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1. Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study

Author

Sharma, Sapna, Dong, Qiuling, Haid, Mark, Adam, Jonathan, Bizzotto, Roberto, Fernandez-Tajes, Juan J., Jones, Angus G., Tura, Andrea, Artati, Anna, Prehn, Cornelia, Kastenmüller, Gabi, Koivula, Robert W., Franks, Paul W., Walker, Mark, Forgie, Ian M., Giordano, Giuseppe, Pavo, Imre, Ruetten, Hartmut, Dermitzakis, Manolis, McCarthy, Mark I., Pedersen, Oluf, Schwenk, Jochen M., Tsirigos, Konstantinos D., De Masi, Federico, Brunak, Soren, Viñuela, Ana, Mari, Andrea, McDonald, Timothy J., Kokkola, Tarja, Adamski, Jerzy, Pearson, Ewan R., and Grallert, Harald

Published
2024
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3. Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine

Author

Tobias, Deirdre K, Merino, Jordi, Ahmad, Abrar, Aiken, Catherine, Benham, Jamie L, Bodhini, Dhanasekaran, Clark, Amy L, Colclough, Kevin, Corcoy, Rosa, Cromer, Sara J, Duan, Daisy, Felton, Jamie L, Francis, Ellen C, Gillard, Pieter, Gingras, Véronique, Gaillard, Romy, Haider, Eram, Hughes, Alice, Ikle, Jennifer M, Jacobsen, Laura M, Kahkoska, Anna R, Kettunen, Jarno LT, Kreienkamp, Raymond J, Lim, Lee-Ling, Männistö, Jonna ME, Massey, Robert, Mclennan, Niamh-Maire, Miller, Rachel G, Morieri, Mario Luca, Most, Jasper, Naylor, Rochelle N, Ozkan, Bige, Patel, Kashyap Amratlal, Pilla, Scott J, Prystupa, Katsiaryna, Raghavan, Sridharan, Rooney, Mary R, Schön, Martin, Semnani-Azad, Zhila, Sevilla-Gonzalez, Magdalena, Svalastoga, Pernille, Takele, Wubet Worku, Tam, Claudia Ha-ting, Thuesen, Anne Cathrine B, Tosur, Mustafa, Wallace, Amelia S, Wang, Caroline C, Wong, Jessie J, Yamamoto, Jennifer M, Young, Katherine, Amouyal, Chloé, Andersen, Mette K, Bonham, Maxine P, Chen, Mingling, Cheng, Feifei, Chikowore, Tinashe, Chivers, Sian C, Clemmensen, Christoffer, Dabelea, Dana, Dawed, Adem Y, Deutsch, Aaron J, Dickens, Laura T, DiMeglio, Linda A, Dudenhöffer-Pfeifer, Monika, Evans-Molina, Carmella, Fernández-Balsells, María Mercè, Fitipaldi, Hugo, Fitzpatrick, Stephanie L, Gitelman, Stephen E, Goodarzi, Mark O, Grieger, Jessica A, Guasch-Ferré, Marta, Habibi, Nahal, Hansen, Torben, Huang, Chuiguo, Harris-Kawano, Arianna, Ismail, Heba M, Hoag, Benjamin, Johnson, Randi K, Jones, Angus G, Koivula, Robert W, Leong, Aaron, Leung, Gloria KW, Libman, Ingrid M, Liu, Kai, Long, S Alice, Lowe, William L, Morton, Robert W, Motala, Ayesha A, Onengut-Gumuscu, Suna, Pankow, James S, Pathirana, Maleesa, Pazmino, Sofia, Perez, Dianna, Petrie, John R, Powe, Camille E, Quinteros, Alejandra, Jain, Rashmi, Ray, Debashree, and Ried-Larsen, Mathias

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Health Services, Diabetes, Clinical Research, Pediatric, Metabolic and endocrine, Good Health and Well Being, Humans, Precision Medicine, Consensus, Diabetes Mellitus, Evidence-Based Medicine, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Published
2023

8. Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

Author

Brown, Andrew A., Fernandez-Tajes, Juan J., Hong, Mun-gwan, Brorsson, Caroline A., Koivula, Robert W., Davtian, David, Dupuis, Théo, Sartori, Ambra, Michalettou, Theodora-Dafni, Forgie, Ian M., Adam, Jonathan, Allin, Kristine H., Caiazzo, Robert, Cederberg, Henna, De Masi, Federico, Elders, Petra J. M., Giordano, Giuseppe N., Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison J., Howald, Cédric, Jones, Angus G., Kokkola, Tarja, Laakso, Markku, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Mourby, Miranda, Musholt, Petra B., Nilsson, Birgitte, Pattou, Francois, Penet, Deborah, Raverdy, Violeta, Ridderstråle, Martin, Romano, Luciana, Rutters, Femke, Sharma, Sapna, Teare, Harriet, ‘t Hart, Leen, Tsirigos, Konstantinos D., Vangipurapu, Jagadish, Vestergaard, Henrik, Brunak, Søren, Franks, Paul W., Frost, Gary, Grallert, Harald, Jablonka, Bernd, McCarthy, Mark I., Pavo, Imre, Pedersen, Oluf, Ruetten, Hartmut, Walker, Mark, Adamski, Jerzy, Schwenk, Jochen M., Pearson, Ewan R., Dermitzakis, Emmanouil T., and Viñuela, Ana

Published
2023
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10. Long-term outcomes after severe childhood malnutrition in adolescents in Malawi (LOSCM): a prospective observational cohort study

Author

Abera, Mubarek, Ameya, Gemechu, Anujo, Kenneth, Arefayine, Melkamu, Girma, Tsinuel, Gonzales, Gerard Bryan, Olga, Laurentya, McKenzie, Kimberley, Thompson, Debbie, Wells, Jonathan C, Kirolos, Amir, Harawa, Philliness P, Chimowa, Takondwa, Divala, Oscar, Freyne, Bridget, Jones, Angus G, Lelijveld, Natasha, Lissauer, Samantha, Maleta, Kenneth, Gladstone, Melissa J, and Kerac, Marko

Published
2024
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11. Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Leal Rodríguez, Cristina, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, and Brunak, Søren

Published
2023
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15. Anomalous blue-shift of terahertz whispering-gallery modes via dielectric and metallic tuning

