Lijuan Peng
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Mei Long
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Hongxiang Deng
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Hongjun Zhao
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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Gelaleti RB, Damasceno DC, Salvadori DMF, Marcondes JPC, Lima PHO, Morceli G, Calderon IMP, Rudge MVC. IRS-1 gene polymorphism and DNA damage in pregnant women with diabetes or mild gestational hyperglycemia. Diabetol Metab Syndr 2015; 7:30. [PMID: 25859280 PMCID: PMC4391297 DOI: 10.1186/s13098-015-0026-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 03/19/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Pregnant women with mild gestational hyperglycemia present a high risk for hypertension and obesity, and appear to reproduce the model of metabolic syndrome in pregnancy, including hyperinsulinemia and insulin resistance. Diabetic patients have a higher frequency of the IRS-1 Gly972Arg variant and this polymorphism is directly related to insulin resistance and subsequent hyperglycemia. In diabetes, hyperglycemia and other associated factors generate reactive oxygen species that increase DNA damage. The aims of this study were to evaluate the presence of the IRS-1 Arg972 polymorphism in pregnant women with diabetes or mild gestational hyperglycemia, and in their newborns. Additionally, we evaluated the level of primary DNA damage in lymphocytes of Brazilian pregnant women and the relationship between the amount of genetic damage and presence of the polymorphism. METHODS A based on the oral glucose tolerance test (OGTT) results and on glycemic profiles (GP), as follows: non-diabetic group, mild gestational hyperglycemia (MGH) and diabetic group. Eighty-five newborns were included in the study. Maternal peripheral blood samples and umbilical cord blood samples (5-10 mL) were collected for genotyping by PCR-RFLP and for comet assays. RESULTS The prevalence of genotype Gly/Arg in pregnant women groups was not statistically significant. In newborns, the frequency of Gly/Arg was significantly higher in the MGH and diabetic groups than in the non-diabetic group. Taken together, groups IIA and IIB (IIA + IIB; diabetes) presented lower amounts of DNA damage than the non-diabetic group (p = 0.064). No significant association was detected between genetic damage and the presence of the Arg972 genotype in pregnant women. CONCLUSION The polymorphism was more prevalent in newborns of diabetic and MGH women. We believe that it is necessary to increase the number of subjects to be examined in order to better determine the biological role of the Arg972 polymorphism in these patients. Despite being classified as low-risk, pregnant women with mild gestational hyperglycemia characterize a population of maternal and perinatal adverse outcomes, and that, together with their newborns, require better monitoring by professionals and health services.
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Affiliation(s)
- Rafael B Gelaleti
- />Department of Gynecology and Obstetrics, Botucatu Medical School, Unesp_Univ Estadual Paulista, Laboratory of Experimental Research in Gynecology and Obstetrics, Distrito de Rubião Júnior s/n, CEP. 18618.000, Botucatu, São Paulo Brazil
| | - Débora C Damasceno
- />Department of Gynecology and Obstetrics, Botucatu Medical School, Unesp_Univ Estadual Paulista, Laboratory of Experimental Research in Gynecology and Obstetrics, Distrito de Rubião Júnior s/n, CEP. 18618.000, Botucatu, São Paulo Brazil
| | - Daisy M F Salvadori
- />Department of Pathology, Laboratory of Toxigenomics and Nutrigenomics, Botucatu Medical School, Unesp_Univ Estadual Paulista, Botucatu, Brazil
| | - João Paulo C Marcondes
- />Department of Pathology, Laboratory of Toxigenomics and Nutrigenomics, Botucatu Medical School, Unesp_Univ Estadual Paulista, Botucatu, Brazil
