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Tsur N, Frankel M, Cahn A, Tsur A. Gestational diabetes and risk of future diabetes in a multi-ethnic population. J Diabetes Complications 2024; 38:108720. [PMID: 38452402 DOI: 10.1016/j.jdiacomp.2024.108720] [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: 02/03/2024] [Revised: 02/28/2024] [Accepted: 03/02/2024] [Indexed: 03/09/2024]
Abstract
AIM To investigate ethnic disparities in risk of gestational diabetes-mellitus (GDM) and future diabetes. METHODS A population-based retrospective cohort study of women who underwent a 100-g oral glucose-tolerance-test (oGTT) during pregnancy between 2007 and 2017 in Clalit-Health-Services of the Jerusalem district. Univariate and multivariate logistic regression analyses were used to compare the risk of GDM in Arab versus Jewish women. Further, Cox-regression analysis was used to establish the risk of future diabetes. RESULTS A total of 9875 women, 71 % of Jewish ethnicity and 29 % of Arab ethnicity were included. Arab women had a higher incidence of GDM compared to Jewish women (17.3 % vs. 10.6 %, p < 0.001), which persisted after adjusting for age, BMI, and metabolic profile (aOR 1.7; CI 1.48-2.0, P < 0.001). Additionally, Arab ethnicity was associated with an increased risk of future diabetes, even after adjusting for GDM status (aHR 5.9; 95 % CI 3.7-9.4, P < 0.001). CONCLUSIONS Women of Arab ethnicity have a higher risk for both GDM and future diabetes, a risk that is beyond the initial increased risk associated with GDM. These findings highlight the need for increased focus on preventing diabetes in women of Arab ethnicity, especially those with a history of GDM.
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Affiliation(s)
- Noa Tsur
- Department of Internal Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Meir Frankel
- Endocrinology Unit, Shaare Zedek Medical Center, Jerusalem, Israel; Department of Endocrinology and Metabolism, Clalit Health Services, Jerusalem, Israel
| | - Avivit Cahn
- The Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel; The Faculty of Medicine, Hadassah Hebrew University, Jerusalem, Israel
| | - Anat Tsur
- Department of Endocrinology and Metabolism, Clalit Health Services, Jerusalem, Israel; The Faculty of Medicine, Hadassah Hebrew University, Jerusalem, Israel.
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Analysis and Prediction of Gestational Diabetes Mellitus by the Ensemble Learning Method. INT J COMPUT INT SYS 2022. [DOI: 10.1007/s44196-022-00110-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
AbstractGestational diabetes mellitus (GDM) is the most common disease in pregnancy and can cause a series of maternal and infant complications. A new study shows that GDM affects one in six deliveries. Identifying and screening for risk factors for GDM can effectively help intervene and improve the condition of women and their children. Therefore, the aim of this paper is to determine the risk factors for GDM and to use the ensemble learning method to judge whether pregnant women suffer from GDM more accurately. First, this study involves six commonly used machine learning algorithms to analyze the GDM data from the Tianchi competition, selects the risk factors according to the ranking of each model, and uses the Shapley additive interpreter method to determine the importance of the selected risk factors. Second, the combined weighting method was used to analyze and evaluate the risk factors for gestational diabetes and to determine a group of important factors. Lastly, a new integrated light gradient-boosting machine-extreme gradient boosting-gradient boosting tree (LightGBM-Xgboost-GB) learning method is proposed to determine whether pregnant women have gestational diabetes mellitus. We used the gray correlation degree to calculate the weight and used a genetic algorithm for optimization. In terms of prediction accuracy and comprehensive effects, the final model is better than the commonly used machine learning model. The ensemble learning model is comprehensive and flexible and can be used to determine whether pregnant women suffer from GDM. In addition to disease prediction, the model can also be extended for use to many other areas of research.
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Dong X, Lin D, Sheng J, Xie Y. Intrauterine hyperglycemia induces liver inflammation in mouse male offspring. Int Immunopharmacol 2021; 99:107974. [PMID: 34358862 DOI: 10.1016/j.intimp.2021.107974] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/23/2021] [Accepted: 07/08/2021] [Indexed: 12/17/2022]
Abstract
Gestational diabetes mellitus (GDM) is a common complication of pregnancy characterized by intrauterine hyperglycemia, which is often associated with a high risk of obesity and diabetes in the offspring. In this study, we established a GDM mouse model by intraperitoneal injection of streptozotocin to investigate the immuno-inflammatory responses in the liver of adult offspring. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were employed to evaluate the glucose tolerance status. Hematoxylin-eosin staining was used to examine the histological changes in the liver. Quantitative real-timePCR (qRT-PCR) was applied to examine the mRNA expression of immune factors. Western blot and immunofluorescence analyses were used to examine the expression of target protein. Additionally, cell experiments were performed to validate the in vivo results. Compared to the control group, the area of fat vacuoles and the number of lymphocyte cells were significantly higher in the 20 weeks-old offspring of GDM mice. The elevated mRNA level of the pro-inflammatory cytokines IL-1β, IL-6, IL-33 and immune receptors CD3 and CD36 were found in the liver of F1-GDM. The protein level of IL-6r and the phosphorylation of JAK2 and STAT3 were significantly up-regulated. Moreover, the mRNA level of IL-6, IL-1β and IL-33 and the phosphorylation of JAK2 and STAT3 were also up-regulated in the hepatocyte treated with high concentration of glucose. Our results suggest that intrauterine hyperglycemia is associated with increased inflammation in the liver of adult male offspring.
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Affiliation(s)
- Xinyan Dong
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Donghui Lin
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Jianzhong Sheng
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, Zhejiang 310058, China.
| | - Yicheng Xie
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, 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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Bakhtiyari A, Haghani K, Bakhtiyari S, Zaimy MA, Noori-Zadeh A, Gheysarzadeh A, Darabi S, Seidkhani-Nahal A, Amraei M, Alipourfard I. Association between ABCC8 Ala1369Ser Polymorphism (rs757110 T/G) and Type 2 Diabetes Risk in an Iranian Population: A Case-Control Study. Endocr Metab Immune Disord Drug Targets 2020; 21:441-447. [PMID: 32660410 DOI: 10.2174/1871530320666200713091827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Glucose metabolism increases ATP/ADP ratio within the β-cells and causes ATP-sensitive K+ (KATP) channel closure and consequently insulin secretion. The enhanced activity of the channel may be a mechanism contributing to the reduced first-phase of insulin secretion observed in T2DM. There is no study to date in the Kurdish ethnic group regarding the relationship between SNP Ala1369Ser (rs757110 T/G) of SUR1 gene and T2DM, and additionally, the results of this association in other populations are inconsistent. Therefore, our aim in this study was to explore the possible association between SNP Ala1369Ser and type 2 diabetes in an Iranian Kurdish ethnic group. METHODS In this study, we checked out the frequency of alleles and genotypes of SNP Ala1369Ser in T2DM individuals (207 patients; men/women: 106/101) and non-T2DM subjects (201 controls; men/women: 97/104), and their effects on anthropometric, clinical, and biochemical parameters. Genomic DNA was extracted from the leukocytes of blood specimens using a standard method. We amplified the ABCC8 rs757110 polymorphic site (T/G) using a polymerase chain reaction (PCR) method and a designed primer pair. To perform the PCR-RFLP method, the amplicons were subjected to restriction enzymes and the resulting fragments separated by gel electrophoresis. RESULTS The frequency of the G-allele of Ala1369Ser polymorphism was significantly (0.01) higher in the case group than the control group (19% vs. 9%, respectively). In the dominant model (TT vs. TG+GG), there was a significant relationship between this SNP and an increased risk of T2DM (P = 0.00). T2DM patients with TG+GG genotypes had significantly higher fasting plasma insulin and HOMA-IR than those who had the TT genotype (P = 0.02 and 0.01, respectively). CONCLUSION Our study is the first study to investigate the association between Ala1369Ser ABCC8 genetic variation and T2DM in the Kurdish population of western Iran. The obtained results clearly show that Ala1369Ser polymorphism of ABCC8 is associated with an increased risk of T2DM in this population.