Author

Vogt, Dominik Walter, Jones, Angus Harvey, Schwefel, Harald G. L., and Leonhardt, Rainer

Subjects
Physics - Optics
Abstract

The vast majority of resonant systems show a red-shift for the resonance frequency when a perturbation, e.g. losses, are introduced to the system. In contrast, here we report for the first time the experimental demonstration of both red- and anomalous blue-shifting of whispering-gallery modes (WGMs) using dielectric and metallic substrates. The maximum blue-shift is more than three times as large as the expected red-shift, proving that the anomalous blue-shift is more than a peculiar curiosity. The experiments are performed in the terahertz (THz) frequency range with coherent continuous-wave spectroscopy. The results establish dielectric and metallic tuning as a novel, and viable approach to tune high quality (high-Q) WGMs, and provide valuable insights into the anomalous blue-shift of WGM cavity systems. The tuning capabilities for these compact monolithic resonators is of significant interest for fundamental science and technological applications alike.

Published
2019
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17. Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Author

't Hart, L.M., Abdalla, M., Adam, J., Adamski, J., Adragni, K., Allin, K.H., Arumugam, M., Atabaki Pasdar, N., Baltauss, T., Banasik, K.B., Baum, P., Bell, J.D., Bergstrom, M., Beulens, J.W., Bianzano, S., Bizzotto, R., Bonneford, A., Brorsson, C.A.B., Brown, A.A., Brunak, S.B., Cabrelli, L., Caiazzo, R., Canouil, M., Dale, M., Davtian, D., Dawed, A.Y., De Masi, F.M., de Preville, N., Dekkers, K.F., Dermitzakis, E.T., Deshmukh, H.A., Dings, C., Donnelly, L., Dutta, A., Ehrhardt, B., Elders, P.J.M., Engel Thomas, C.E.T., Engelbrechtsen, L., Eriksen, R.G., Eriksen, R.E., Fan, Y., Fernandez, J., Ferrer, J., Fitipaldi, H., Forgie, I.M., Forman, A., Franks, P.W., Frau, F., Fritsche, A., Froguel, P., Frost, G., Gassenhuber, J., Giordano, G.N., Giorgino, T., Gough, S., Graefe-Mody, U., Grallert, H., Grempler, R., Groeneveld, L., Groop, L., Gudmundsdóttir, V.G., Gupta, R.G., Haid, M., Hansen, T., Hansen, T.H., Hattersley, A.T., Haussler, R.S., Heggie, A.J., Hennige, A.M., Hill, A.V., Holl, R.W., Hong, M.-G., Hudson, M., Jablonka, B., Jennison, C., Jiao, J., Johansen, J.J., Jones, A.G., Jonsson, A., Karaderi, T.K., Kaye, J., Klintenberg, M., Koivula, R.W., Kokkola, T., Koopman, A.D.M., Kurbasic, A, Kuulasmaa, T., Laakso, M., Lehr, T., Loftus, H., Lundbye Allesøe, R.L.A, Mahajan, A., Mari, A., Mazzoni, G.M., McCarthy, M.I., McDonald, T.J., McEvoy, D., McRobert, N., McVittie, I., Mourby, M., Musholt, P., Mutie, P, Nice, R., Nicolay, C., Nielsen, A.M.N., Nilsson, B.N., Palmer, C.N., Pattou, F., Pavo, I., Pearson, E.R., Pedersen, O., Pedersen, H.K.P., Perry, M.H., Pomares-Millan, H., Ramisch, A., Rasmussen, S.R., Raverdi, V., Ridderstrale, M., Robertson, N., Roderick, R.C., Rodriquez, M., Ruetten, H., Rutters, F., Sackett, W., Scherer, N., Schwenk, J.M., Shah, N., Sharma, S., Sihinevich, I., Sondertoft, N.B., Staerfeldt, H., Steckel-Hamann, B., Teare, H., Thomas, M.K., Thomas, E.L., Thomsen, H.S., Thorand, B., Thorne, C.E., Tillner, J., Troen Lundgaard, A.T.L., Troll, M., Tsirigos, K.D.T., Tura, A., Uhlen, M., van Leeuwen, N., van Oort, S., Verkindt, H., Vestergaard, H., Viñuela, A., Vogt, J.K, Wad Sackett, P.W.S, Wake, D., Walker, M., Wesolowska-Andersen, A., Whitcher, B., White, M.W., Wu, H., Dawed, Adem Y, Mari, Andrea, Brown, Andrew, McDonald, Timothy J, Li, Lin, Wang, Shuaicheng, Hong, Mun-Gwan, Sharma, Sapna, Robertson, Neil R, Mahajan, Anubha, Wang, Xuan, Walker, Mark, Gough, Stephen, Hart, Leen M ‘t, Zhou, Kaixin, Forgie, Ian, Ruetten, Hartmut, Pavo, Imre, Bhatnagar, Pallav, Jones, Angus G, and Pearson, Ewan R

Published
2023
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21. Switching to reusable cartridge insulin pens can reduce National Health Service costs while delivering environmental benefits.

Author

Simpson, Vincent and Jones, Angus

Subjects
*INSULIN therapy, *ENVIRONMENTAL health, *NATIONAL health services, *ECOLOGICAL impact, *MEDICAL equipment reuse, *COST benefit analysis, *DRUG infusion pumps, *DISPOSABLE medical devices, *DRUGS, *HEALTH care industry, *GREENHOUSE gases, *DIABETES, *MEDICAL care costs
Abstract

The article focuses on the environmental impact of insulin delivery methods within the UK's National Health Service (NHS) amid efforts to address the climate crisis. Topics include the carbon footprint and plastic waste associated with disposable versus reusable insulin pens, the lack of national guidelines for sustainable prescribing practices, and the need for data on the environmental effects of different insulin delivery systems to inform clinicians and patients.

Published
2024
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22. Autoantibodies to Truncated GAD(96-585) Antigen Stratify Risk of Early Insulin Requirement in Adult-Onset Diabetes.

Author

Grace, Sian L., Gillespie, Kathleen M., Williams, Claire L., Lampasona, Vito, Achenbach, Peter, Pearson, Ewan R., Williams, Alistair J.K., Long, Anna E., McDonald, Timothy J., and Jones, Angus G.