| | - Paula H O Lima
- />Department of Gynecology and Obstetrics, Botucatu Medical School, Unesp_Univ Estadual Paulista, Laboratory of Experimental Research in Gynecology and Obstetrics, Distrito de Rubião Júnior s/n, CEP. 18618.000, Botucatu, São Paulo Brazil
| | - Glilciane Morceli
- />Department of Gynecology and Obstetrics, Botucatu Medical School, Unesp_Univ Estadual Paulista, Laboratory of Experimental Research in Gynecology and Obstetrics, Distrito de Rubião Júnior s/n, CEP. 18618.000, Botucatu, São Paulo Brazil
| | - Iracema M P Calderon
- />Department of Gynecology and Obstetrics, Botucatu Medical School, Unesp_Univ Estadual Paulista, Laboratory of Experimental Research in Gynecology and Obstetrics, Distrito de Rubião Júnior s/n, CEP. 18618.000, Botucatu, São Paulo Brazil
| | - Marilza V C Rudge
- />Department of Gynecology and Obstetrics, Botucatu Medical School, Unesp_Univ Estadual Paulista, Laboratory of Experimental Research in Gynecology and Obstetrics, Distrito de Rubião Júnior s/n, CEP. 18618.000, Botucatu, São Paulo Brazil
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Zhao H, Liu S, Long M, Peng L, Deng H, You Y. Arg972insulin receptor substrate-1 polymorphism and risk and severity of rheumatoid arthritis. Int J Rheum Dis 2014; 19:141-5. [PMID: 25424426 DOI: 10.1111/1756-185x.12366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Hongjun Zhao
- Department of Rheumatology and Immunology; Xiangya Hospital; Central South University; Changsha China
| | - Shiqing Liu
- Department of Rheumatology and Immunology; Xiangya Hospital; Central South University; Changsha China
| | - Mei Long
- Department of Rheumatology and Immunology; Xiangya Hospital; Central South University; Changsha China
| | - Lijuan Peng
- Department of Rheumatology and Immunology; Xiangya Hospital; Central South University; Changsha China
| | - Hongxiang Deng
- Department of Rheumatology and Immunology; Xiangya Hospital; Central South University; Changsha China
| | - Yunhui You
- Department of Rheumatology and Immunology; Xiangya Hospital; Central South University; Changsha China
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Alharbi KK, Khan IA, Munshi A, Alharbi FK, Al-Sheikh Y, Alnbaheen MS. Association of the genetic variants of insulin receptor substrate 1 (IRS-1) with type 2 diabetes mellitus in a Saudi population. Endocrine 2014; 47:472-7. [PMID: 24493031 DOI: 10.1007/s12020-014-0177-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 01/13/2014] [Indexed: 12/16/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic degenerative disease, phenotypically and genetically heterogeneous, characterized by high levels of glucose and metabolic complications. Insulin receptor substrate 1 (IRS-1) plays a key role in the insulin-stimulated signal transduction pathway. A glycine-to-arginine substitution at codon 972 (G972R) (rs1801278) in the IRS-1 gene has been associated with impaired insulin action. Another SNP rs2943641 in the IRS-1 gene has been found to be associated with T2DM and insulin resistance in genome-wide association studies. The aim of the present study was to evaluate whether rs1801278 and rs2943641 are associated with increased risk of T2DM in the Saudi population. The study included 376 T2DM cases and 380 healthy controls. Genomic DNA was isolated using a commercially available kit supplied by Norgen Biotech Corp. Genotyping was performed by PCR and RFLP analysis. There was a significant difference in the genotypic distribution as well as allelic frequency between the T2DM cases and controls in case of both the polymorphisms for rs1801278 (1.752, 95 % CI 1.002-3.121; p = 0.04), and for rs2943641 (OR = 1.482, 95 % CI 1.176-1.867; p = 0.001). In conclusion, both the (rs1801278 and rs2943641) polymorphisms are associated with T2DM in the Saudi population.