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Affiliation(s)
- Amin Bakhtiyari
- Department of Genetics, Biology Research Center, Zanjan Branch, Islamic Azad University, Zanjan, Iran.,Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Karimeh Haghani
- Department of Clinical Biochemistry, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Salar Bakhtiyari
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran.,Department of Clinical Biochemistry, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Mohammad A Zaimy
- Department of Medical Genetics, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Ali Noori-Zadeh
- Department of Clinical Biochemistry, Faculty of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran
| | - Ali Gheysarzadeh
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran.,Department of Biology, Faculty of Science, Ilam University, Ilam, Iran
| | - Shahram Darabi
- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Ali Seidkhani-Nahal
- Department of Clinical Biochemistry, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Mansour Amraei
- Department of Physiology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Iraj Alipourfard
- School of Pharmacy, Faculty of Sciences, University of Rome Tor Vergata, Rome, Italy
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Zhou X, Chen C, Yin D, Zhao F, Bao Z, Zhao Y, Wang X, Li W, Wang T, Jin Y, Lv D, Lu Q, Yin X. A Variation in the ABCC8 Gene Is Associated with Type 2 Diabetes Mellitus and Repaglinide Efficacy in Chinese Type 2 Diabetes Mellitus Patients. Intern Med 2019; 58:2341-2347. [PMID: 31118371 PMCID: PMC6746626 DOI: 10.2169/internalmedicine.2133-18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Objective Previous studies have suggested that variations in the ABCC8 gene may be closely associated with T2DM susceptibility and repaglinide response. However, these results have not been entirely consistent, and there are no related studies in a Chinese population, suggesting the need for further exploration. The current study investigated the associations of the ABCC8 rs1801261 polymorphism with type 2 diabetes mellitus (T2DM) susceptibility and repaglinide therapeutic efficacy in Chinese Han T2DM patients. Methods A total of 234 T2DM patients and 105 healthy subjects were genotyped for ABCC8 rs1801261 polymorphism by a polymerase chain reaction-restriction fragment length polymorphism assay. A total of 70 patients with the same genotypes of CYP2C8*3 139Arg and OATP1B1 521TT were randomized to orally take 3 mg repaglinide per day (1 mg each time before meals) for 8 consecutive weeks. The pharmacodynamic parameters of repaglinide and biochemical indicators were then determined before and after repaglinide treatment. Results The frequency of ABCC8 rs1801261 allele was higher in T2DM patients than in the control subjects (22.6% vs.11.0%, p<0.01). After repaglinide treatment, T2DM patients carrying genotype CT showed a significantly attenuated efficacy on FPG (p<0.01) and HbA1c (p<0.01) compared with those with genotype CC. Conclusion These results suggested that the ABCC8 rs1801261 polymorphism might influence T2DM susceptibility and the therapeutic effect of repaglinide in Chinese Han T2DM patients. This study was registered in the Chinese Clinical Trial Register on May 14, 2013 (No. ChiCTR-CCC13003536).
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Affiliation(s)
- Xueyan Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
| | - Chunxia Chen
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
| | - Di Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
| | - Feng Zhao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
| | - Zejun Bao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
| | - Yun Zhao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
| | - Xi Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
| | - Wei Li
- Department of Endocrinology, The Affiliated Hospital of Xuzhou Medical University, People's Republic of China
| | - Tao Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
- Department of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, People's Republic of China
| | - Yingliang Jin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
| | - Dongmei Lv
- Department of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, People's Republic of China
| | - Qian Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
| | - Xiaoxing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, People's Republic of China
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Engwa GA, Nwalo FN, Chikezie CC, Onyia CO, Ojo OO, Mbacham WF, Ubi BE. Possible association between ABCC8 C49620T polymorphism and type 2 diabetes in a Nigerian population. BMC MEDICAL GENETICS 2018; 19:78. [PMID: 29751826 PMCID: PMC5948806 DOI: 10.1186/s12881-018-0601-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 05/01/2018] [Indexed: 01/08/2023]
Abstract
BACKGROUND The association between ABCC8 gene C49620T polymorphism and type 2 diabetes (T2D) in populations of diverse ethnic backgrounds has been reported. However, such occurrence in an African population is yet to be established. This case-control study involving 73 T2D and 75 non-diabetic (ND) patients investigated the occurrence of this polymorphism among T2D patients in Nigeria and assessed its relationship with body lipids of patients. METHODS Demographic and clinical characteristics of patients were collected and lipid profile indices including total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL) were assayed. Restriction fragment length polymorphism-PCR (RFLP-PCR) was employed to genotype the ABCC8-C49620T polymorphism using PstI restriction enzyme. RESULTS This study revealed significantly (p < 0.05) higher prevalence of the T allele of the ABCC8 gene in T2D patients (33.1%) compared to ND patients (28.0%). The mutant TT genotype was also higher than the CC and CT genotypes in T2D patients compared to ND patients but did not show any significant risk (p>0.05) of T2D for the unadjusted codominant, dominant and recessive models. Following age adjustment, the mutant genotypes (CT and TT) showed significant (p<0.05) risk of T2D for all the models with the recessive model presenting the greatest risk of T2D (OR: 2.39, 95% CI: 1.16-4.91, p<0.018). The TT genotype significantly (p<0.05) associated with high level of HDL and reduced levels of TC, TG and LDL in non-diabetic patients but was not associated with any of the demographic and clinical characteristics among T2D patients. CONCLUSIONS ABCC8 C49620T polymorphism showed possible association with T2D marked by predominance of the mutant TT genotype in T2D patients. However, the relationship between TT genotype and lipid abnormalities for possible beneficial effect on people suffering from T2D is unclear.
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Affiliation(s)
- Godwill Azeh Engwa
- Biochemistry, Department of Chemical Sciences, Godfrey Okoye University, P.M.B 01014, Thinkers Corner, Enugu, Nigeria
- Department of Biotechnology, Ebonyi State University, P.M.B. 53, Abakaliki, Nigeria
| | - Friday Nweke Nwalo
- Department of Biotechnology, Federal University, Ndufu-Alike Ikwo (FUNAI), P.M.B. 1010, Abakaliki, Nigeria
| | | | - Christie Oby Onyia
- Department of Biotechnology, Godfrey Okoye University, P.M.B 01014, Thinkers Corner, Enugu, Nigeria
| | - Opeolu Oyejide Ojo
- Department of Biology, Chemistry and Forensic Science, School of Sciences, University of Wolverhampton, Wolverhampton, WV1 1LY UK
- Bioscience Research Education and Advisory Centre, Ibadan, Nigeria
| | - Wilfred Fon Mbacham
- Laboratory for Public Health Research Biotechnologies, The Biotechnology Centre, University of Yaounde I, BP 8094 Yaounde, Cameroon
| | - Benjamin Ewa Ubi
- Department of Biotechnology, Ebonyi State University, P.M.B. 53, Abakaliki, Nigeria
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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: 115] [Impact Index Per Article: 14.4] [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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Singh S, Usman K, Banerjee M. Pharmacogenetic studies update in type 2 diabetes mellitus. World J Diabetes 2016; 7:302-315. [PMID: 27555891 PMCID: PMC4980637 DOI: 10.4239/wjd.v7.i15.302] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 05/30/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment.
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Sokolova EA, Bondar IA, Shabelnikova OY, Pyankova OV, Filipenko ML. Replication of KCNJ11 (p.E23K) and ABCC8 (p.S1369A) Association in Russian Diabetes Mellitus 2 Type Cohort and Meta-Analysis. PLoS One 2015; 10:e0124662. [PMID: 25955821 PMCID: PMC4425644 DOI: 10.1371/journal.pone.0124662] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 03/17/2015] [Indexed: 12/26/2022] Open
Abstract
The genes ABCC8 and KCNJ11 have received intense focus in type 2 diabetes mellitus (T2DM) research over the past two decades. It has been hypothesized that the p.E23K (KCNJ11) mutation in the 11p15.1 region may play an important role in the development of T2DM. In 2009, Hamming et al. found that the p.1369A (ABCC8) variant may be a causal factor in the disease; therefore, in this study we performed a meta-analysis to evaluate the association between these single nucleotide polymorphisms (SNPs), including our original data on the Siberian population (1384 T2DM and 414 controls). We found rs5219 and rs757110 were not associated with T2DM in this population, and that there was linkage disequilibrium in Siberians (D’=0.766, r2= 0.5633). In addition, the haplotype rs757110[T]-rs5219[C] (p.23K/p.S1369) was associated with T2DM (OR = 1.52, 95% CI: 1.04-2.24). We included 44 original studies published by June 2014 in a meta-analysis of the p.E23K association with T2DM. The total OR was 1.14 (95% CI: 1.11-1.17) for p.E23K for a total sample size of 137,298. For p.S1369A, a meta-analysis was conducted on a total of 10 studies with a total sample size of 14,136 and pooled OR of 1.14 [95% CI (1.08-1.19); p = 2 x 10-6]. Our calculations identified causal genetic variation within the ABCC8/KCNJ11 region for T2DM with an OR of approximately 1.15 in Caucasians and Asians. Moreover, the OR value was not dependent on the frequency of p.E23K or p.S1369A in the populations.