Subjects
GENETIC risk score, TYPE 2 diabetes, TYPE 1 diabetes, INSULIN therapy, INSULIN
Abstract

We investigated whether characterization of full-length GAD (f-GADA) antibody (GADA) responses could identify early insulin requirement in adult-onset diabetes. In 179 f-GADA–positive participants diagnosed with type 2 diabetes, we assessed associations of truncated GADA (t-GADA) positivity, f-GADA IgG subclasses, and f-GADA affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. t-GADA positivity was lower in f-GADA–positive without early insulin in comparison with f-GADA–positive type 2 diabetes requiring insulin within 5 years, and T1D (75% vs. 91% and 95% respectively, P < 0.0001). t-GADA positivity (in those f-GADA positive) identified a group with a higher T1D genetic susceptibility (mean T1D GRS 0.248 vs. 0.225, P = 0.003), lower C-peptide (1,156 pmol/L vs. 4,289 pmol/L, P = 1 × 10−7), and increased IA-2 antigen positivity (23% vs. 6%, P = 0.03). In survival analysis, t-GADA positivity was associated with early insulin requirement compared with those only positive for f-GADA, independently from age of diagnosis, f-GADA titer, and duration of diabetes (adjusted hazard ratio 5.7 [95% CI 1.4, 23.5], P = 0.017). The testing of t-GADA in f-GADA–positive individuals with type 2 diabetes identifies those who have genetic and clinical characteristics comparable to T1D and stratifies those at higher risk of early insulin requirement. Article Highlights: Progression to insulin therapy is highly variable in adult-onset GAD antibody (GADA)–positive diabetes. We further characterized GADA in adult-onset diabetes and assessed whether these are associated with early insulin requirement. Truncated GADA positivity was associated with a type 1 diabetes–like phenotype and stratified risk of early insulin requirement. Those GADA positive who were negative for truncated GADA had the characteristics and progression of classic type 2 diabetes. Assessing full-length GADA IgG subclass and affinity did not further stratify risk of progression. Truncated GADA assessment remains underused in clinical practice but could assist correct therapy allocation in adult-onset diabetes. [ABSTRACT FROM AUTHOR]

Published
2024
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23. Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study

Author

Wesolowska-Andersen, Agata, Brorsson, Caroline A., Bizzotto, Roberto, Mari, Andrea, Tura, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Prehn, Cornelia, Artati, Anna, Hong, Mun-Gwan, Musholt, Petra B., Kurbasic, Azra, De Masi, Federico, Tsirigos, Kostas, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Thomas, Cecilia Engel, Banasik, Karina, Jennison, Chrisopher, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, Louise, Frost, Gary, Thomsen, Henrik, Allin, Kristine, Hansen, Tue Haldor, Vestergaard, Henrik, Hansen, Torben, Rutters, Femke, Elders, Petra, t’Hart, Leen, Bonnefond, Amelie, Canouil, Mickaël, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Hattersley, Andrew, McDonald, Timothy, Teare, Harriet, Ridderstrale, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Froguel, Philippe, Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, Pearson, Ewan, McCarthy, Mark I., and Brunak, Søren

Published
2022
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25. Author Correction: Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Leal Rodríguez, Cristina, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, and Brunak, Søren

Published
2023
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26. The Association of Cardiometabolic, Diet and Lifestyle Parameters With Plasma Glucagon-like Peptide-1: An IMI DIRECT Study

Author

Eriksen, Rebeca, White, Margaret C, Dawed, Adem Y, Perez, Isabel Garcia, Posma, Joram M, Haid, Mark, Sharma, Sapna, Prehn, Cornelia, Thomas, E Louise, Koivula, Robert W, Bizzotto, Roberto, Mari, Andrea, Giordano, Giuseppe N, Pavo, Imre, Schwenk, Jochen M, De Masi, Federico, Tsirigos, Konstantinos D, Brunak, Søren, Viñuela, Ana, Mahajan, Anubha, McDonald, Timothy J, Kokkola, Tarja, Rutters, Femke, Beulens, Joline, Muilwijk, Mirthe, Blom, Marieke, Elders, Petra, Hansen, Tue H, Fernandez-Tajes, Juan, Jones, Angus, Jennison, Chris, Walker, Mark, McCarthy, Mark I, Pedersen, Oluf, Ruetten, Hartmut, Forgie, Ian, Holst, Jens J, Thomsen, Henrik S, Ridderstråle, Martin, Bell, Jimmy D, Adamski, Jerzy, Franks, Paul W, Hansen, Torben, Holmes, Elaine, Frost, Gary, and Pearson, Ewan R

Published
2024
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28. Ethnic differences in the manifestation of early-onset type 2 diabetes

Author

Kibirige, Davis, primary, Hill, Anita V, additional, Katte, Jean Claude, additional, Sekitoleko, Isaac, additional, Lumu, William, additional, Knupp, Julieanne, additional, Squires, Steven, additional, Hattersley, Andrew, additional, Smeeth, Liam, additional, Jones, Angus G, additional, and Nyirenda, Moffat J, additional

Published
2024
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29. Long-term outcomes after severe childhood malnutrition in adolescents in Malawi (LOSCM): a prospective observational cohort study

Author

Kirolos, Amir, primary, Harawa, Philliness P, additional, Chimowa, Takondwa, additional, Divala, Oscar, additional, Freyne, Bridget, additional, Jones, Angus G, additional, Lelijveld, Natasha, additional, Lissauer, Samantha, additional, Maleta, Kenneth, additional, Gladstone, Melissa J, additional, Kerac, Marko, additional, Abera, Mubarek, additional, Ameya, Gemechu, additional, Anujo, Kenneth, additional, Arefayine, Melkamu, additional, Girma, Tsinuel, additional, Gonzales, Gerard Bryan, additional, Olga, Laurentya, additional, McKenzie, Kimberley, additional, Thompson, Debbie, additional, and Wells, Jonathan C, additional

Published
2024
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30. Clinical prediction models combining routine clinical measures have high accuracy in identifying youth-onset type 2 diabetes defined by maintained endogenous insulin secretion: The SEARCH for Diabetes in Youth Study