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Affiliation(s)
- Khalid Khalaf Alharbi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Kingdom of Saudi Arabia
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Zhang Y, Sun CM, Hu XQ, Zhao Y. Relationship between melatonin receptor 1B and insulin receptor substrate 1 polymorphisms with gestational diabetes mellitus: a systematic review and meta-analysis. Sci Rep 2014; 4:6113. [PMID: 25146448 PMCID: PMC4141258 DOI: 10.1038/srep06113] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
Studies have investigated the relationship between genetic variants and risk of gestational diabetes mellitus (GDM). However, the results remain inconclusive. The aim of this study was to investigate the association of rs10830963 and rs1387153 variants in melatonin receptor 1B (MTNR1B) and rs1801278 variant in insulin receptor substrate 1 (IRS1) with GDM susceptibility. Electronic database of PubMed, Medline, Embase, and CNKI (China National Knowledge Infrastructure) were searched for relevant studies between 2005 and 2014. The odds ratio (OR) with its 95% confidence interval (CI) were employed to estimate the association. Total ten case-control studies, including 3428 GDM cases and 4637 healthy controls, met the inclusion criteria. Our results showed a significant association between the three genetic variants and GDM risk, rs10830963 with a P-value less than 0.0001, rs1387153 with a P-value of 0.0002, and rs1801278 with a P-value of 0.001. Furthermore, all the genetic models in these three polymorphisms were associated with increased risks of GDM as well (P< = 0.009). In conclusion, our study found that the genetic polymorphisms rs10830963 and rs1387153 in MTNR1B and rs1801278 in IRS1 were associated with an increased risk of developing GDM. However, further studies with gene-gene and gene-environmental interactions should be considered.
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Affiliation(s)
- Yan Zhang
- School of Nursing, Tianjin Medical University, Tianjin, 300070, P.R., China
- These authors contributed equally to this work
| | - Cheng-Ming Sun
- Department of Clinical Laboratory, Yuhuangding Hospital, Yantai, 264000, P.R., China
- These authors contributed equally to this work
| | - Xiang-Qin Hu
- Tianjin Central Hospital of Gynecology and Obstetrics, Tianjin, 300100, P.R., China
| | - Yue Zhao
- School of Nursing, Tianjin Medical University, Tianjin, 300070, P.R., China
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Ahles A, Engelhardt S. Polymorphic variants of adrenoceptors: pharmacology, physiology, and role in disease. Pharmacol Rev 2014; 66:598-637. [PMID: 24928328 DOI: 10.1124/pr.113.008219] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
The human genome encodes nine different adrenoceptor genes. These are grouped into three families, namely, the α1-, α2-, and β-adrenoceptors, with three family members each. Adrenoceptors are expressed by most cell types of the human body and are primary targets of the catecholamines epinephrine and norepinephrine that are released from the sympathetic nervous system during its activation. Upon catecholamine binding, adrenoceptors change conformation, couple to and activate G proteins, and thereby initiate various intracellular signaling cascades. As the primary receivers and transducers of sympathetic activation, adrenoceptors have a central role in human physiology and disease and are important targets for widely used drugs. All nine adrenoceptor subtypes display substantial genetic variation, both in their coding sequence as well as in adjacent regions. Despite the fact that some of the adrenoceptor variants range among the most frequently studied genetic variants assessed in pharmacogenetics to date, their functional relevance remains ill defined in many cases. A substantial fraction of the associations reported from early candidate gene approaches have not subsequently been confirmed in different cohorts or in genome-wide association studies, which have increasingly been conducted in recent years. This review aims to provide a comprehensive overview of all adrenoceptor variants that have reproducibly been detected in the larger genome sequencing efforts. We evaluate these variants with respect to the modulation of receptor function and expression and discuss their role in physiology and disease.
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Affiliation(s)
- Andrea Ahles
- Institut für Pharmakologie und Toxikologie, Technische Universität München, Munich, Germany (A.A., S.E.); and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (S.E.)
| | - Stefan Engelhardt
- Institut für Pharmakologie und Toxikologie, Technische Universität München, Munich, Germany (A.A., S.E.); and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (S.E.)