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Affiliation(s)
- Ekaterina Alekseevna Sokolova
- Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Siberian Division, Russian Academy of Sciences, Novosibirsk, Russia
- Novosibirsk State University, Novosibirsk, Russia
| | - Irina Arkadievna Bondar
- Novosibirsk State Regional Hospital, Regional Diabetes center, Novosibirsk, Russia
- Novosibirsk State Medical University, Novosibirsk, Russia
| | - Olesya Yurievna Shabelnikova
- Novosibirsk State Regional Hospital, Regional Diabetes center, Novosibirsk, Russia
- Novosibirsk State Medical University, Novosibirsk, Russia
| | - Olga Vladimirovna Pyankova
- Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Siberian Division, Russian Academy of Sciences, Novosibirsk, Russia
- Novosibirsk State University, Novosibirsk, Russia
| | - Maxim Leonidovich Filipenko
- Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Siberian Division, Russian Academy of Sciences, Novosibirsk, Russia
- Kazan Federal University, Kazan, Russia
- * E-mail:
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Bonfanti DH, Alcazar LP, Arakaki PA, Martins LT, Agustini BC, de Moraes Rego FG, Frigeri HR. ATP-dependent potassium channels and type 2 diabetes mellitus. Clin Biochem 2015; 48:476-82. [PMID: 25583094 DOI: 10.1016/j.clinbiochem.2014.12.026] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 12/29/2014] [Accepted: 12/30/2014] [Indexed: 12/24/2022]
Abstract
Diabetes mellitus is a public health problem, which affects a millions worldwide. Most diabetes cases are classified as type 2 diabetes mellitus, which is highly associated with obesity. Type 2 diabetes is considered a multifactorial disorder, with both environmental and genetic factors contributing to its development. An important issue linked with diabetes development is the failure of the insulin releasing mechanism involving abnormal activity of the ATP-dependent potassium channel, KATP. This channel is a transmembrane protein encoded by the KCNJ11 and ABCC8 genes. Furthermore, polymorphisms in these genes have been linked to type 2 diabetes because of the role of KATP in insulin release. While several genetic variations have been reported to be associated with this disease, the E23K polymorphism is most commonly associated with this pathology, as well as to obesity. Here, we review the molecular genetics of the potassium channel and discusses its most described polymorphisms and their associations with type 2 diabetes mellitus.
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Affiliation(s)
- Dianne Heloisa Bonfanti
- Health and Biosciences School, Pontifical Catholic University of Parana, Curitiba, Parana, Brazil
| | - Larissa Pontes Alcazar
- Health and Biosciences School, Pontifical Catholic University of Parana, Curitiba, Parana, Brazil
| | - Priscila Akemi Arakaki
- Health and Biosciences School, Pontifical Catholic University of Parana, Curitiba, Parana, Brazil
| | - Laysa Toschi Martins
- Health and Biosciences School, Pontifical Catholic University of Parana, Curitiba, Parana, Brazil
| | - Bruna Carla Agustini
- Health and Biosciences School, Pontifical Catholic University of Parana, Curitiba, Parana, Brazil
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12
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The genetics of diabetic pregnancy. Best Pract Res Clin Obstet Gynaecol 2014; 29:102-9. [PMID: 25438929 DOI: 10.1016/j.bpobgyn.2014.08.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 08/16/2014] [Indexed: 01/19/2023]
Abstract
Advancements in molecular technology coupled with a greater awareness of the human genome and epigenome have broadened our understanding of the genetic contributions to the diabetic pregnancy. There are multiple genes and pathways that can result in a hyperglycemic environment for the fetus. Exposure to this environment in utero has an impact on the risk of adult-onset chronic diseases. How identification of an individual's genetic variants will impact clinical care and outcomes will continue to evolve as our understanding grows.
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Haghverdizadeh P, Sadat Haerian M, Haghverdizadeh P, Sadat Haerian B. ABCC8 genetic variants and risk of diabetes mellitus. Gene 2014; 545:198-204. [DOI: 10.1016/j.gene.2014.04.040] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 04/18/2014] [Indexed: 12/16/2022]
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Wang X, Chang X, Li J, Yin L, Sun K. DNA methylation of microRNA-375 in impaired glucose tolerance. Exp Ther Med 2014; 8:775-780. [PMID: 25120598 PMCID: PMC4113527 DOI: 10.3892/etm.2014.1816] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 05/28/2014] [Indexed: 12/21/2022] Open
Abstract
In the present study, the expression levels and DNA methylation status of microRNA (miRNA)-375 in patients with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) were analyzed and the role of DNA methylation of miRNA-375 in the pathogenesis of T2DM was investigated. Compared with the miR-375 levels in patients with normal glucose tolerance (NGT; n=53), the samples from patients with IGT (n=44) exhibited downregulation of miR-375, while those from patients with T2DM (n=54) exhibited upregulation of miR-375 in the plasma. Additionally, the samples from patients with IGT were observed to be hypermethylated compared with those from patients with T2DM and NGT (P=0.042). Analysis of three CpG units (CpG1.2, CpG20 and CpG25.26.27) from 17 CpG sites (between −990 and −1,258 bp, relative to the transcription start site) revealed higher methylation levels in patients with IGT compared with those in patients with NGT (P<0.05). The methylation of two CpG units (CpG1.2 and CpG25.26.27) was higher in patients with IGT than in the patients with T2DM (P<0.05). Thus, the present study demonstrated that the miR-375 promoter was hypermethylated and the levels of miR-375 in the plasma were downregulated in the patients with IGT. DNA hypomethylation may have an important role in the regulation of miR-375 expression and may contribute to the pathogenesis of T2DM.
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Affiliation(s)
- Xiaoli Wang
- Departments of Endocrinology and Metabolism, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Xiangyun Chang
- Departments of Endocrinology and Metabolism, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Jun Li
- Departments of Endocrinology and Metabolism, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Liang Yin
- Departments of Endocrinology and Metabolism, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Kan Sun
- Departments of Endocrinology and Metabolism, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
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Venkatesan R, Bodhini D, Narayani N, Mohan V. Association study of the ABCC8 gene variants with type 2 diabetes in south Indians. INDIAN JOURNAL OF HUMAN GENETICS 2014; 20:37-42. [PMID: 24959012 PMCID: PMC4065476 DOI: 10.4103/0971-6866.132752] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND: The ABCC8 gene which encodes the sulfonylurea receptor plays a major role in insulin secretion and is a potential candidate for type 2 diabetes. The -3c → t (rs1799854) and Thr759Thr (C → T, rs1801261) single nucleotide polymorphisms (SNPs) of the ABCC8 gene have been associated with type 2 diabetes in many populations. The present study was designed to investigate the association of these two SNPs in an Asian Indian population from south India. MATERIALS AND METHODS: A total of 1,300 subjects, 663 normal glucose tolerant (NGT) and 637 type 2 diabetic subjects were randomly selected from the Chennai Urban Rural Epidemiology Study (CURES). The -3c → t and Thr759Thr were genotyped in these subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and a few variants were confirmed by direct sequencing. RESULTS: The frequency of the ‘t’ allele of the -3c → t SNP was found to be 0.27 in NGT and 0.29 in type 2 diabetic subjects (P = 0.44). There was no significant difference in the genotypic frequency between the NGT and type 2 diabetic group (P = 0.18). Neither the genotypic frequency nor the allele frequency of the Thr759Thr polymorphism was found to differ significantly between the NGT and type 2 diabetic groups. CONCLUSION: The -3c → t and the Thr759Thr polymorphisms of the ABCC8 gene were not associated with type 2 diabetes in this study. However, an effect of these genetic variants on specific unidentified sub groups of type 2 diabetes cannot be excluded.
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Affiliation(s)
- Radha Venkatesan
- Department of Molecular Genetics, World Health Organization Collaborating Centre for Non Communicable Diseases Prevention and Control, International Diabetes Federation Centre for Education, Gopalapuram, Chennai, Tamil Nadu, India
| | - Dhanasekaran Bodhini
- Department of Molecular Genetics, World Health Organization Collaborating Centre for Non Communicable Diseases Prevention and Control, International Diabetes Federation Centre for Education, Gopalapuram, Chennai, Tamil Nadu, India
| | - Nagarajan Narayani
- Department of Molecular Genetics, World Health Organization Collaborating Centre for Non Communicable Diseases Prevention and Control, International Diabetes Federation Centre for Education, Gopalapuram, Chennai, Tamil Nadu, India
| | - Viswanathan Mohan
- Diabteology, Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialities Centre, World Health Organization Collaborating Centre for Non Communicable Diseases Prevention and Control, International Diabetes Federation Centre for Education, Gopalapuram, Chennai, Tamil Nadu, India
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Association of adiponectin (AdipoQ) and sulphonylurea receptor (ABCC8) gene polymorphisms with Type 2 Diabetes in North Indian population of Punjab. Gene 2013; 527:228-34. [PMID: 23764562 DOI: 10.1016/j.gene.2013.05.075] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 05/27/2013] [Accepted: 05/30/2013] [Indexed: 12/18/2022]
Abstract
In Type 2 Diabetes (T2D), adiponectin (AdipoQ) and sulphonylurea receptor genes (ABCC8) are important targets for candidate gene association studies. The single nucleotide polymorphisms (SNPs) in these genes have been associated with features of the metabolic syndrome across various populations. The present case-control study undertaken in the population of Punjab, evaluates the association of +45T>G polymorphism in AdipoQ gene; and Exon16-3C>T as well as Exon18C>T polymorphisms in ABCC8 gene with T2D. These SNPs were genotyped in 200 T2D cases and 200 non-diabetic healthy controls using the PCR-RFLP method. The frequency of the minor G-allele for AdipoQ+45(T>G) polymorphism was significantly higher in T2D cases (29.0%) than in controls (21.5%) [P=0.02, OR=1.49 (1.07-2.04)]. The genetic model analysis revealed that the G-allele cumulatively provides nearly 1.59-1.78 fold increased risk to T2D under the additive (P=0.009; OR=1.59, 1.12-2.25 at 95% CI), dominant (TG/GG vs. TT) (P=0.034, OR=1.64, 1.04-2.56 at 95% CI) and codominant model (TG vs. TT/GG) (P=0.014; OR=1.78, 1.12-2.82 at 95% CI) after adjusting for confounding factors. However, no difference in the distribution of genotype and allele frequencies was observed for both the ABCC8 polymorphisms. The distribution of obesity profiles (BMI, WC and WHR) was also significantly different between cases and controls (P<0.05). Higher BMI and central obesity were observed to increase the risk of T2D. G-allele of +45(T>G) polymorphism in the adiponectin gene appears to be associated with increased risk of T2D, but the polymorphisms in sulphonylurea receptor gene do not seem to be associated with T2D in the population of Punjab.
