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11 results on '"Walker, Mark"'

1. Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity

Author

Yaghootkar, Hanieh, Zhang, Yiying, Spracklen, Cassandra N, Karaderi, Tugce, Huang, Lam Opal, Bradfield, Jonathan, Schurmann, Claudia, Fine, Rebecca S, Preuss, Michael H, Kutalik, Zoltan, Wittemans, Laura BL, Lu, Yingchang, Metz, Sophia, Willems, Sara M, Li-Gao, Ruifang, Grarup, Niels, Wang, Shuai, Molnos, Sophie, Sandoval-Zárate, América A, Nalls, Mike A, Lange, Leslie A, Haesser, Jeffrey, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Feitosa, Mary F, Sitlani, Colleen M, Venturini, Cristina, Mahajan, Anubha, Kacprowski, Tim, Wang, Carol A, Chasman, Daniel I, Amin, Najaf, Broer, Linda, Robertson, Neil, Young, Kristin L, Allison, Matthew, Auer, Paul L, Blüher, Matthias, Borja, Judith B, Bork-Jensen, Jette, Carrasquilla, Germán D, Christofidou, Paraskevi, Demirkan, Ayse, Doege, Claudia A, Garcia, Melissa E, Graff, Mariaelisa, Guo, Kaiying, Hakonarson, Hakon, Hong, Jaeyoung, Ida Chen, Yii-Der, Jackson, Rebecca, Jakupović, Hermina, Jousilahti, Pekka, Justice, Anne E, Kähönen, Mika, Kizer, Jorge R, Kriebel, Jennifer, LeDuc, Charles A, Li, Jin, Lind, Lars, Luan, Jian'an, Mackey, David A, Mangino, Massimo, Männistö, Satu, Martin Carli, Jayne F, Medina-Gomez, Carolina, Mook-Kanamori, Dennis O, Morris, Andrew P, de Mutsert, Renée, Nauck, Matthias, Prokic, Ivana, Pennell, Craig E, Pradhan, Arund D, Psaty, Bruce M, Raitakari, Olli T, Scott, Robert A, Skaaby, Tea, Strauch, Konstantin, Taylor, Kent D, Teumer, Alexander, Uitterlinden, Andre G, Wu, Ying, Yao, Jie, Walker, Mark, North, Kari E, Kovacs, Peter, Ikram, M Arfan, van Duijn, Cornelia M, Ridker, Paul M, Lye, Stephen, Homuth, Georg, Ingelsson, Erik, Spector, Tim D, McKnight, Barbara, Province, Michael A, Lehtimäki, Terho, Adair, Linda S, Rotter, Jerome I, Reiner, Alexander P, and Wilson, James G

Subjects
Genetics, Nutrition, Prevention, Obesity, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Metabolic and endocrine, Cardiovascular, Stroke, Cancer, Adiposity, Gene Expression Regulation, Developmental, Genetic Variation, Genotype, Humans, Leptin, Models, Molecular, Protein Conformation, Racial Groups, Medical and Health Sciences, Endocrinology & Metabolism
Abstract

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

Published
2020

2. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Author

Walford, Geoffrey A, Gustafsson, Stefan, Rybin, Denis, Stančáková, Alena, Chen, Han, Liu, Ching-Ti, Hong, Jaeyoung, Jensen, Richard A, Rice, Ken, Morris, Andrew P, Mägi, Reedik, Tönjes, Anke, Prokopenko, Inga, Kleber, Marcus E, Delgado, Graciela, Silbernagel, Günther, Jackson, Anne U, Appel, Emil V, Grarup, Niels, Lewis, Joshua P, Montasser, May E, Landenvall, Claes, Staiger, Harald, Luan, Jian’an, Frayling, Timothy M, Weedon, Michael N, Xie, Weijia, Morcillo, Sonsoles, Martínez-Larrad, María Teresa, Biggs, Mary L, Chen, Yii-Der Ida, Corbaton-Anchuelo, Arturo, Færch, Kristine, Gómez-Zumaquero, Juan Miguel, Goodarzi, Mark O, Kizer, Jorge R, Koistinen, Heikki A, Leong, Aaron, Lind, Lars, Lindgren, Cecilia, Machicao, Fausto, Manning, Alisa K, Martín-Núñez, Gracia María, Rojo-Martínez, Gemma, Rotter, Jerome I, Siscovick, David S, Zmuda, Joseph M, Zhang, Zhongyang, Serrano-Rios, Manuel, Smith, Ulf, Soriguer, Federico, Hansen, Torben, Jørgensen, Torben J, Linnenberg, Allan, Pedersen, Oluf, Walker, Mark, Langenberg, Claudia, Scott, Robert A, Wareham, Nicholas J, Fritsche, Andreas, Häring, Hans-Ulrich, Stefan, Norbert, Groop, Leif, O’Connell, Jeff R, Boehnke, Michael, Bergman, Richard N, Collins, Francis S, Mohlke, Karen L, Tuomilehto, Jaakko, März, Winfried, Kovacs, Peter, Stumvoll, Michael, Psaty, Bruce M, Kuusisto, Johanna, Laakso, Markku, Meigs, James B, Dupuis, Josée, Ingelsson, Erik, and Florez, Jose C