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Wang W, Yang L, Tan L, Wu X, Jiang B, Shen X. Arg972 insulin receptor substrate-1 polymorphism and risk and severity of Alzheimer's disease. J Clin Neurosci 2014; 21:1233-7. [PMID: 24589556 DOI: 10.1016/j.jocn.2013.09.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Revised: 09/23/2013] [Accepted: 09/25/2013] [Indexed: 02/01/2023]
Abstract
We explored the association between the Arg972 insulin receptor substrate-1 (IRS1) polymorphism and the risk and severity of Alzheimer's disease (AD). We genotyped the Arg972 IRS1 (rs1801278) polymorphism in 1123 pairs of age, sex, body mass index, residence area and education level-matched Han Chinese AD patients and controls. AD severity was assessed with Mini-Mental State Examination (MMSE) scores. The AA (homozygous Arg972 IRS1) and GA (heterozygous Arg972 IRS1) genotypes were associated with an increased risk of AD after adjustment for comorbidities including type 2 diabetes mellitus, coronary heart disease, and hypertension (p<0.001; adjusted odds ratio [OR] 3.93 and 2.90, respectively). The A allele was associated with an increased risk of AD after adjustment for comorbidities (p<0.001; adjusted OR 2.26; 95% confidence interval 1.92-2.80). The percentage of Arg972 IRS1 AA homozygotes was higher in the MMSE score ⩽14 category than in the MMSE score 15-26 category overall and in each age group (p<0.001), while the wild type IRS1 GG homozygotes were predominantly found in the MMSE score 15-26 category overall and in each age group. The GG homozygote group had higher MMSE score than the GA heterozygote group, which in turn had higher MMSE score than the AA homozygote group overall and in each age group (p<0.05). In conclusion, the Arg972 IRS1 polymorphism is an independent risk factor for AD and the A allele has a gene dosage effect on AD severity in Han Chinese. This study adds fresh insights into the pathogenesis of AD.
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Affiliation(s)
- Wei Wang
- Department of Neurology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan 410011, People's Republic of China
| | - Liang Yang
- Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Liming Tan
- Department of Neurology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan 410011, People's Republic of China
| | - Xiaomei Wu
- Department of Neurology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan 410011, People's Republic of China
| | - Bo Jiang
- Department of Neurology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan 410011, People's Republic of China
| | - Xiangmin Shen
- Department of Neurology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan 410011, People's Republic of China.
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Insulin receptor substrate-1 (IRS-1) Gly927Arg: correlation with gestational diabetes mellitus in Saudi women. BIOMED RESEARCH INTERNATIONAL 2014; 2014:146495. [PMID: 24695443 PMCID: PMC3948357 DOI: 10.1155/2014/146495] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Accepted: 01/10/2014] [Indexed: 02/07/2023]
Abstract
Pregnant women with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share a common pathophysiology associated with similar risk factors. Genetic variants used to determine the risk of developing T2DM might also be associated with the prevalence of GDM. The aim of the present study was to scrutinize the relationship between the G972R polymorphism of the insulin receptor substrate-1 (IRS-1) gene with GDM in the Saudi female population. This is a case-control study that monitored 500 Saudi women. Subjects with GDM (n = 200) were compared with non-GDM (n = 300) controls. We opted to evaluate rs1801278 polymorphism in the IRS1 gene, which plays a critical role in the insulin-signaling pathway. Genotyping was performed with the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. The frequency of the rs1801278 polymorphism was significantly higher in women with GDM than in women with non-GDM (for TT + CT versus CC: P = 0.02). Additionally, there was a significant increase in the frequency of the Arg-encoding mutant allele from GDM to non-GDM (for T versus C: P = 0.01). Our results suggest that the rs1801278 polymorphism in the IRS-1 gene is involved in the occurrence of GDM in the Saudi population.