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The common C49620T polymorphism in the sulfonylurea receptor gene SUR1 (ABCC8) in patients with gestational diabetes and subsequent glucose metabolism abnormalities. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:712617. [PMID: 22927833 PMCID: PMC3426201 DOI: 10.1155/2012/712617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2012] [Accepted: 07/09/2012] [Indexed: 01/08/2023]
Abstract
AIM The aim of this study is to investigate the relationship between the common C49620T polymorphism in the sulfonylurea receptor (SUR1) gene and glucose metabolism, β-cell secretory function and insulin resistance in women with a history of gestational diabetes (GDM). MATERIAL AND METHODS Study group included 199 women, diagnosed GDM within the last 5-12 years and control group of comparable 50 women in whom GDM was excluded during pregnancy. Blood glucose and insulin levels were measured during oral glucose tolerance test. Indices of insulin resistance (HOMA-IR) and β-cell function (HOMA %B) were calculated. In all patients, the C49620T polymorphism in intron 15 of the SUR1 gene was determined. RESULTS The distribution of the studied polymorphism in the two groups did not differ from each other (χ(2) = 0.34, P = 0.8425). No association between the distribution of polymorphisms and coexisting glucose metabolism disorders (χ(2) = 7,13, P = 0, 3043) was found. No association was also observed between the polymorphism and HOMA %B or HOMA-IR. CONCLUSIONS The polymorphism C49620T in the SUR1 gene is not associated with insulin resistance and/or insulin secretion in women with a history of GDM and does not affect the development of GDM, or the development of glucose intolerance in the studied population.
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Effects of Single Nucleotide Polymorphisms in KATP Channel Genes on Type 2 Diabetes in a Turkish Population. Arch Med Res 2012; 43:317-23. [DOI: 10.1016/j.arcmed.2012.06.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Accepted: 05/24/2012] [Indexed: 01/12/2023]
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Sato R, Watanabe H, Genma R, Takeuchi M, Maekawa M, Nakamura H. ABCC8 polymorphism (Ser1369Ala): influence on severe hypoglycemia due to sulfonylureas. Pharmacogenomics 2011; 11:1743-50. [PMID: 21142918 DOI: 10.2217/pgs.10.135] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIMS Sulfonylureas are categorized according to their binding sites of the ATP-sensitive K+ channel (K(ATP) channel) complex in pancreatic β-cells. The binding sites are classified as A, B and A + B site (both A and B sites), respectively. The Ser1369Ala variant in the sulfonylurea receptor gene ABCC8 which encodes a subunit of the K(ATP) channel complex has been demonstrated to be associated with the hypoglycemic effect of gliclazide, which binds to the A site. However, the hypoglycemic effect of the Ser1369Ala variant on treatment with A + B binding site sulfonylureas, such as glimepiride or glibenclamide, is still uncertain. MATERIALS & METHODS In a case-control study, 32 patients with Type 2 diabetes admitted to hospital with severe hypoglycemia and 125 consecutive Type 2 diabetic outpatients without severe hypoglycemia were enrolled. We determined the genotypes of the ABCC8 polymorphism (Ser1369Ala) in the patients with or without severe hypoglycemia. All of the patients were taking glimepiride or glibenclamide. RESULTS In the patients treated with glimepiride or glibenclamide, we found no significant differences in the distribution of the Ser1369Ala genotype between patients with or without severe hypoglycemia (p = 0.26). Moreover, the Ala1369 minor allele tended to be less frequent in the hypoglycemic group (31 vs 43%; OR: 1.65; 95% CI: 0.92-2.96; p = 0.09). CONCLUSION Our findings suggest that the Ser1369Ala variant is not a major predictive factor of severe hypoglycemia due to glimepiride or glibenclamide, both of which bind to the A + B site. It is likely that severe hypoglycemia due to A + B binding site sulfonylureas will be mediated by other factors, and not the Ala1369 minor allele.
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Affiliation(s)
- Ryosuke Sato
- Department of Endocrinology & Metabolism, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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20
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A new strategy for the chemoselective sulfonamide N-alkylation of sulfonyl ureas under neutral and mild conditions. Tetrahedron Lett 2010. [DOI: 10.1016/j.tetlet.2010.06.054] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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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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Chistiakov DA, Potapov VA, Khodirev DC, Shamkhalova MS, Shestakova MV, Nosikov VV. Genetic variations in the pancreatic ATP-sensitive potassium channel, beta-cell dysfunction, and susceptibility to type 2 diabetes. Acta Diabetol 2009; 46:43-9. [PMID: 18758683 DOI: 10.1007/s00592-008-0056-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2008] [Accepted: 07/20/2008] [Indexed: 12/22/2022]
Abstract
The KCNJ11 and ABCC8 genes encode the components of the pancreatic ATP-sensitive potassium (KATP) channel, which regulates insulin secretion by beta-cells and hence could be involved in the pathogenesis of type 2 diabetes (T2D). The KCNJ11 E23K and ABCC8 exon 31 variants have been studied in 127 Russian T2D patients and 117 controls using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. The KCNJ11 E23 variant and the ABCC8 exon 31 allele A were associated with higher risk of T2D [Odds ratio (OR) of 1.53 (P=0.023) and 2.41 (P=1.95 x 10(-5))], respectively. Diabetic carriers of the ABCC8 G/G variant had reduced 2 h glucose compared to A/A+A/G (P=0.031). The G/G genotype of ABCC8 was also significantly associated with increased both fasting and 2 h serum insulin in diabetic and non-diabetic patients. A HOMA-beta value characterizing the beta-cell homeostasis was higher in the non-diabetic carriers homozygous for G/G (98.0+/-46.9) then for other genotypes (HOMA-beta = 85.6+/-45.5 for A/A+A/G, P=0.0015). The KCNJ11 E23K and ABCC8 exon 31 variants contribute to susceptibility to T2D diabetes, glucose intolerance and altered insulin secretion in a Russian population.
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Affiliation(s)
- D A Chistiakov
- Department of Pathology, University of Pittsburgh, A709 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261, USA.
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Cho YM, Kim TH, Lim S, Choi SH, Shin HD, Lee HK, Park KS, Jang HC. Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population. Diabetologia 2009; 52:253-61. [PMID: 19002430 DOI: 10.1007/s00125-008-1196-4] [Citation(s) in RCA: 172] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2008] [Accepted: 10/10/2008] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS New genetic variants associated with susceptibility to type 2 diabetes mellitus have been discovered in recent genome-wide association (GWA) studies. The aim of the present study was to examine the association between these diabetogenic variants and gestational diabetes mellitus (GDM). METHODS The study included 869 Korean women with GDM and 345 female and 287 male Korean non-diabetic controls. We genotyped the single nucleotide polymorphisms (SNPs) rs7756992 and rs7754840 in CDKAL1; rs564398, rs1333040, rs10757278 and rs10811661 in the CDKN2A-CDKN2B region; rs8050136 in FTO; rs1111875, rs5015480 and rs7923837 in HHEX; rs4402960 in IGF2BP2; and rs13266634 in SLC30A8. In addition, rs7903146 and rs12255372 in TCF7L2; rs5215 and rs5219 in KCNJ11; and rs3856806 and rs1801282 in PPARG were genotyped. The genotype frequencies in the GDM patients were compared with those in the non-diabetic controls. RESULTS Compared with controls (men and women combined), GDM was associated with rs7756992 and rs7754840 (OR 1.55, 95% CI 1.34-1.79, p = 4.17 x 10(-9)) in CDKAL1; rs10811661 (OR 1.49, 95% CI 1.29-1.72, p = 1.05 x 10(-7)) in the CDKN2A-CDKN2B region; rs1111875 (OR 1.27, 95% CI 1.09-1.49, p = 0.003), rs5015480, and rs7923837 in HHEX; rs4402960 (OR 1.18, 95% CI 1.01-1.38, p = 0.03) in IGF2BP2; rs13266634 (OR 1.24, 95% CI 1.07-1.43, p = 0.005) in SLC30A8; and rs7903146 (OR 1.58, 95% CI 1.03-2.43, p = 0.038) in TCF7L2. The risk alleles of the SNPs rs7756992 and rs7754840 in CDKAL1; rs10811661 in the CDKN2A-CDKN2B region; and rs1111875, rs5015480 and rs7923837 in HHEX were associated with significant decreases in the insulin AUC during a 100 g OGTT performed at the time of diagnosis of GDM. CONCLUSIONS/INTERPRETATION Some of the type 2 diabetes-associated genetic variants that were discovered in the recent GWA studies are also associated with GDM in Koreans.