Subjects
Biomedical and Clinical Sciences, Genetics, Prevention, Human Genome, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Chemokines, CC, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Male, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-bcl-2, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Published
2016

3. Association Analysis of 29,956 Individuals Confirms That a Low-Frequency Variant at CCND2 Halves the Risk of Type 2 Diabetes by Enhancing Insulin Secretion

Author

Yaghootkar, Hanieh, Stancáková, Alena, Freathy, Rachel M., Vangipurapu, Jagadish, Weedon, Michael N., Xie, Weijia, Wood, Andrew R., Ferrannini, Ele, Mari, Andrea, Ring, Susan M., Lawlor, Debbie A., Davey Smith, George, Jørgensen, Torben, Hansen, Torben, Pedersen, Oluf, Steinthorsdottir, Valgerdur, Gubjartsson, Daniel F., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Stefansson, Kari, Hattersley, Andrew T., Walker, Mark, Morris, Andrew D., McCarthy, Mark I., Palmer, Colin N.A., Laakso, Markku, and Frayling, Timothy M.

Published
2015
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4. Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity

Author

Scott, Robert A., Fall, Tove, Pasko, Dorota, Barker, Adam, Sharp, Stephen J., Arriola, Larraitz, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Boeing, Heiner, Clavel-Chapelon, Françoise, Crowe, Francesca L., Dekker, Jacqueline M., Fagherazzi, Guy, Ferrannini, Ele, Forouhi, Nita G., Franks, Paul W., Gavrila, Diana, Giedraitis, Vilmantas, Grioni, Sara, Groop, Leif C., Kaaks, Rudolf, Key, Timothy J., Kühn, Tilman, Lotta, Luca A., Nilsson, Peter M., Overvad, Kim, Palli, Domenico, Panico, Salvatore, Quirós, J. Ramón, Rolandsson, Olov, Roswall, Nina, Sacerdote, Carlotta, Sala, Núria, Sánchez, María-José, Schulze, Matthias B., Siddiq, Afshan, Slimani, Nadia, Sluijs, Ivonne, Spijkerman, Annemieke M.W., Tjonneland, Anne, Tumino, Rosario, van der A, Daphne L., Yaghootkar, Hanieh, McCarthy, Mark I., Semple, Robert K., Riboli, Elio, Walker, Mark, Ingelsson, Erik, Frayling, Tim M., Savage, David B., Langenberg, Claudia, and Wareham, Nicholas J.

Published
2014
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5. Genetic Evidence for a Normal-Weight “Metabolically Obese” Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes

Author

Yaghootkar, Hanieh, Scott, Robert A., White, Charles C., Zhang, Weihua, Speliotes, Elizabeth, Munroe, Patricia B., Ehret, Georg B., Bis, Joshua C., Fox, Caroline S., Walker, Mark, Borecki, Ingrid B., Knowles, Joshua W., Yerges-Armstrong, Laura, Ohlsson, Claes, Perry, John R.B., Chambers, John C., Kooner, Jaspal S., Franceschini, Nora, Langenberg, Claudia, Hivert, Marie-France, Dastani, Zari, Richards, J. Brent, Semple, Robert K., and Frayling, Timothy M.

Published
2014
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7. Profiles of Glucose Metabolism in Different Prediabetes Phenotypes, Classified by Fasting Glycemia, 2-Hour OGTT, Glycated Hemoglobin, and 1-Hour OGTT: An IMI DIRECT Study.