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Liu W, Zhou X, Yu F, Hu J, Hu W. Arg972 Insulin receptor substrate-1 is associated with decreased serum angiotensin-converting enzyme 2 levels in acute myocardial infarction patients: in vivo and in vitro evidence. Cardiovasc Diabetol 2013; 12:151. [PMID: 24134599 PMCID: PMC4015180 DOI: 10.1186/1475-2840-12-151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 10/02/2013] [Indexed: 12/17/2022] Open
Abstract
Background Activation of the renin-angiotensin system (RAS) plays a critical role in the pathophysiology of myocardial infarction (MI) and the development of heart failure. Both angiotensin-converting enzyme 2 (ACE2) and insulin/insulin receptor substrate-1 (IRS-1) show cardioprotective effects after acute MI. The Arg972 IRS-1 polymorphism is associated with diminished activity of insulin. In the present study, we explored the association among Arg972 IRS-1, acute MI, and serum levels of ACE2. Methods A total of 711 subjects, including 351 subjects with first-time acute MI and 360 subjects without a history of MI were genotyped for Arg972 IRS-1 polymorphism. Serum levels of ACE2 and MI severity scores were determined. Primary human cardiomyocytes with overexpression of wild type IRS-1 or Arg972 IRS-1 or knockdown of endogenous IRS-1 were exposed to normoxia and hypoxia, and the expression levels of ACE2 were determined. Results The serum ACE2 level was significantly increased in acute MI patients compared with that of non-MI controls. Compared with wild type IRS-1 carriers, Arg972 IRS-1 carriers exhibited decreased serum ACE2 levels and increased MI severity scores after MI. Our in vitro data demonstrate that impairment of insulin/IRS-1/PI3K signaling by overexpression of Arg972-IRS-1, knockdown of endogenous IRS-1, or PI3K inhibitor can abolish hypoxia-induced IRS-1-associated PI3K activity and ACE2 expression in human cardiomyocytes, which suggests a causal relationship between Arg972-IRS-1 and decreased serum ACE2 levels in acute MI patients. Our in vitro data also indicate that insulin/IRS-1/PI3K signaling is required for ACE2 expression in cardiomyocytes, and that hypoxia can enhance the induction effect of insulin/IRS-1/PI3K signaling on ACE2 expression in cardiomyocytes. Conclusions This study provides the first evidence of crosstalk between insulin/IRS-1/PI3K signaling and RAS after acute MI, thereby adding fresh insights into the pathophysiology and treatment of acute MI.
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Affiliation(s)
| | | | | | | | - Wen Hu
- Department of Thoracic and Cardiovascular Surgery, Second Xiangya Hospital, Central South University, 138 Renmin Road, Changsha, Hunan 410011, P,R, China.
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Zhang C, Bao W, Rong Y, Yang H, Bowers K, Yeung E, Kiely M. Genetic variants and the risk of gestational diabetes mellitus: a systematic review. Hum Reprod Update 2013; 19:376-90. [PMID: 23690305 DOI: 10.1093/humupd/dmt013] [Citation(s) in RCA: 191] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Several studies have examined associations between genetic variants and the risk of gestational diabetes mellitus (GDM). However, inferences from these studies were often hindered by limited statistical power and conflicting results. We aimed to systematically review and quantitatively summarize the association of commonly studied single nucleotide polymorphisms (SNPs) with GDM risk and to identify important gaps that remain for consideration in future studies. METHODS Genetic association studies of GDM published through 1 October 2012 were searched using the HuGE Navigator and PubMed databases. A SNP was included if the SNP-GDM associations were assessed in three or more independent studies. Two reviewers independently evaluated the eligibility for inclusion and extracted the data. The allele-specific odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random effects models accounting for heterogeneity. RESULTS Overall, 29 eligible articles capturing associations of 12 SNPs from 10 genes were included for the systematic review. The minor alleles of rs7903146 (TCF7L2), rs12255372 (TCF7L2), rs1799884 (-30G/A, GCK), rs5219 (E23K, KCNJ11), rs7754840 (CDKAL1), rs4402960 (IGF2BP2), rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs1801278 (Gly972Arg, IRS1) were significantly associated with a higher risk of GDM. Among them, genetic variants in TCF7L2 showed the strongest association with GDM risk, with ORs (95% CIs) of 1.44 (1.29-1.60, P < 0.001) per T allele of rs7903146 and 1.46 (1.15-1.84, P = 0.002) per T allele of rs12255372. CONCLUSIONS In this systematic review, we found significant associations of GDM risk with nine SNPs in seven genes, most of which have been related to the regulation of insulin secretion.