Author

Jones, Angus G., primary, Shields, Beverley M, primary, A Oram, Richard, primary, M Dabelea, Dana, primary, A Hagopian, William, primary, Lustigova, Eva, primary, S Shah, Amy, primary, Knupp, Julieanne, primary, K Mottl, Amy, primary, B. D`Agostino Jr, Ralph, primary, Williams, Adrienne, primary, Pihoker, Catherine, primary, Divers, Jasmin, primary, and Redondo, Maria J, primary

Published
2024
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33. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Author

Jennison, Christopher, Ehrhardt, Beate, Baum, Patrick, Schoelsch, Corinna, Freijer, Jan, Grempler, Rolf, Graefe-Mody, Ulrike, Hennige, Anita, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinecich, Iryna, Pattou, Francois, Raverdi, Violeta, Caiazzo, Robert, Torres, Fanelly, Verkindt, Helene, Mari, Andrea, Tura, Andrea, Giorgino, Toni, Bizzotto, Roberto, Froguel, Philippe, Bonneford, Amelie, Canouil, Mickael, Dhennin, Veronique, Brorsson, Caroline, Brunak, Soren, De Masi, Federico, Gudmundsdóttir, Valborg, Pedersen, Helle, Banasik, Karina, Thomas, Cecilia, Sackett, Peter, Staerfeldt, Hans-Henrik, Lundgaard, Agnete, Nilsson, Birgitte, Nielsen, Agnes, Mazzoni, Gianluca, Karaderi, Tugce, Rasmussen, Simon, Johansen, Joachim, Allesøe, Rosa, Fritsche, Andreas, Thorand, Barbara, Adamski, Jurek, Grallert, Harald, Haid, Mark, Sharma, Sapna, Troll, Martina, Adam, Jonathan, Ferrer, Jorge, Eriksen, Heather, Frost, Gary, Haussler, Ragna, Hong, Mun-gwan, Schwenk, Jochen, Uhlen, Mathias, Nicolay, Claudia, Pavo, Imre, Steckel-Hamann, Birgit, Thomas, Melissa, Adragni, Kofi, Wu, Han, Hart, Leen't, Roderick, Slieker, van Leeuwen, Nienke, Dekkers, Koen, Frau, Francesca, Gassenhuber, Johann, Jablonka, Bernd, Musholt, Petra, Ruetten, Hartmut, Tillner, Joachim, Baltauss, Tania, Bernard Poenaru, Oana, de Preville, Nathalie, Rodriquez, Marianne, Arumugam, Manimozhiyan, Allin, Kristine, Engelbrechtsen, Line, Hansen, Torben, Hansen, Tue, Forman, Annemette, Jonsson, Anna, Pedersen, Oluf, Dutta, Avirup, Vogt, Josef, Vestergaard, Henrik, Laakso, Markku, Kokkola, Tarja, Kuulasmaa, Teemu, Franks, Paul, Giordano, Nick, Pomares-Millan, Hugo, Fitipaldi, Hugo, Mutie, Pascal, Klintenberg, Maria, Bergstrom, Margit, Groop, Leif, Ridderstrale, Martin, Atabaki Pasdar, Naeimeh, Deshmukh, Harshal, Heggie, Alison, Wake, Dianne, McEvoy, Donna, McVittie, Ian, Walker, Mark, Hattersley, Andrew, Hill, Anita, Jones, Angus, McDonald, Timothy, Perry, Mandy, Nice, Rachel, Hudson, Michelle, Thorne, Claire, Dermitzakis, Emmanouil, Viñuela, Ana, Cabrelli, Louise, Loftus, Heather, Dawed, Adem, Donnelly, Louise, Forgie, Ian, Pearson, Ewan, Palmer, Colin, Brown, Andrew, Koivula, Robert, Wesolowska-Andersen, Agata, Abdalla, Moustafa, McRobert, Nicky, Fernandez, Juan, Jiao, Yunlong, Robertson, Neil, Gough, Stephen, Kaye, Jane, Mourby, Miranda, Mahajan, Anubha, McCarthy, Mark, Shah, Nisha, Teare, Harriet, Holl, Reinhard, Koopman, Anitra, Rutters, Femke, Beulens, Joline, Groeneveld, Lenka, Bell, Jimmy, Thomas, Louise, Whitcher, Brandon, Wilman, Henry R., Parisinos, Constantinos A., Atabaki-Pasdar, Naeimeh, Kelly, Matt, Thomas, E. Louise, Neubauer, Stefan, Hingorani, Aroon D., Patel, Riyaz S., Hemingway, Harry, Franks, Paul W., Bell, Jimmy D., Banerjee, Rajarshi, and Yaghootkar, Hanieh

Published
2019
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35. The clinical utility of measuring endogenous insulin secretion in diabetes

Author

Jones, Angus George

Subjects
616.4
Abstract

Treatment response in type 2 diabetes varies greatly: the same glucose lowering medication may have a marked effect in one individual but little effect in another. This is likely to have at least a partly biological basis (type 2 diabetes is a highly heterogeneous condition), raising the possibility of a personalised or 'stratified' approach to treatment where the therapy most likely to be effective for an individual is prescribed based on that person's clinical characteristics or biomarkers. One aspect of type 2 diabetes that varies greatly is beta cell insulin secretion. While many patients will be highly insulin resistant with relatively preserved insulin secretion, others are insulin sensitive with marked beta cell failure. It is plausible that these differences will be associated with variation in treatment response, particularly to treatments exerting their effect through beta cell dependant mechanisms. Insulin secretion is best assessed in clinical practice by measuring C-peptide, co-secreted in equimolar amounts to endogenous insulin. However the measurements commonly used in research are not practical for general clinical use. The aim of this thesis is to assess practical methods of measuring insulin secretion that could be incorporated into routine clinical practice and to examine the utility of these methods in diabetes treatment stratification. In Chapter 1 we review the current evidence on asseSSing insulin secretion and its potential use in diabetes treatment stratification. 3 In Chapters 2 and 3 we assess practical alternatives to the 'gold standard' mixed meal tolerance test stimulated C-peptide for assessing insulin secretion. We show that urine C-peptide creatinine ratio (UCPCR) and fasting C-peptide provide valid alternatives to stimulated blood tests for clinical practice, with high sensitivity and specificity for commonly used clinical thresholds. We demonstrate that a mixed meal test to assess insulin secretion can be undertaken with concurrent insulin given, retaining a high discriminative value for absolute insulin deficiency despite a marked reduction in hyperglycaemia. In Chapter 4 we demonstrate a strong inverse relationship between postprandial glucose rise and C-peptide, including fasting C-peptide and UCPCR. We demonstrate that those who have preserved insulin secretion have markedly reduced response to prandial (meal time) fast acting insulin. In Chapters 5 and 6 we explore problems of confounding by baseline glycaemia in studies of diabetes treatment stratification; we demonstrate that adjustment for baseline HbA 1 c in studies of stratification is both necessary and appropriate. In Chapter 7 we demonstrate in a large prospective cohort that markers of insulin deficiency, including low fasting C-peptide and positive GAD antibodies, are associated with reduced glycaemic response to GLP-1 agonist therapy in patients with a clinical diagnosis of type 2 diabetes. Participants who were Cpeptide negative and/or autoantibody positive had markedly reduced response to these therapies. An overview of the major finding of each chapter and their implications potential future research are discussed in Chapter 8.