Author

Tura, Andrea, Grespan, Eleonora, Göbl, Christian S., Koivula, Robert W., Franks, Paul W., Pearson, Ewan R., Walker, Mark, Forgie, Ian M., Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Dermitzakis, Emmanouil T., McCarthy, Mark I., Pedersen, Oluf, Schwenk, Jochen M., Adamski, Jerzy, De Masi, Federico, Tsirigos, Konstantinos D., Brunak, Søren, and Viñuela, Ana

Subjects
GLYCOSYLATED hemoglobin, GLUCOSE metabolism, INSULIN sensitivity, PREDIABETIC state, TYPE 2 diabetes
Abstract

Differences in glucose metabolism among categories of prediabetes have not been systematically investigated. In this longitudinal study, participants (N = 2,111) underwent a 2-h 75-g oral glucose tolerance test (OGTT) at baseline and 48 months. HbA1c was also measured. We classified participants as having isolated prediabetes defect (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or HbA1c indicative of prediabetes [IA1c]), two defects (IFG+IGT, IFG+IA1c, or IGT+IA1c), or all defects (IFG+IGT+IA1c). β-Cell function (BCF) and insulin sensitivity were assessed from OGTT. At baseline, in pooling of participants with isolated defects, they showed impairment in both BCF and insulin sensitivity compared with healthy control subjects. Pooled groups with two or three defects showed progressive further deterioration. Among groups with isolated defect, those with IGT showed lower insulin sensitivity, insulin secretion at reference glucose (ISRr), and insulin secretion potentiation (P < 0.002). Conversely, those with IA1c showed higher insulin sensitivity and ISRr (P < 0.0001). Among groups with two defects, we similarly found differences in both BCF and insulin sensitivity. At 48 months, we found higher type 2 diabetes incidence for progressively increasing number of prediabetes defects (odds ratio >2, P < 0.008). In conclusion, the prediabetes groups showed differences in type/degree of glucometabolic impairment. Compared with the pooled group with isolated defects, those with double or triple defect showed progressive differences in diabetes incidence. [ABSTRACT FROM AUTHOR]

Published
2021
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8. 333-LB: Impact of Aging on Mitochondrial Respiratory Chain Expression and Pancreatic Islet Cell Composition by Using a Mitochondrial DNA Mutator Mouse Model

Author

YU, XUEFEI, primary, ARDEN, CATHERINE, additional, CHEN, CHUN, additional, BRADSHAW, CARLA, additional, WHITEHALL, JULIA, additional, WHITE, MICHAEL G., additional, ANDERSON, SCOTT J., additional, SHAW, JAMES A., additional, TURNBULL, DOUG, additional, GREAVES, LAURA, additional, and WALKER, MARK, additional

Published
2019
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10. A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