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Affiliation(s)
- Cuilin Zhang
- Epidemiology Branch, Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd, Rockville, MD 20852, USA
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Arg(972) insulin receptor substrate-1 is associated with elevated plasma endothelin-1 level in hypertensives. J Hypertens 2012; 30:1751-7. [PMID: 22759779 DOI: 10.1097/hjh.0b013e3283561400] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To explore the association among Arg(972) insulin receptor substrate-1 (IRS-1), hypertension, insulin resistance, and plasma levels of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1). METHODS A total of 1030 patients, including 521 healthy controls, 142 patients with both primary hypertension and insulin resistance, 184 patients with primary hypertension but no insulin resistance, and 183 patients with insulin resistance but no hypertension were genotyped for the Arg(972) IRS-1 polymorphism. Serum levels of ET-1 and eNOS were determined by ELISA. Shear stress was applied to human umbilical vein endothelial cells (HUVECs) overexpressing wild type IRS-1 or Arg(972) IRS-1, and the mRNA and secreted protein levels of ET-1 were measured by real-time RT-PCR and ELISA, respectively. RESULTS There was no significant difference in allelic frequency between patients with and without primary hypertension or insulin resistance, in the hypertensives, heterozygous Arg(972) IRS-1 carriers had significantly higher plasma ET-1 levels and blood pressure (BP) than the homozygous carriers. Although shear stress decreased ET-1 expression in control HUVECs as well as cells transfected with wild type Arg(972) IRS-1, it increased the mRNA dose-dependently and secreted protein levels of ET-1 in cells transfected with Arg(972) IRS-1. CONCLUSIONS Based on both in-vivo and in-vitro data, we have shown a potential causal association between Arg(972) IRS-1 and elevated plasma ET-1 level in hypertensives, which may account for the aggravated hypertension observed in hypertensives with heterozygous Arg(972) IRS-1. This study for the first time provides insights into the role of Arg(972) IRS-1 in hypertension.
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Pappa KI, Gazouli M, Economou K, Daskalakis G, Anastasiou E, Anagnou NP, Antsaklis A. Gestational diabetes mellitus shares polymorphisms of genes associated with insulin resistance and type 2 diabetes in the Greek population. Gynecol Endocrinol 2011; 27:267-272. [PMID: 20540670 DOI: 10.3109/09513590.2010.490609] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Gestational diabetes mellitus (GDM) and type 2 diabetes (T2D) share common pathophysiological features, including β-cell dysfunction and insulin resistance. In this study, we investigated the association between GDM and five recently identified T2D susceptibility loci, in a Greek population. We studied 148 women with GDM and 107 non-diabetic unrelated pregnant Greek women, for polymorphisms in the TCF7L2 gene (rs7903146 C/T), the PPARG gene (Pro12Ala), the KCNJ11 gene (E23K), the IRS1 gene (G972R) and in the FOXC2 gene (-512C>T). The T-allele of the TCF7L2 rs7903146 (C/T) polymorphism was found to be significantly associated with an increased risk of GDM [p = 0.0003; odds ratio (OR) 2.04 (95%CI 1.38-3.00)]. Additionally, CT and TT genotypes were significantly overrepresented in women with GDM compared to controls (p = 0.0003 and p = 0.0148, respectively). Analysis of the IRS1 G972R polymorphism showed that the R-allele frequency was increased in women with GDM [(p = 0.009; OR 1.67 (95%CI 1.14-2.47)]. The genotypes and allele frequencies of the other polymorphisms studied did not statistically differ between the GDM and the control women. Thus, our data suggest that the common T2D susceptibility polymorphism of TCF7L2 (rs7903146 C/T) gene, and the G972R polymorphism of the IRS1 gene, seem to predispose to GDM in Greek women.
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Affiliation(s)
- Kalliopi I Pappa
- First Department of Obstetrics and Gynecology, University of Athens, School of Medicine, Athens, Greece.
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Abstract
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study of over 23000 diabetes-free pregnancies has shown that at a population level an unequivocal linear relationship exists between maternal glucose concentrations around the beginning of the third trimester of pregnancy and the risk of their baby being born above the ninetieth centile for weight. With the rising incidence of gestational diabetes (GDM) across the developed world, largely paralleling the increased prevalence of obesity, there has been a sharp increase in the risk of pregnancy complications developing related to the birth of macrosomic babies. The associated additional long-term complications of GDM pregnancies means that in the future there is likely to be a large increase in the incidence of type 2 diabetes and associated conditions in both the mothers and their affected offspring. The present review seeks to highlight recent advances and remaining gaps in knowledge about GDM in terms of its genetics (where some of the recently discovered polymorphic risk factors for type 2 diabetes have also proved to be risk factors for GDM) and its treatment by diet, exercise and drugs.