Published
2014

36. Clinical prediction models combining routine clinical measures identify participants with youth-onset diabetes who maintain insulin secretion in the range associated with type 2 diabetes: The SEARCH for Diabetes in Youth Study

Author

Jones, Angus G, primary, Shields, Beverley, additional, Oram, Richard A, additional, Dabelea, Dana M, additional, Hagopian, William A, additional, Lustigova, Eva, additional, Shah, Amy S, additional, Knupp, Julieanne, additional, Mottl, Amy K, additional, D`Agostino, Ralph B, additional, Williams, Adrienne, additional, Marcovina, Santica M, additional, Pihoker, Catherine, additional, Divers, Jasmin, additional, and Redondo, Maria J, additional

Published
2023
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37. Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study

Author

Gudmundsdottir, Valborg, Pedersen, Helle Krogh, Mazzoni, Gianluca, Allin, Kristine H., Artati, Anna, Beulens, Joline W., Banasik, Karina, Brorsson, Caroline, Cederberg, Henna, Chabanova, Elizaveta, De Masi, Federico, Elders, Petra J., Forgie, Ian, Giordano, Giuseppe N., Grallert, Harald, Gupta, Ramneek, Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison, Hong, Mun-Gwan, Jones, Angus G., Koivula, Robert, Kokkola, Tarja, Laakso, Markku, Løngreen, Peter, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Musholt, Petra B., Pavo, Imre, Prehn, Cornelia, Ruetten, Hartmut, Ridderstråle, Martin, Rutters, Femke, Sharma, Sapna, Slieker, Roderick C., Syed, Ali, Tajes, Juan Fernandez, Thomas, Cecilia Engel, Thomsen, Henrik S., Vangipurapu, Jagadish, Vestergaard, Henrik, Viñuela, Ana, Wesolowska-Andersen, Agata, Walker, Mark, Adamski, Jerzy, Schwenk, Jochen M., McCarthy, Mark I., Pearson, Ewan, Dermitzakis, Emmanouil, Franks, Paul W., Pedersen, Oluf, and Brunak, Søren

Published
2020
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38. Phenotype-based targeted treatment of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Author

Cardoso, Pedro, primary, Young, Katie G., additional, Nair, Anand T.N., additional, Hopkins, Rhian, additional, McGovern, Andrew P, additional, Haider, Eram, additional, Karunaratne, Piyumanga, additional, Donnelly, Louise, additional, Mateen, Bilal A., additional, Sattar, Naveed, additional, Holman, Rury R., additional, Bowden, Jack, additional, Hattersley, Andrew T., additional, Pearson, Ewan R., additional, Jones, Angus G., additional, Shields, Beverley M., additional, McKinley, Trevelyan J., additional, and Dennis, John M., additional

Published
2023
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39. Corrigendum to ‘Identifying type 1 and 2 diabetes in research datasets where classification biomarkers are unavailable: assessing the accuracy of published approaches’ [Journal of Clinical Epidemiology (2023) 34-44]

Author

Thomas, Nicholas J., primary, McGovern, Andrew, additional, Young, Katherine G., additional, Sharp, Seth A., additional, Weedon, Michael N., additional, Hattersley, Andrew T., additional, Dennis, John, additional, and Jones, Angus G., additional

Published
2023
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42. Type 2 Diabetes risk alleles in Peptidyl-glycine Alpha-amidating Monooxygenase influence GLP-1 levels and response to GLP-1 Receptor Agonists

Author

Umapathysivam, Mahesh M, primary, Araldi, Elisa, additional, Hastoy, Benoit, additional, Dawed, Adem Y, additional, Vatandaslar, Hasan, additional, Sengupta, Shahana, additional, Kaufmann, Adrian, additional, Thomsen, Søren, additional, Hartmann, Bolette, additional, Jonsson, Anna E, additional, Kabakci, Hasan, additional, Thaman, Swaraj, additional, Grarup, Niels, additional, Have, Christian T, additional, Færch, Kristine, additional, Gjesing, Anette P, additional, Nawaz, Sameena, additional, Cheeseman, Jane, additional, Neville, Matthew J, additional, Pedersen, Oluf, additional, Walker, Mark, additional, Jennison, Christopher, additional, Hattersley, Andrew T, additional, Hansen, Torben, additional, Karpe, Fredrik, additional, Holst, Jens J, additional, Jones, Angus G, additional, Ristow, Michael, additional, McCarthy, Mark I, additional, Pearson, Ewan R, additional, Stoffel, Markus, additional, and Gloyn, Anna L, additional

Published
2023
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43. Pharmacogenomics of GLP-1 receptor agonists : a genome-wide analysis of observational data and large randomised controlled trials