Author

Manning, Alisa, primary, Highland, Heather M., additional, Gasser, Jessica, additional, Sim, Xueling, additional, Tukiainen, Taru, additional, Fontanillas, Pierre, additional, Grarup, Niels, additional, Rivas, Manuel A., additional, Mahajan, Anubha, additional, Locke, Adam E., additional, Cingolani, Pablo, additional, Pers, Tune H., additional, Viñuela, Ana, additional, Brown, Andrew A., additional, Wu, Ying, additional, Flannick, Jason, additional, Fuchsberger, Christian, additional, Gamazon, Eric R., additional, Gaulton, Kyle J., additional, Im, Hae Kyung, additional, Teslovich, Tanya M., additional, Blackwell, Thomas W., additional, Bork-Jensen, Jette, additional, Burtt, Noël P., additional, Chen, Yuhui, additional, Green, Todd, additional, Hartl, Christopher, additional, Kang, Hyun Min, additional, Kumar, Ashish, additional, Ladenvall, Claes, additional, Ma, Clement, additional, Moutsianas, Loukas, additional, Pearson, Richard D., additional, Perry, John R.B., additional, Rayner, N. William, additional, Robertson, Neil R., additional, Scott, Laura J., additional, van de Bunt, Martijn, additional, Eriksson, Johan G., additional, Jula, Antti, additional, Koskinen, Seppo, additional, Lehtimäki, Terho, additional, Palotie, Aarno, additional, Raitakari, Olli T., additional, Jacobs, Suzanne B.R., additional, Wessel, Jennifer, additional, Chu, Audrey Y., additional, Scott, Robert A., additional, Goodarzi, Mark O., additional, Blancher, Christine, additional, Buck, Gemma, additional, Buck, David, additional, Chines, Peter S., additional, Gabriel, Stacey, additional, Gjesing, Anette P., additional, Groves, Christopher J., additional, Hollensted, Mette, additional, Huyghe, Jeroen R., additional, Jackson, Anne U., additional, Jun, Goo, additional, Justesen, Johanne Marie, additional, Mangino, Massimo, additional, Murphy, Jacquelyn, additional, Neville, Matt, additional, Onofrio, Robert, additional, Small, Kerrin S., additional, Stringham, Heather M., additional, Trakalo, Joseph, additional, Banks, Eric, additional, Carey, Jason, additional, Carneiro, Mauricio O., additional, DePristo, Mark, additional, Farjoun, Yossi, additional, Fennell, Timothy, additional, Goldstein, Jacqueline I., additional, Grant, George, additional, Hrabé de Angelis, Martin, additional, Maguire, Jared, additional, Neale, Benjamin M., additional, Poplin, Ryan, additional, Purcell, Shaun, additional, Schwarzmayr, Thomas, additional, Shakir, Khalid, additional, Smith, Joshua D., additional, Strom, Tim M., additional, Wieland, Thomas, additional, Lindstrom, Jaana, additional, Brandslund, Ivan, additional, Christensen, Cramer, additional, Surdulescu, Gabriela L., additional, Lakka, Timo A., additional, Doney, Alex S.F., additional, Nilsson, Peter, additional, Wareham, Nicholas J., additional, Langenberg, Claudia, additional, Varga, Tibor V., additional, Franks, Paul W., additional, Rolandsson, Olov, additional, Rosengren, Anders H., additional, Farook, Vidya S., additional, Thameem, Farook, additional, Puppala, Sobha, additional, Kumar, Satish, additional, Lehman, Donna M., additional, Jenkinson, Christopher P., additional, Curran, Joanne E., additional, Hale, Daniel Esten, additional, Fowler, Sharon P., additional, Arya, Rector, additional, DeFronzo, Ralph A., additional, Abboud, Hanna E., additional, Syvänen, Ann-Christine, additional, Hicks, Pamela J., additional, Palmer, Nicholette D., additional, Ng, Maggie C.Y., additional, Bowden, Donald W., additional, Freedman, Barry I., additional, Esko, Tõnu, additional, Mägi, Reedik, additional, Milani, Lili, additional, Mihailov, Evelin, additional, Metspalu, Andres, additional, Narisu, Narisu, additional, Kinnunen, Leena, additional, Bonnycastle, Lori L., additional, Swift, Amy, additional, Pasko, Dorota, additional, Wood, Andrew R., additional, Fadista, João, additional, Pollin, Toni I., additional, Barzilai, Nir, additional, Atzmon, Gil, additional, Glaser, Benjamin, additional, Thorand, Barbara, additional, Strauch, Konstantin, additional, Peters, Annette, additional, Roden, Michael, additional, Müller-Nurasyid, Martina, additional, Liang, Liming, additional, Kriebel, Jennifer, additional, Illig, Thomas, additional, Grallert, Harald, additional, Gieger, Christian, additional, Meisinger, Christa, additional, Lannfelt, Lars, additional, Musani, Solomon K., additional, Griswold, Michael, additional, Taylor, Herman A., additional, Wilson, Gregory, additional, Correa, Adolfo, additional, Oksa, Heikki, additional, Scott, William R., additional, Afzal, Uzma, additional, Tan, Sian-Tsung, additional, Loh, Marie, additional, Chambers, John C., additional, Sehmi, Jobanpreet, additional, Kooner, Jaspal Singh, additional, Lehne, Benjamin, additional, Cho, Yoon Shin, additional, Lee, Jong-Young, additional, Han, Bok-Ghee, additional, Käräjämäki, Annemari, additional, Qi, Qibin, additional, Qi, Lu, additional, Huang, Jinyan, additional, Hu, Frank B., additional, Melander, Olle, additional, Orho-Melander, Marju, additional, Below, Jennifer E., additional, Aguilar, David, additional, Wong, Tien Yin, additional, Liu, Jianjun, additional, Khor, Chiea-Chuen, additional, Chia, Kee Seng, additional, Lim, Wei Yen, additional, Cheng, Ching-Yu, additional, Chan, Edmund, additional, Tai, E Shyong, additional, Aung, Tin, additional, Linneberg, Allan, additional, Isomaa, Bo, additional, Meitinger, Thomas, additional, Tuomi, Tiinamaija, additional, Hakaste, Liisa, additional, Kravic, Jasmina, additional, Jørgensen, Marit E., additional, Lauritzen, Torsten, additional, Deloukas, Panos, additional, Stirrups, Kathleen E., additional, Owen, Katharine R., additional, Farmer, Andrew J., additional, Frayling, Timothy M., additional, O'Rahilly, Stephen P., additional, Walker, Mark, additional, Levy, Jonathan C., additional, Hodgkiss, Dylan, additional, Hattersley, Andrew T., additional, Kuulasmaa, Teemu, additional, Stančáková, Alena, additional, Barroso, Inês, additional, Bharadwaj, Dwaipayan, additional, Chan, Juliana, additional, Chandak, Giriraj R., additional, Daly, Mark J., additional, Donnelly, Peter J., additional, Ebrahim, Shah B., additional, Elliott, Paul, additional, Fingerlin, Tasha, additional, Froguel, Philippe, additional, Hu, Cheng, additional, Jia, Weiping, additional, Ma, Ronald C.W., additional, McVean, Gilean, additional, Park, Taesung, additional, Prabhakaran, Dorairaj, additional, Sandhu, Manjinder, additional, Scott, James, additional, Sladek, Rob, additional, Tandon, Nikhil, additional, Teo, Yik Ying, additional, Zeggini, Eleftheria, additional, Watanabe, Richard M., additional, Koistinen, Heikki A., additional, Kesaniemi, Y. Antero, additional, Uusitupa, Matti, additional, Spector, Timothy D., additional, Salomaa, Veikko, additional, Rauramaa, Rainer, additional, Palmer, Colin N.A., additional, Prokopenko, Inga, additional, Morris, Andrew D., additional, Bergman, Richard N., additional, Collins, Francis S., additional, Lind, Lars, additional, Ingelsson, Erik, additional, Tuomilehto, Jaakko, additional, Karpe, Fredrik, additional, Groop, Leif, additional, Jørgensen, Torben, additional, Hansen, Torben, additional, Pedersen, Oluf, additional, Kuusisto, Johanna, additional, Abecasis, Gonçalo, additional, Bell, Graeme I., additional, Blangero, John, additional, Cox, Nancy J., additional, Duggirala, Ravindranath, additional, Seielstad, Mark, additional, Wilson, James G., additional, Dupuis, Josee, additional, Ripatti, Samuli, additional, Hanis, Craig L., additional, Florez, Jose C., additional, Mohlke, Karen L., additional, Meigs, James B., additional, Laakso, Markku, additional, Morris, Andrew P., additional, Boehnke, Michael, additional, Altshuler, David, additional, McCarthy, Mark I., additional, Gloyn, Anna L., additional, and Lindgren, Cecilia M., additional