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Affiliation(s)
- Clive J Petry
- Department of Paediatrics, University of Cambridge, Cambridge, UK.
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Fallucca S, Vasta M, Sciullo E, Balducci S, Fallucca F. Birth weight: genetic and intrauterine environment in normal pregnancy. Diabetes Care 2009; 32:e149. [PMID: 19940212 DOI: 10.2337/dc09-1489] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Sara Fallucca
- Department of Clinical Sciences, II Faculty “Sapienza” University, Rome, Italy
| | - Mario Vasta
- Diabetes Unit, Urbino Hospital, Urbino, Italy
| | - Ernesta Sciullo
- Department of Clinical Sciences, II Faculty “Sapienza” University, Rome, Italy
| | - Stefano Balducci
- Department of Clinical Sciences, II Faculty “Sapienza” University, Rome, Italy
| | - Francesco Fallucca
- Department of Clinical Sciences, II Faculty “Sapienza” University, Rome, Italy
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Kim K, Heo K, Won YL, Ko KS, Kim TG, Lee M, Park J, Paik S. Overweight of Korean male workers and genetic polymorphism of insulin receptor substrate 1 (IRS1) gene. Anim Cells Syst (Seoul) 2009. [DOI: 10.1080/19768354.2009.9647203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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Kurokawa N, Young EH, Oka Y, Satoh H, Wareham NJ, Sandhu MS, Loos RJF. The ADRB3 Trp64Arg variant and BMI: a meta-analysis of 44 833 individuals. Int J Obes (Lond) 2008; 32:1240-9. [PMID: 18574485 DOI: 10.1038/ijo.2008.90] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The beta-3 adrenergic receptor gene (ADRB3) is part of the adrenergic system, which is known to play a key role in energy metabolism. The association between the Trp64Arg variant in the ADRB3 and body mass index (BMI) has been widely examined, but previous studies have been small and results have been inconsistent. METHODS We assessed the association between the ADRB3 Trp64Arg variant and BMI in a large UK population-based cohort of 4854 middle-aged men and women. We also performed a meta-analysis of 97 studies, involving 44 833 individuals, to place our findings in context. RESULTS Although we found no significant difference in BMI (0.20 kg/m(2), P=0.40) between the Trp64Trp homozygotes and Arg64 allele carriers in our UK population-based cohort, the meta-analysis showed significant association between the Arg64Trp variant and BMI, with Arg64-allele carriers having a 0.24 kg/m(2) (P=0.0002) higher BMI compared with noncarriers. However, we also found substantial heterogeneity among the studies (P=2.2 x 10(-14)). The difference in East Asians (0.31 kg/m(2), P=0.001) was 3.9 times larger than that in Europeans in whom no significant association was observed (0.08 kg/m(2), P=0.36). This was consistent with the chronological cumulative decrease in the effect size, which decreased steadily in Europeans and reached nonsignificance after 11 studies in 1996. In East Asians, the cumulative effect size decreased after the first reports, but reached a steady state at a significant effect size of 0.24 kg/m(2) in 2000. Although the funnel plot indicated no apparent publication bias, smaller studies tended to report greater differences in BMI, compared with larger studies. CONCLUSIONS Collectively, these data suggest that the Trp64Arg ADRB3 genetic variant might be associated with BMI in East Asians, but not Europeans. More generally, our study shows the importance of meta-analyses in the field of genetic association studies for common traits. Each genetic variant makes only a small contribution to variation in BMI, and large sample sizes are needed to reliably assess and interpret gene-phenotype associations.