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Affiliation(s)
- Y M Cho
- Department of Internal Medicine, College of Medicine, Seoul National University, 28 Yongon-Dong Chongno-Gu, Seoul 110-744, Korea
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Feng Y, Mao G, Ren X, Xing H, Tang G, Li Q, Li X, Sun L, Yang J, Ma W, Wang X, Xu X. Ser1369Ala variant in sulfonylurea receptor gene ABCC8 is associated with antidiabetic efficacy of gliclazide in Chinese type 2 diabetic patients. Diabetes Care 2008; 31:1939-44. [PMID: 18599530 PMCID: PMC2551631 DOI: 10.2337/dc07-2248] [Citation(s) in RCA: 138] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The purpose of this study was to investigate whether genetic variants could influence the antidiabetic efficacy of gliclazide in type 2 diabetic patients. RESEARCH DESIGN AND METHODS A total of 1,268 type 2 diabetic patients whose diabetes was diagnosed within the past 5 years and who had no recent hypoglycemic treatment were enrolled from 23 hospitals in China. All of the patients were treated with gliclazide for 8 weeks. Fasting and oral glucose tolerance test 2-h plasma glucose, fasting insulin, and A1C were measured at baseline and after 8 weeks of treatment. We used two independent cohorts to test the associations of 25 single nuclear polymorphisms in 11 candidate genes with the antidiabetic efficacy of gliclazide. A general linear regression model was used to test the association with adjustment for important covariates. RESULTS After 8 weeks of gliclazide therapy, mean fasting plasma glucose (FPG) was reduced from 11.1 mmol/l at baseline to 7.7 mmol/l. In cohort 1, we genotyped all 25 SNPs (n = 661) and found that Ser1369Ala of the ABCC8 gene and rs5210 of the KCNJ11 gene were significantly associated with decreases in FPG (P = 0.002). We further genotyped Ser1369Ala in cohort 2 (n = 607) and confirmed the association identified in cohort 1. In the pooled analysis, compared with subjects with the Ser/Ser genotype, subjects with the Ala/Ala genotype had a 7.7% greater decrease in FPG (P < 0.001), an 11.9% greater decrease in 2-h plasma glucose (P = 0.003), and a 3.5% greater decrease in A1C (P = 0.06) after 8 weeks of treatment with gliclazide. CONCLUSIONS In two independent cohorts of Chinese type 2 diabetic patients, we found consistent evidence that the Ser1369Ala variant in the ABCC8 gene can influence the antidiabetic efficacy of gliclazide.
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Affiliation(s)
- Yan Feng
- Anhui Biomedical Institute, Anhui Medical University, Hefei, China
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Chistiakov DA, Potapov VA, Khodirev DS, Shamkhalova MS, Shestakova MV, Nosikov VV. The KCNJ11 E23K and ABCC8 exon 31 variants contribute to susceptibility to type 2 diabetes, glucose intolerance and altered insulin secretion in a Russian population. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 2008. [DOI: 10.1016/j.dsx.2008.04.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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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: 99] [Impact Index Per Article: 5.8] [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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Kilpeläinen TO, Lakka TA, Laaksonen DE, Laukkanen O, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Aunola S, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Tuomilehto J, Uusitupa M, Laakso M. Physical activity modifies the effect of SNPs in the SLC2A2 (GLUT2) and ABCC8 (SUR1) genes on the risk of developing type 2 diabetes. Physiol Genomics 2007; 31:264-72. [PMID: 17636114 DOI: 10.1152/physiolgenomics.00036.2007] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Single nucleotide polymorphisms (SNPs) in two genes regulating insulin secretion, SLC2A2 (encoding GLUT2) and ABCC8 (encoding SUR1), were associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes (T2D) in the Finnish Diabetes Prevention Study (DPS). We determined whether physical activity (PA), assessed annually with a questionnaire, modified the association of SNPs in SLC2A2 and ABCC8 with the conversion to T2D in the combined intervention and control groups of the DPS. Finnish overweight subjects with IGT (N = 479) were followed for an average of 4.1 yr. The interaction of the SNPs with the change in PA on the conversion to T2D was assessed using Cox regression with adjustments for the other components of the intervention (dietary changes, weight reduction). The carriers of the common homozygous genotype of rs5393, rs5394, or rs5404 of SLC2A2 and rs3758947 of ABCC8 who were in the lower third of the change in moderate-to-vigorous PA during the follow-up had a 2.6- to 3.7-fold increased risk of developing T2D compared with the upper third, whereas the rare allele carriers seemed to be unresponsive to changes in moderate-to-vigorous PA (for the interaction of genotype with change in PA, P = 0.022-0.027 for the SNPs in SLC2A2, and P = 0.007 for rs3758947). We conclude that moderate-to-vigorous PA may modify the risk of developing T2D associated with genes regulating insulin secretion (SLC2A2, ABCC8) in persons with IGT.
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Affiliation(s)
- T O Kilpeläinen
- Institute of Biomedicine, Physiology, University of Kuopio, Kuopio, Finland.
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Zhang H, Liu X, Kuang H, Yi R, Xing H. Association of sulfonylurea receptor 1 genotype with therapeutic response to gliclazide in type 2 diabetes. Diabetes Res Clin Pract 2007; 77:58-61. [PMID: 17118480 DOI: 10.1016/j.diabres.2006.10.021] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2006] [Revised: 09/10/2006] [Accepted: 10/06/2006] [Indexed: 12/14/2022]
Abstract
To investigate the effects of sulfonylurea receptor 1 (SUR1) exon 33 (TCC-->GCC, S1369A) polymorphism on responsiveness to gliclazide. About 115 patients with type 2 diabetes were treated with gliclazide for 8 weeks. SUR1 genotypes were tested by Taqman-PCR. After gliclazide treatment, there was association between T/G polymorphism and decrease of HbA1c. G carriers were more sensitive to gliclazide and the decrease of HbA1c was more significant than TT genotype (TT, 0.76%+/-1.70%; TG+GG, 1.60%+/-1.39%, P=0.044). The polymorphism of SUR1S1369A was associated with the therapeutic efficacy of gliclazide.
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Affiliation(s)
- Huijuan Zhang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Affiliation(s)
- Thomas A Buchanan
- Departments of Medicine, Obstetrics and Gynecology, and Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
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Litou H, Anastasiou E, Thalassinou L, Sarika HL, Philippou G, Alevizaki M. Increased prevalence of VNTR III of the insulin gene in women with gestational diabetes mellitus (GDM). Diabetes Res Clin Pract 2007; 76:223-8. [PMID: 17011062 DOI: 10.1016/j.diabres.2006.08.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2006] [Revised: 06/18/2006] [Accepted: 08/29/2006] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The VNTR polymorphism in the promoter region of the insulin gene (INS-VNTR) affects transcription rate and has been associated with insulin resistance and DM2. Gestational diabetes mellitus (GDM) is a multifactorial disorder, where both impaired insulin secretion and action may be involved. The aim of the study was to examine the distribution of the INS-VNTRs in women with GDM and to investigate possible associations with features of beta cell function and glycaemic control in this population. METHODS One hundred and sixty-one women with GDM and 111 normal pregnant women (n) were genotyped for INS-VNTR during the 24th-32nd pregnancy week. Glucose and insulin levels were determined during the diagnostic OGTT. The majority of the previous GDM women were also examined at 3-6 months post-partum. RESULTS VNTR class III/III genotype was significantly more frequent in the GDM group 8.7% versus 2.7%, p=0.02 giving an OR of 3.97 (1.1-14.29). An increased frequency of the VNTR class III allele was found in those GDM women who required insulin for treatment compared to those controlled with diet alone (12.4% versus 4%, p<0.001). Basal insulin levels tended to be lower in GDM women homozygous for the class III allele without reaching statistical significance (p=0.09). CONCLUSIONS The INS-VNTR class III is more frequent in women who develop GDM, and may be associated with decreased ability of the beta cell to meet the increased insulin requirements as reflected by the need for insulin supplementation for adequate glycaemic control.