Published
2017
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11. A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants.

Author

Wood AR, Jonsson A, Jackson AU, Wang N, van Leewen N, Palmer ND, Kobes S, Deelen J, Boquete-Vilarino L, Paananen J, Stančáková A, Boomsma DI, de Geus EJC, Eekhoff EMW, Fritsche A, Kramer M, Nijpels G, Simonis-Bik A, van Haeften TW, Mahajan A, Boehnke M, Bergman RN, Tuomilehto J, Collins FS, Mohlke KL, Banasik K, Groves CJ, McCarthy MI, Pearson ER, Natali A, Mari A, Buchanan TA, Taylor KD, Xiang AH, Gjesing AP, Grarup N, Eiberg H, Pedersen O, Chen YD, Laakso M, Norris JM, Smith U, Wagenknecht LE, Baier L, Bowden DW, Hansen T, Walker M, Watanabe RM, 't Hart LM, Hanson RL, and Frayling TM

Subjects
Alleles, C-Peptide genetics, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 physiopathology, Genetic Variation genetics, Genome-Wide Association Study, Genotype, Genotyping Techniques, Glucose Tolerance Test methods, Humans, Insulin metabolism, Insulin Secretion, Insulin-Secreting Cells metabolism, Linear Models, Liver metabolism, Blood Glucose metabolism, Diabetes Mellitus, Type 2 genetics, Genetic Variation physiology, Insulin genetics, Transcription Factor 7-Like 2 Protein physiology
Abstract

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A , IGF2BP2 , KCNQ1 , HNF1B , VPS13C/C2CD4A , FAF1 , PTPRD , AP3S2 , KCNK16 , MAEA , LPP, WFS1 , and TMPRSS6 loci. The fasting glucose-raising allele near PDX1 , a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits., (© 2017 by the American Diabetes Association.)

Published
2017
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