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Affiliation(s)
- N Kurokawa
- MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
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The genetics of gestational diabetes mellitus: evidence for relationship with type 2 diabetes mellitus. Genet Med 2008; 10:240-50. [PMID: 18414206 DOI: 10.1097/gim.0b013e31816b8710] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Gestational diabetes is a major public health problem because of its prevalence, its associated complications during pregnancy, and its increased risk for type 2 diabetes later in life. Insulin resistance is one of many physiological changes occurring during pregnancy, and when insulin resistance is accompanied by pancreatic beta-cell insufficiency, gestational diabetes may develop. Several lines of evidence suggest that gestational diabetes shares a common etiology with type 2 diabetes and support the hypothesis that gestational diabetes serves as a window to reveal a predisposition to type 2 diabetes. Pregnancy is an environmental stressor that may catalyze the progression to a diabetic state in genetically predisposed women; therefore, identification of these women during pregnancy could decrease the occurrence of type 2 diabetes through targeted prevention. This review presents an overview of the genetics of gestational diabetes, focusing on human association studies with candidate genes common to both type 2 diabetes and gestational diabetes.
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Shaat N, Lernmark A, Karlsson E, Ivarsson S, Parikh H, Berntorp K, Groop L. A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus. Diabetologia 2007; 50:972-9. [PMID: 17342473 DOI: 10.1007/s00125-007-0623-2] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2006] [Accepted: 01/21/2007] [Indexed: 12/18/2022]
Abstract
AIMS/HYPOTHESIS Genetic and epidemiological studies suggest an association between gestational diabetes mellitus and type 2 diabetes. Both are polygenic multifactorial disorders characterised by beta cell dysfunction and insulin resistance. Our aim was to investigate whether common genetic variants that have previously been associated with type 2 diabetes or related phenotypes would also confer risk for gestational diabetes mellitus. MATERIALS AND METHODS In 1,881 unrelated pregnant Scandinavian women (649 women with gestational diabetes mellitus, 1,232 non-diabetic control subjects) we genotyped the transcription factor 7-like 2 (TCF7L2 rs7903146), adiponectin (ADIPOQ +276G > T), peroxisome-proliferator activated receptor, gamma 2 (PPARG Pro12Ala), PPARG-coactivator, 1 alpha (PPARGC1A Gly482Ser), forkhead box C2 (FOXC2 -512C > T) and beta3-adrenergic receptor (ADRB3 Trp64Arg) polymorphisms using TaqMan allelic discrimination assay or RFLP. RESULTS The CC, CT and TT genotype frequencies of the TCF7L2 rs7903146 variant differed significantly between women with gestational diabetes mellitus and control women (46.3, 43.6 and 10.1% vs 58.5, 35.3 and 6.2%, p = 3.7 x 10(-6), corrected p value [Pc] for multiple testing Pc = 2.2 x 10(-5)). The T-allele was associated with an increased risk of gestational diabetes mellitus (odds ratio 1.49 [95% CI 1.28-1.75], p = 4.9 x 10(-7) [Pc = 2.8 x 10(-6)]). Compared with wild-type CC-genotype carriers, heterozygous (CT-genotype) and homozygous (TT-genotype) carriers had a 1.6-fold (95% CI 1.26-1.93, p = 3.7 x 10(-5) [Pc = 0.0002]) and a 2.1-fold (95% CI 1.41-2.99, p = 0.0001 [Pc = 0.0008]) increased risk of gestational diabetes mellitus, respectively. The other polymorphisms studied were not significantly associated with gestational diabetes mellitus (ADIPOQ +276G > T: 1.17 [1.01-1.36], p = 0.039 [Pc = 0.23]; PPARG Pro12Ala: 1.06 [0.87-1.29], p = 0.53; PPARGC1A Gly482Ser: 0.96 [0.83-1.10], p = 0.54; FOXC2 -512C > T: 1.01 [0.87-1.16], p = 0.94; and ADRB3 Trp64Arg: 1.22 [0.95-1.56], p = 0.12). CONCLUSIONS/INTERPRETATION The TCF7L2 rs7903146 variant is associated with an increased risk of gestational diabetes mellitus in Scandinavian women.
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Affiliation(s)
- N Shaat
- Department of Clinical Sciences/Diabetes & Endocrinology, Malmö University Hospital, Lund University, Malmö, Sweden.
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