Author

Dawed, Adem Y., Mari, Andrea, Brown, Andrew, McDonald, Timothy J., Li, Lin, Wang, Shuaicheng, Hong, Mun-Gwan, Sharma, Sapna, Robertson, Neil R., Mahajan, Anubha, Wang, Xuan, Walker, Mark, Gough, Stephen, Hart, Leen M. 't, Zhou, Kaixin, Forgie, Ian, Ruetten, Hartmut, Pavo, Imre, Bhatnagar, Pallav, Jones, Angus G., Pearson, Ewan R., DIRECT consortium, for the D. I. R. E. C. T. consortium, Dawed, Adem Y., Mari, Andrea, Brown, Andrew, McDonald, Timothy J., Li, Lin, Wang, Shuaicheng, Hong, Mun-Gwan, Sharma, Sapna, Robertson, Neil R., Mahajan, Anubha, Wang, Xuan, Walker, Mark, Gough, Stephen, Hart, Leen M. 't, Zhou, Kaixin, Forgie, Ian, Ruetten, Hartmut, Pavo, Imre, Bhatnagar, Pallav, Jones, Angus G., Pearson, Ewan R., and DIRECT consortium, for the D. I. R. E. C. T. consortium

Abstract

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged >= 18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G -> A (Gly168Ser) in the GLP1R (0.08% [95% CI 0.04-0.12] or 0.9 mmol/mol lower reduction in HbA1c per serine, p=6.0 x 10(-5)) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6.7 x 10(-8)), largely driven by rs140226575G -> A (Thr370Met; 0.25% [SE 0.06] or 2.7 mmol/mol [SE 0.7] greater HbA1c reduction per methionine, p=5.2 x 10(-6)). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6-11%) than in White European populations. Combining these two genes i

Published
2023
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44. Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine