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Affiliation(s)
- Hariklia Litou
- Endocrine Unit, Evgenideion Hospital, Department of Clinical Therapeutics, Alexandra University Hospital, 115 28 Athens, Greece
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Abstract
The etiology of type 2 diabetes (T2D) is complex and remains poorly understood. Differences in individual susceptibility to this condition reflect the action of multiple variants, each of which confers a modest effect, and their interactions with a variety of environmental exposures. Several complementary approaches to the identification of the etiological variants have been adopted, though, for all, association analyses provide the final common pathway. The genes and/or chromosomal regions studied have been selected on the basis of their presumed biological relevance to diabetes, known involvement in monogenic forms, or animal models of the condition and/or signals arising from whole-genome linkage scans. These association studies have featured a wide variety of designs and analytical approaches, but reliable biological insights have been few, largely because of difficulties in obtaining reproducible findings. However, in recent years, several examples of robustly replicated associations have emerged, largely as a result of an emphasis on the need for improved power and more appropriate analysis and interpretation. New strategies for the large-scale identification of T2D susceptibility variants are now becoming possible, including the prospect of genuine genome-wide association scans, but caution in their design, analysis, and interpretation remains essential.
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Affiliation(s)
- Eleftheria Zeggini
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK
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32
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Yokoi N, Kanamori M, Horikawa Y, Takeda J, Sanke T, Furuta H, Nanjo K, Mori H, Kasuga M, Hara K, Kadowaki T, Tanizawa Y, Oka Y, Iwami Y, Ohgawara H, Yamada Y, Seino Y, Yano H, Cox NJ, Seino S. Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects. Diabetes 2006; 55:2379-86. [PMID: 16873704 DOI: 10.2337/db05-1203] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic beta-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2-2, NKX6-1, and NEUROD1) and genes encoding the ATP-sensitive K(+) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 -3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97-1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.
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Affiliation(s)
- Norihide Yokoi
- Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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Shaat N, Ekelund M, Lernmark A, Ivarsson S, Almgren P, Berntorp K, Groop L. Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus. Diabetologia 2005; 48:2544-51. [PMID: 16320083 DOI: 10.1007/s00125-005-0035-0] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2005] [Accepted: 08/22/2005] [Indexed: 02/06/2023]
Abstract
AIMS/HYPOTHESIS Gestational diabetes mellitus (GDM) and type 2 diabetes share a common pathophysiological background, including beta cell dysfunction and insulin resistance. In addition, women with GDM are at increased risk of developing type 2 diabetes later in life. Our aim was to investigate whether, like type 2 diabetes, GDM has a genetic predisposition by studying five common polymorphisms in four candidate genes that have previously been associated with type 2 diabetes. MATERIALS AND METHODS We studied 1,777 unrelated Scandinavian women (588 with GDM and 1,189 pregnant non-diabetic controls) for polymorphisms in the genes encoding potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11 E23K), insulin receptor substrate 1 (IRS1 G972R), uncoupling protein 2 (UCP2 -866G-->A) and calpain 10 (CAPN10 SNP43 and SNP44). RESULTS The EE, EK and KK genotype frequencies of the KCNJ11 E23K polymorphism differed significantly between GDM and control women (31.5, 52.7 and 15.8% vs 37.3, 48.8 and 13.9%, respectively; p=0.050). In addition, the frequency of the K allele was increased in women with GDM (odds ratio [OR]=1.17, 95% CI 1.02-1.35; p=0.027), and this effect was greater under a dominant model (KK/EK vs EE) (OR=1.3, 95% CI 1.05-1.60; p=0.016). Analysis of the IRS1 G972R polymorphism showed that RR homozygosity was found exclusively in women with GDM (91.0, 8.3 and 0.7% vs 90.7, 9.3 and 0.0% for GG, GR and RR genotypes, respectively; p=0.014). The genotype and allele frequencies of the other polymorphisms studied were not statistically different between the GDM and control women. CONCLUSIONS/INTERPRETATION The E23K polymorphism of KCNJ11 seems to predispose to GDM in Scandinavian women.
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Affiliation(s)
- N Shaat
- Department of Clinical Sciences/Diabetes and Endocrinology, Malmö University Hospital, Lund University, Malmö, Sweden.
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Hansen SK, Nielsen EMD, Ek J, Andersen G, Glümer C, Carstensen B, Mouritzen P, Drivsholm T, Borch-Johnsen K, Jørgensen T, Hansen T, Pedersen O. Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes. J Clin Endocrinol Metab 2005; 90:3629-37. [PMID: 15797964 DOI: 10.1210/jc.2004-1942] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
The separate and combined effects of the PPARG Pro(12)Ala polymorphism and the KCNJ11 Glu(23)Lys polymorphisms on risk of type 2 diabetes were investigated in relatively large-scale, case-control studies. Separate effects of the variants were examined among 1187/1461 type 2 diabetic patients and 4791/4986 middle-aged, glucose-tolerant subjects. The combined analysis involved 1164 type 2 diabetic patients and 4733 middle-aged, glucose-tolerant subjects. In the separate analyses, the K allele of the KCNJ11 Glu(23)Lys associated with type 2 diabetes (odds ratio, 1.19; P = 0.0002), whereas the PPARG Pro(12)Ala showed no significant association with type 2 diabetes. The combined analysis indicated that the two polymorphisms acted in an additive manner to increase the risk of type 2 diabetes, and we found no evidence for a synergistic interaction between them. Analysis of a model with equal additive effects of the two variants showed that the odds ratio for type 2 diabetes increased with 1.14/risk allele (P = 0.003). Together, the two polymorphisms conferred a population-attributable risk for type 2 diabetes of 28%. In conclusion, our results showed no evidence of a synergistic interaction between the KCNJ11 Glu(23)Lys and PPARG Pro(12)Ala polymorphisms, but indicated that they may act in an additive manner to increase the risk of type 2 diabetes.
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Affiliation(s)
- Sara K Hansen
- Steno Diabetes Center and Hagedorn Research Institute, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark
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Hussain K, Cosgrove KE. From congenital hyperinsulinism to diabetes mellitus: the role of pancreatic beta-cell KATP channels. Pediatr Diabetes 2005; 6:103-13. [PMID: 15963039 DOI: 10.1111/j.1399-543x.2005.00109.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Pancreatic beta-cell adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels play a pivotal role in linking glucose metabolism to regulated insulin secretion. K(ATP) channels are hetero-octameric complexes comprising two subunits Kir6.2 and sulfonylurea receptor 1 (SUR1). Changes in the intracellular concentration of nucleotides (ATP) cause alterations in the resting and opening state of the K(ATP) channels. Loss-of-function mutations in the genes encoding the two subunits of K(ATP) channels lead to the most common form of congenital hyperinsulinism (CHI). This causes persistent and severe hypoglycemia in the neonatal and infancy period. CHI can cause mental retardation and epilepsy if not treated properly. On the other hand, now there is evidence of an association between polymorphisms in the Kir6.2 gene and type 2 diabetes mellitus, mutations in the Kir6.2 gene and neonatal diabetes mellitus, and mutations in the SUR1 gene and diabetes mellitus. Interestingly, for reasons that are unclear at present, mice knockout models of K(ATP) channels are different from the human phenotype of CHI. This article is a review focusing on how abnormalities in the pancreatic beta-cell K(ATP) channels can lead to severe hypoglycemia on the one hand and diabetes mellitus on the other.
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Affiliation(s)
- Khalid Hussain
- The London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children NHS Trust, London, UK.
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36
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Abstract
Gestational diabetes mellitus (GDM) is defined as glucose intolerance of various degrees that is first detected during pregnancy. GDM is detected through the screening of pregnant women for clinical risk factors and, among at-risk women, testing for abnormal glucose tolerance that is usually, but not invariably, mild and asymptomatic. GDM appears to result from the same broad spectrum of physiological and genetic abnormalities that characterize diabetes outside of pregnancy. Indeed, women with GDM are at high risk for having or developing diabetes when they are not pregnant. Thus, GDM provides a unique opportunity to study the early pathogenesis of diabetes and to develop interventions to prevent the disease.
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Affiliation(s)
- Thomas A Buchanan
- Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California 90089-9317, USA.
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37
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Abstract
Type 2 diabetes (T2D) has become a health-care problem worldwide, with the rise in disease prevalence being all the more worrying as it not only affects the developed world but also developing nations with fewer resources to cope with yet another major disease burden. Furthermore, the problem is no longer restricted to the ageing population, as young adults and children are also being diagnosed with T2D. In recent years, there has been a surge in the number of genetic studies of T2D in attempts to identify some of the underlying risk factors. In this review, I highlight the main genes known to cause uncommon monogenic forms of diabetes (e.g. maturity-onset diabetes of the young--MODY--and insulin resistance syndromes), as well as describe some of the main approaches used to identify genes involved in the more common forms of T2D that result from the interaction between environmental risk factors and predisposing genotypes. Linkage and candidate gene studies have been highly successful in the identification of genes that cause the monogenic variants of diabetes and, although progress in the more common forms of T2D has been slow, a number of genes have now been reproducibly associated with T2D risk in multiple studies. These are discussed, as well as the main implications that the diabetes gene discoveries will have in diabetes treatment and prevention.
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Affiliation(s)
- I Barroso
- Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge, UK.