Author

Tobias, Deirdre K., Merino, Jordi, Ahmad, Abrar, Aiken, Catherine, Benham, Jamie L., Bodhini, Dhanasekaran, Clark, Amy L., Colclough, Kevin, Corcoy, Rosa, Cromer, Sara J., Duan, Daisy, Felton, Jamie L., Francis, Ellen C., Gillard, Pieter, Gingras, Véronique, Gaillard, Romy, Haider, Eram, Hughes, Alice, Ikle, Jennifer M., Jacobsen, Laura M., Kahkoska, Anna R., Kettunen, Jarno L.T., Kreienkamp, Raymond J., Lim, Lee Ling, Männistö, Jonna M.E., Massey, Robert, Mclennan, Niamh Maire, Miller, Rachel G., Morieri, Mario Luca, Most, Jasper, Naylor, Rochelle N., Ozkan, Bige, Patel, Kashyap Amratlal, Pilla, Scott J., Prystupa, Katsiaryna, Raghavan, Sridharan, Rooney, Mary R., Schön, Martin, Semnani-Azad, Zhila, Sevilla-Gonzalez, Magdalena, Svalastoga, Pernille, Takele, Wubet Worku, Tam, Claudia Ha ting, Thuesen, Anne Cathrine B., Tosur, Mustafa, Wallace, Amelia S., Wang, Caroline C., Wong, Jessie J., Yamamoto, Jennifer M., Young, Katherine, Amouyal, Chloé, Andersen, Mette K., Bonham, Maxine P., Chen, Mingling, Cheng, Feifei, Chikowore, Tinashe, Chivers, Sian C., Clemmensen, Christoffer, Dabelea, Dana, Dawed, Adem Y., Deutsch, Aaron J., Dickens, Laura T., DiMeglio, Linda A., Dudenhöffer-Pfeifer, Monika, Evans-Molina, Carmella, Fernández-Balsells, María Mercè, Fitipaldi, Hugo, Fitzpatrick, Stephanie L., Gitelman, Stephen E., Goodarzi, Mark O., Grieger, Jessica A., Guasch-Ferré, Marta, Habibi, Nahal, Hansen, Torben, Huang, Chuiguo, Harris-Kawano, Arianna, Ismail, Heba M., Hoag, Benjamin, Johnson, Randi K., Jones, Angus G., Koivula, Robert W., Leong, Aaron, Leung, Gloria K.W., Libman, Ingrid M., Liu, Kai, Long, S. Alice, Lowe, William L., Morton, Robert W., Motala, Ayesha A., Onengut-Gumuscu, Suna, Pankow, James S., Pathirana, Maleesa, Pazmino, Sofia, Perez, Dianna, Petrie, John R., Powe, Camille E., Quinteros, Alejandra, Jain, Rashmi, Ray, Debashree, Ried-Larsen, Mathias, Saeed, Zeb, Santhakumar, Vanessa, Kanbour, Sarah, Sarkar, Sudipa, Monaco, Gabriela S.F., Scholtens, Denise M., Selvin, Elizabeth, Sheu, Wayne Huey Herng, Speake, Cate, Stanislawski, Maggie A., Steenackers, Nele, Steck, Andrea K., Stefan, Norbert, Støy, Julie, Taylor, Rachael, Tye, Sok Cin, Ukke, Gebresilasea Gendisha, Urazbayeva, Marzhan, Van der Schueren, Bart, Vatier, Camille, Wentworth, John M., Hannah, Wesley, White, Sara L., Yu, Gechang, Zhang, Yingchai, Zhou, Shao J., Beltrand, Jacques, Polak, Michel, Aukrust, Ingvild, de Franco, Elisa, Flanagan, Sarah E., Maloney, Kristin A., McGovern, Andrew, Molnes, Janne, Nakabuye, Mariam, Njølstad, Pål Rasmus, Pomares-Millan, Hugo, Provenzano, Michele, Saint-Martin, Cécile, Zhang, Cuilin, Zhu, Yeyi, Auh, Sungyoung, de Souza, Russell, Fawcett, Andrea J., Gruber, Chandra, Mekonnen, Eskedar Getie, Mixter, Emily, Sherifali, Diana, Eckel, Robert H., Nolan, John J., Philipson, Louis H., Brown, Rebecca J., Billings, Liana K., Boyle, Kristen, Costacou, Tina, Dennis, John M., Florez, Jose C., Gloyn, Anna L., Gomez, Maria F., Gottlieb, Peter A., Greeley, Siri Atma W., Griffin, Kurt, Hattersley, Andrew T., Hirsch, Irl B., Hivert, Marie France, Hood, Korey K., Josefson, Jami L., Kwak, Soo Heon, Laffel, Lori M., Lim, Siew S., Loos, Ruth J.F., Ma, Ronald C.W., Mathieu, Chantal, Mathioudakis, Nestoras, Meigs, James B., Misra, Shivani, Mohan, Viswanathan, Murphy, Rinki, Oram, Richard, Owen, Katharine R., Ozanne, Susan E., Pearson, Ewan R., Perng, Wei, Pollin, Toni I., Pop-Busui, Rodica, Pratley, Richard E., Redman, Leanne M., Redondo, Maria J., Reynolds, Rebecca M., Semple, Robert K., Sherr, Jennifer L., Sims, Emily K., Sweeting, Arianne, Tuomi, Tiinamaija, Udler, Miriam S., Vesco, Kimberly K., Vilsbøll, Tina, Wagner, Robert, Rich, Stephen S., Franks, Paul W., Tobias, Deirdre K., Merino, Jordi, Ahmad, Abrar, Aiken, Catherine, Benham, Jamie L., Bodhini, Dhanasekaran, Clark, Amy L., Colclough, Kevin, Corcoy, Rosa, Cromer, Sara J., Duan, Daisy, Felton, Jamie L., Francis, Ellen C., Gillard, Pieter, Gingras, Véronique, Gaillard, Romy, Haider, Eram, Hughes, Alice, Ikle, Jennifer M., Jacobsen, Laura M., Kahkoska, Anna R., Kettunen, Jarno L.T., Kreienkamp, Raymond J., Lim, Lee Ling, Männistö, Jonna M.E., Massey, Robert, Mclennan, Niamh Maire, Miller, Rachel G., Morieri, Mario Luca, Most, Jasper, Naylor, Rochelle N., Ozkan, Bige, Patel, Kashyap Amratlal, Pilla, Scott J., Prystupa, Katsiaryna, Raghavan, Sridharan, Rooney, Mary R., Schön, Martin, Semnani-Azad, Zhila, Sevilla-Gonzalez, Magdalena, Svalastoga, Pernille, Takele, Wubet Worku, Tam, Claudia Ha ting, Thuesen, Anne Cathrine B., Tosur, Mustafa, Wallace, Amelia S., Wang, Caroline C., Wong, Jessie J., Yamamoto, Jennifer M., Young, Katherine, Amouyal, Chloé, Andersen, Mette K., Bonham, Maxine P., Chen, Mingling, Cheng, Feifei, Chikowore, Tinashe, Chivers, Sian C., Clemmensen, Christoffer, Dabelea, Dana, Dawed, Adem Y., Deutsch, Aaron J., Dickens, Laura T., DiMeglio, Linda A., Dudenhöffer-Pfeifer, Monika, Evans-Molina, Carmella, Fernández-Balsells, María Mercè, Fitipaldi, Hugo, Fitzpatrick, Stephanie L., Gitelman, Stephen E., Goodarzi, Mark O., Grieger, Jessica A., Guasch-Ferré, Marta, Habibi, Nahal, Hansen, Torben, Huang, Chuiguo, Harris-Kawano, Arianna, Ismail, Heba M., Hoag, Benjamin, Johnson, Randi K., Jones, Angus G., Koivula, Robert W., Leong, Aaron, Leung, Gloria K.W., Libman, Ingrid M., Liu, Kai, Long, S. Alice, Lowe, William L., Morton, Robert W., Motala, Ayesha A., Onengut-Gumuscu, Suna, Pankow, James S., Pathirana, Maleesa, Pazmino, Sofia, Perez, Dianna, Petrie, John R., Powe, Camille E., Quinteros, Alejandra, Jain, Rashmi, Ray, Debashree, Ried-Larsen, Mathias, Saeed, Zeb, Santhakumar, Vanessa, Kanbour, Sarah, Sarkar, Sudipa, Monaco, Gabriela S.F., Scholtens, Denise M., Selvin, Elizabeth, Sheu, Wayne Huey Herng, Speake, Cate, Stanislawski, Maggie A., Steenackers, Nele, Steck, Andrea K., Stefan, Norbert, Støy, Julie, Taylor, Rachael, Tye, Sok Cin, Ukke, Gebresilasea Gendisha, Urazbayeva, Marzhan, Van der Schueren, Bart, Vatier, Camille, Wentworth, John M., Hannah, Wesley, White, Sara L., Yu, Gechang, Zhang, Yingchai, Zhou, Shao J., Beltrand, Jacques, Polak, Michel, Aukrust, Ingvild, de Franco, Elisa, Flanagan, Sarah E., Maloney, Kristin A., McGovern, Andrew, Molnes, Janne, Nakabuye, Mariam, Njølstad, Pål Rasmus, Pomares-Millan, Hugo, Provenzano, Michele, Saint-Martin, Cécile, Zhang, Cuilin, Zhu, Yeyi, Auh, Sungyoung, de Souza, Russell, Fawcett, Andrea J., Gruber, Chandra, Mekonnen, Eskedar Getie, Mixter, Emily, Sherifali, Diana, Eckel, Robert H., Nolan, John J., Philipson, Louis H., Brown, Rebecca J., Billings, Liana K., Boyle, Kristen, Costacou, Tina, Dennis, John M., Florez, Jose C., Gloyn, Anna L., Gomez, Maria F., Gottlieb, Peter A., Greeley, Siri Atma W., Griffin, Kurt, Hattersley, Andrew T., Hirsch, Irl B., Hivert, Marie France, Hood, Korey K., Josefson, Jami L., Kwak, Soo Heon, Laffel, Lori M., Lim, Siew S., Loos, Ruth J.F., Ma, Ronald C.W., Mathieu, Chantal, Mathioudakis, Nestoras, Meigs, James B., Misra, Shivani, Mohan, Viswanathan, Murphy, Rinki, Oram, Richard, Owen, Katharine R., Ozanne, Susan E., Pearson, Ewan R., Perng, Wei, Pollin, Toni I., Pop-Busui, Rodica, Pratley, Richard E., Redman, Leanne M., Redondo, Maria J., Reynolds, Rebecca M., Semple, Robert K., Sherr, Jennifer L., Sims, Emily K., Sweeting, Arianne, Tuomi, Tiinamaija, Udler, Miriam S., Vesco, Kimberly K., Vilsbøll, Tina, Wagner, Robert, Rich, Stephen S., and Franks, Paul W.