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van Dam RM, Hoebee B, Seidell JC, Schaap MM, de Bruin TWA, Feskens EJM. Common variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance: population-based studies and meta-analyses. Diabet Med 2005; 22:590-8. [PMID: 15842514 DOI: 10.1111/j.1464-5491.2005.01465.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
AIMS To evaluate the relation between common variants in the ATP-sensitive K+ channel genes and glucose intolerance. METHODS We conducted a meta-analysis of reported association studies in Caucasian populations for common variants in the ABCC8 (exons 16 and 18) and the KCNJ11 (E23K) gene and examined sources of heterogeneity in the results. The meta-analysis was based on 7768-10216 subjects (depending on the gene variant), and included two new population-based studies in the Netherlands with 725 cases and 742 controls. RESULTS For the KCNJ11 variant, the summary odds ratio (OR) for glucose intolerance was 1.12 (1.01-1.23, P=0.03) for the EK genotype and 1.44 (1.17-1.78, P=0.0007) for the KK genotype, as compared with the EE genotype. For the ABCC8 exon 16 variant, the OR was 1.06 (0.94-1.19, P=0.34) for ct and 0.93 (0.71-1.20, P=0.56) for tt, as compared with the cc genotype. For ABCC8 exon 18, the OR was 1.20 (0.97-1.49, P=0.10) for CT/TT, as compared with the CC genotype. Studies of the ABCC8 variants that were published first or had smaller sample sizes (for the exon 18 variant) showed stronger associations, which may indicate publication bias. For the ABCC8 exon 18 and the KCNJ11 variant, associations were stronger for studies of clinical diabetes than newly detected glucose intolerance. The population attributable risk for clinical Type 2 diabetes was 6.2% for the KCNJ11 KK genotype and 10.1% for the KCNJ11 EK and KK genotype combined. CONCLUSIONS The common KCNJ11 E23K gene variant, but not the ABCC8 exon 16 or exon 18 variant, was consistently associated with Type 2 diabetes.
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Affiliation(s)
- R M van Dam
- Centre of Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
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39
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Abstract
Gestational diabetes mellitus (GDM) is defined as glucose intolerance of various degrees that is first detected during pregnancy. GDM is detected through the screening of pregnant women for clinical risk factors and, among at-risk women, testing for abnormal glucose tolerance that is usually, but not invariably, mild and asymptomatic. GDM appears to result from the same broad spectrum of physiological and genetic abnormalities that characterize diabetes outside of pregnancy. Indeed, women with GDM are at high risk for having or developing diabetes when they are not pregnant. Thus, GDM provides a unique opportunity to study the early pathogenesis of diabetes and to develop interventions to prevent the disease.
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Affiliation(s)
- Thomas A Buchanan
- Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California 90089-9317, USA.
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40
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Lauenborg J, Damm P, Ek J, Glümer C, Jørgensen T, Borch-Johnsen K, Vestergaard H, Hornnes P, Pedersen O, Hansen T. Studies of the Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene and the relationship to beta-cell function during an OGTT in glucose-tolerant women with and without previous gestational diabetes mellitus. Diabet Med 2004; 21:1310-5. [PMID: 15569134 DOI: 10.1111/j.1464-5491.2004.01343.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
AIMS In pregnancies complicated by gestational diabetes mellitus (GDM) an increased demand for insulin is not met due to beta-cell dysfunction. An Ala/Val polymorphism at codon 98 of the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene has been associated with decreased serum insulin and C-peptide responses during an oral glucose tolerance test (OGTT) in glucose-tolerant subjects. The aims of the present study were to evaluate the influence of the polymorphism on the serum insulin and C-peptide responses to an OGTT in glucose-tolerant women with and without previous GDM and to investigate if this polymorphism is associated with GDM. METHODS The Ala/Val98 polymorphism was measured in 376 women of Danish origin with previous GDM, and in 724 age-matched and 310 middle-aged glucose tolerant women using polymerase chain reaction-restriction fragment length polymorphism. RESULTS The allelic frequency of the Ala/Val98 polymorphism was 0.043 [95% confidence interval (CI) 0.028, 0.057] in women with previous GDM vs. 0.037 (95% CI 0.028, 0.047) in age-matched and 0.039 (95% CI 0.024, 0.054) in middle-age women. Among 117 glucose-tolerant women with previous GDM, 10 carriers of the Ala/Val98 polymorphism had a non-significant 27% and 22% reduction in serum C-peptide and insulin levels, respectively, at 30 min during an OGTT. Seventy-eight control subjects carrying the Ala/Val98 polymorphism had a 10% (P = 0.001) and 16% (P = 0.004) reduction in serum C-peptide and insulin levels, respectively, compared with 956 Ala/Ala control subjects. CONCLUSIONS The Ala/Val polymorphism at codon98 of HNF-1alpha is not associated with GDM in Danish women. However, the codon 98 variant is associated with a significant impairment of serum insulin and C-peptide responses during an OGTT in glucose-tolerant women without previous GDM.
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Affiliation(s)
- J Lauenborg
- Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark.
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Florez JC, Burtt N, de Bakker PIW, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 2004; 53:1360-8. [PMID: 15111507 DOI: 10.2337/diabetes.53.5.1360] [Citation(s) in RCA: 238] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The genes for the sulfonylurea receptor (SUR1; encoded by ABCC8) and its associated islet ATP-sensitive potassium channel (Kir6.2; encoded by KCNJ11) are adjacent to one another on human chromosome 11. Multiple studies have reported association of the E23K variant of Kir6.2 with risk of type 2 diabetes. Whether and how E23K itself-or other variant(s) in either of these two closely linked genes-influences type 2 diabetes remains to be fully determined. To better understand genotype-phenotype correlation at this important candidate gene locus, we 1) characterized haplotype structures across the gene region by typing 77 working, high-frequency markers spanning 207 kb and both genes; 2) performed association studies of E23K and nearby markers in >3,400 patients (type 2 diabetes and control) not previously reported in the literature; and 3) analyzed the resulting data for measures of insulin secretion. These data independently replicate the association of E23K with type 2 diabetes with an odds ratio (OR) in the new data of 1.17 (P = 0.003) as compared with an OR of 1.14 provided by meta-analysis of previously published, nonoverlapping data (P = 0.0002). We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S) in the neighboring SUR1 gene (r(2) > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region are most likely responsible for the reported association. We show that E23K is also associated with decreased insulin secretion in glucose-tolerant control subjects, supporting a mechanism whereby beta-cell dysfunction contributes to the common form of type 2 diabetes. Like peroxisome proliferator-activated receptor gamma, the SUR1/Kir6.2 gene region both contributes to the inherited risk of type 2 diabetes and encodes proteins that are targets for hypoglycemic medications, providing an intriguing link between the underlying mechanism of disease and validated targets for pharmacological treatment.
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Affiliation(s)
- Jose C Florez
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
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Shaat N, Ekelund M, Lernmark A, Ivarsson S, Nilsson A, Perfekt R, Berntorp K, Groop L. Genotypic and phenotypic differences between Arabian and Scandinavian women with gestational diabetes mellitus. Diabetologia 2004; 47:878-84. [PMID: 15095040 DOI: 10.1007/s00125-004-1388-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2003] [Accepted: 03/01/2004] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS Gestational diabetes mellitus is a heterogeneous disorder characterised by impaired insulin secretion and action. Our aim was to study whether autoimmunity, variations in genes affecting insulin secretion and action, or both, contribute to the development of gestational diabetes and whether the pathogenesis of the disease differs between women with a Scandinavian or Arabian background. METHODS We studied a total of 500 unrelated women with gestational diabetes (400 Scandinavian and 100 Arabian) and 550 unrelated pregnant non-diabetic control women (428 Scandinavian and 122 Arabian) matched for ethnicity. RESULTS Arabian women with gestational diabetes were 50% more insulin resistant for the same BMI compared with Scandinavian women with the disease (homeostasis model assessment [HOMA-IR]; 3.2+/-0.3 vs 2.2+/-0.2, p=0.02). Both Scandinavian (4.2% vs 0.9%, p=0.008) and Arabian (4.6% vs 0.0%, p=0.03) women with gestational diabetes had a higher frequency of GAD antibodies (GAD65Ab) than the matched controls. The frequency of HLA-DQB1 risk genotypes was slightly higher in Scandinavian women with gestational diabetes than in the Scandinavian controls (46.3% vs 38.8%, p=0.03) but no significant difference was found between the Arabian women with gestational diabetes and the Arabian controls (47% vs 51.6%, p=0.47). There were no significant differences in the frequency of the insulin gene variable number of tandem repeat ( INS VNTR) alleles and genotypes or the peroxisome proliferator-activated receptor-gamma 2 ( PPAR gamma 2-Pro12Ala) polymorphism between the women with gestational diabetes and the control women either in Arabian or in Scandinavian women. CONCLUSIONS/INTERPRETATION Gestational diabetes mellitus was associated with the presence of GAD65Ab in both study groups. Scandinavian women with gestational diabetes may share some genetic features with Type 1 diabetes. In addition, Arabian women with gestational diabetes are more insulin resistant than Scandinavian women with gestational diabetes and with the same BMI.
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Affiliation(s)
- N Shaat
- Department of Endocrinology, Lund University, Wallenberg Laboratory, University Hospital MAS, Malmo, Sweden.
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43
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Florez JC, Hirschhorn J, Altshuler D. The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits. Annu Rev Genomics Hum Genet 2003; 4:257-91. [PMID: 14527304 DOI: 10.1146/annurev.genom.4.070802.110436] [Citation(s) in RCA: 201] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Diabetes encompasses a heterogeneous group of diseases, each with a substantial genetic component. We review the division of diabetes into different subtypes based on clinical phenotype, the fruitful pursuit of genes underlying monogenic forms of the disease, the successes and drawbacks of whole-genome linkage scans in type 1 and type 2 diabetes, and the recent identification of several diabetes genes by large association studies. We use the lessons learned from this extensive body of evidence to illustrate general implications for the genetic analysis of complex traits.
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Affiliation(s)
- Jose C Florez
- Diabetes Unit and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
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44
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Seino S, Miki T. Physiological and pathophysiological roles of ATP-sensitive K+ channels. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2003; 81:133-76. [PMID: 12565699 DOI: 10.1016/s0079-6107(02)00053-6] [Citation(s) in RCA: 383] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
ATP-sensitive potassium (K(ATP)) channels are present in many tissues, including pancreatic islet cells, heart, skeletal muscle, vascular smooth muscle, and brain, in which they couple the cell metabolic state to its membrane potential, playing a crucial role in various cellular functions. The K(ATP) channel is a hetero-octamer comprising two subunits: the pore-forming subunit Kir6.x (Kir6.1 or Kir6.2) and the regulatory subunit sulfonylurea receptor SUR (SUR1 or SUR2). Kir6.x belongs to the inward rectifier K(+) channel family; SUR belongs to the ATP-binding cassette protein superfamily. Heterologous expression of differing combinations of Kir6.1 or Kir6.2 and SUR1 or SUR2 variant (SUR2A or SUR2B) reconstitute different types of K(ATP) channels with distinct electrophysiological properties and nucleotide and pharmacological sensitivities corresponding to the various K(ATP) channels in native tissues. The physiological and pathophysiological roles of K(ATP) channels have been studied primarily using K(ATP) channel blockers and K(+) channel openers, but there is no direct evidence on the role of the K(ATP) channels in many important cellular responses. In addition to the analyses of naturally occurring mutations of the genes in humans, determination of the phenotypes of mice generated by genetic manipulation has been successful in clarifying the function of various gene products. Recently, various genetically engineered mice, including mice lacking K(ATP) channels (knockout mice) and mice expressing various mutant K(ATP) channels (transgenic mice), have been generated. In this review, we focus on the physiological and pathophysiological roles of K(ATP) channels learned from genetic manipulation of mice and naturally occurring mutations in humans.
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Affiliation(s)
- Susumu Seino
- Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8760, Japan.
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Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 2003; 52:568-72. [PMID: 12540637 DOI: 10.2337/diabetes.52.2.568] [Citation(s) in RCA: 507] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.
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Affiliation(s)
- Anna L Gloyn
- Centre for Molecular Genetics, Peninsula Medical School, Exeter, UK
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Abstract
The rapid increase of diabetes prevalence in the US population and across all westernized world has been associated with environmental changes that promote obesity. Although dietary factors, such as total caloric intake, relative excess of dietary saturated fats content and lack of fibers, together with reduced level of physical activity clearly determine the main features of the "obesogenic" environment typical of "western" societies, the impact of lifestyle factors on obesity and diabetes appears to differ in various ethnic groups. Although ethnic-related differences in lifestyle factors may account for some of the predisposition to obesity and diabetes of various ethnic groups, genetic factors may play a more determinant role. These observations pose important public health questions in regard to strategies for treatment and prevention of diabetes both within the multiethnic US population and in the population of origin of various ethnicities. The elucidation of the pathophysiologic mechanisms responsible for the heterogeneous relationship between obesity and type 2 diabetes in various ethnicities may give important contributions to better understand the complex mechanisms involved in the development of this disease. This review examines epidemiological and pathophysiological aspects of the interaction between environment and ethnic predisposition to type 2 diabetes.
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Affiliation(s)
- Nicola Abate
- Center for Human Nutrition, UT Southwestern Medical Center at Dallas, USA.
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Abstract
The critical involvement of ATP-sensitive potassium (KATP) channels in insulin secretion is confirmed both by the demonstration that mutations that reduce KATP channel activity underlie many if not most cases of persistent hyperinsulinemia, and by the ability of sulfonylureas, which inhibit KATP channels, to enhance insulin secretion in type II diabetics. By extrapolation, we contend that mutations that increase beta-cell KATP channel activity should inhibit glucose-dependent insulin secretion and underlie, or at least predispose to, a diabetic phenotype. In transgenic animal models, this prediction seems to be borne out. Although earlier genetic studies failed to demonstrate a linkage between KATP mutations and diabetes in humans, recent studies indicate significant association of KATP channel gene mutations or polymorphisms and type II diabetes. We suggest that further efforts to understand the involvement of KATP channels in diabetes are warranted.
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Affiliation(s)
- C G Nichols
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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Abstract
Methylation has been implied in a number of biological processes and has been shown to vary under environmental influences as well as in age. Most results on the correlation of methylation patterns with phenotypic characteristics of cells have been obtained by analysis of very few or even single genomic fragments for methylation. However, variation of methylation may more often than not be a phenomenon that affects multiple genomic loci. The role of methylation has been most conclusively demonstrated in complex disease, with cancer being the most prominent example. The influence of aging and environmental influences such as diet seems to be on global methylation patterns, in turn exerting local effects on groups of genes. Hence, methylation seems literally to be orchestrating complex genetic systems. It could, therefore, be considered an archetypal "genomics" parameter. In consequence, technologies used to analyze methylation patterns should be as industrialized as possible to capture the local events across the entire genome. Epigenomics' research team is the first to have achieved the industrialized production of genome sequence-specific wide methylation data. Our microarray and mass-spectrometry-based detection platform currently allow the analysis of up to 50,000 methylation positions per day, for the first time making methylation data amenable to sophisticated information mining. The information content of methylation position has never been analyzed using the high-dimensional statistical methods that are recognized to be required for the analysis of, for example, mRNA expression profiles or proteomic data. As methylation patterns are nothing but a quasi-digital form of expression data, their information content must be evaluated using similar but adapted algorithms. This article presents a broad set of studies that demonstrate that methylation yields information that is comparable or even superior to the current state of the art, namely, mRNA profiling. We argue that the resulting robust, digital and-because of the highly stable nature of DNA as the analyte-more reproducible information could become the "gold standard" for clinical diagnostics and disease gene identification in age-related, environmentally influenced and epigenetic disease in general, substituting for mRNA expression.
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Gloyn AL, Hashim Y, Ashcroft SJ, Ashfield R, Wiltshire S, Turner RC. Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53). Diabet Med 2001; 18:206-12. [PMID: 11318841 DOI: 10.1046/j.1464-5491.2001.00449.x] [Citation(s) in RCA: 136] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIMS The beta-cell ATP-sensitive potassium channel consists of two subunits, SUR1 and Kir6.2. Population association studies have shown that three variants in SUR1 and one in Kir6.2 are associated with Type 2 diabetes. These polymorphisms do not result in a functional change or affect splicing, suggesting that they could be in linkage disequilibrium with a pathogenic mutation. The present study aimed firstly to screen the promoter regions of SUR1 and Kir6.2 to determine whether mutations in linkage disequilibrium with the silent variants lie in regulatory regions, which might lead to changes in gene expression. Secondly, novel and previously described variants associated with Type 2 diabetes (SUR1 exon 16-3t, exon 18 T, and Kir6.2 E23K) were investigated in the UKPDS cohort. METHODS The promoter sequences of both genes were screened by single-stranded conformational polymorphism analysis for variants associated with Type 2 diabetes. The previously reported variants were evaluated in 364 Type 2 diabetic and 328 normoglycaemic control subjects. RESULTS Two variants were detected in the SUR1 promoter, a three base insertion (caa) at -522 bp and a single base substitution at - 679 bp (c-->g). Neither of the variants were associated with diabetes, nor were they in a sequence consensus region for transcription factors. No association with diabetes was observed for either SUR1 variant. However, in contrast, analysis of the Kir6.2 E23K variant showed that the KK homozygosity was more frequent in Type 2 diabetic than control subjects. Variants were not associated with clinical characteristics nor did they affect response to sulphonylurea therapy CONCLUSION There is no support at present for mutations in either Kir6.2 or SUR1 promoter sequences contributing to Type 2 diabetes. However, the minimal promoter region of SUR1 has yet to be investigated. The E23K variant of Kir6.2 is associated with Type 2 diabetes mellitus in the UKPDS cohort.
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Affiliation(s)
- A L Gloyn
- Diabetes Research Laboratories, Nuffield Department of Clinical Medicine, University of Oxford, Radcliffe Infirmary, Oxford, UK.
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