Abstract

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Published
2023

45. Type 2 Diabetes risk alleles in Peptidyl-glycine Alpha-amidating Monooxygenase influence GLP-1 levels and response to GLP-1 Receptor Agonists

Author

Umapathysivam, Mahesh M, Araldi, Elisa, Hastoy, Benoit, Dawed, Adem Y, Vatandaslar, Hasan, Sengupta, Shahana, Kaufmann, Adrian, Thomsen, Søren, Hartmann, Bolette, Jonsson, Anna E, Kabakci, Hasan, Thaman, Swaraj, Grarup, Niels, Have, Christian T, Færch, Kristine, Gjesing, Anette P, Nawaz, Sameena, Cheeseman, Jane, Neville, Matthew J, Pedersen, Oluf, Walker, Mark, Jennison, Christopher, Hattersley, Andrew T, Hansen, Torben, Karpe, Fredrik, Holst, Jens J, Jones, Angus G, Ristow, Michael, McCarthy, Mark I, Pearson, Ewan R, Stoffel, Markus, Gloyn, Anna L, Umapathysivam, Mahesh M, Araldi, Elisa, Hastoy, Benoit, Dawed, Adem Y, Vatandaslar, Hasan, Sengupta, Shahana, Kaufmann, Adrian, Thomsen, Søren, Hartmann, Bolette, Jonsson, Anna E, Kabakci, Hasan, Thaman, Swaraj, Grarup, Niels, Have, Christian T, Færch, Kristine, Gjesing, Anette P, Nawaz, Sameena, Cheeseman, Jane, Neville, Matthew J, Pedersen, Oluf, Walker, Mark, Jennison, Christopher, Hattersley, Andrew T, Hansen, Torben, Karpe, Fredrik, Holst, Jens J, Jones, Angus G, Ristow, Michael, McCarthy, Mark I, Pearson, Ewan R, Stoffel, Markus, and Gloyn, Anna L

Abstract

UNLABELLED: Patients with type 2 diabetes vary in their response to currently available therapeutic agents (including GLP-1 receptor agonists) leading to suboptimal glycemic control and increased risk of complications. We show that human carriers of hypomorphic T2D-risk alleles in the gene encoding peptidyl-glycine alpha-amidating monooxygenase (PAM), as well as Pam- knockout mice, display increased resistance to GLP-1 in vivo . Pam inactivation in mice leads to reduced gastric GLP-1R expression and faster gastric emptying: this persists during GLP-1R agonist treatment and is rescued when GLP-1R activity is antagonized, indicating resistance to GLP-1's gastric slowing properties. Meta-analysis of human data from studies examining GLP-1R agonist response (including RCTs) reveals a relative loss of 44% and 20% of glucose lowering (measured by glycated hemoglobin) in individuals with hypomorphic PAM alleles p.S539W and p.D536G treated with GLP-1R agonist. Genetic variation in PAM has effects on incretin signaling that alters response to medication used commonly for treatment of T2D. (Funded by the Wellcome, Medical Research Council, European Union, NIHR Oxford Biomedical Research Centre, United Kingdom, Registered on ClinicalTrials.gov, NCT02723110 .). SUMMARY PARAGRAPH: Type 2 diabetes (T2D) is a leading cause of morbidity and mortality globally 1 . Current management of T2D patients focuses on lowering glycemic exposure and reducing complications with lifestyle and pharmacological interventions 2 . Despite the availability of multiple medications to lower glycated hemoglobin (HbA1c), only 53% of individuals with T2D reach the glycemic target (HbA1c <7%) 3, 4 . There is potential to improve medication selection through "precision medicine" where patient specific factors (e.g. genetic markers) are used to indicate whether a patient is more or less likely to respond to a medication. Here we show that human carriers of hypomorphic T2D-risk alleles in the gen

Published
2023

46. Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models:[with Author Correction]

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B, De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T, 't Hart, Leen M, Pattou, Francois, Raverdy, Violeta, Brage, Soren, Ridderstråle, Martin, Pedersen, Oluf, Hansen, Torben, Banasik, Karina, Rasmussen, Simon, Brunak, Søren, Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B, De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T, 't Hart, Leen M, Pattou, Francois, Raverdy, Violeta, Brage, Soren, Ridderstråle, Martin, Pedersen, Oluf, Hansen, Torben, Banasik, Karina, Rasmussen, Simon, and Brunak, Søren

Abstract

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

Published
2023

47. Precision medicine in type 2 diabetes: A systematic review of treatment effect heterogeneity for GLP1-receptor agonists and SGLT2-inhibitors

Author

Young, Katherine G, McInnes, Eram Haider, Massey, Robert J, Kahkohska, Anna R, Pilla, Scott J, Raghaven, Sridharan, Stanislawski, Maggie A, Tobias, Deirdre K, McGovern, Andrew P, Dawed, Adem Y, Jones, Angus G, Pearson, Ewan R, and Dennis, John M

Subjects
Article
Abstract

BACKGROUND: A precision medicine approach in type 2 diabetes requires identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy. METHODS: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. RESULTS: After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review. The majority of papers had methodological limitations precluding robust assessment of treatment effect heterogeneity. For glycaemic outcomes, most cohorts were observational, with multiple analyses identifying lower renal function as a predictor of lesser glycaemic response with SGLT2-inhibitors and markers of reduced insulin secretion as predictors of lesser response with GLP1-receptor agonists. For cardiovascular and renal outcomes, the majority of included studies were post-hoc analyses of randomized control trials (including meta-analysis studies) which identified limited clinically relevant treatment effect heterogeneity. CONCLUSIONS: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care. PLAIN LANGUAGE SUMMARY: This review identifies research that helps understand which clinical and biological factors that are associated with different outcomes for specific type 2 diabetes treatments. This information could help clinical providers and patients make better informed personalized decisions about type 2 diabetes treatments. We focused on two common type 2 diabetes treatments: SGLT2-inhibitors and GLP1-receptor agonists, and three outcomes: blood glucose control, heart disease, and kidney disease. We identified some potential factors that are likely to lessen blood glucose control including lower kidney function for SGLT2-inhibitors and lower insulin secretion for GLP1-receptor agonists. We did not identify clear factors that alter heart and renal disease outcomes for either treatment. Most of the studies had limitations, meaning more research is needed to fully understand the factors that influence treatment outcomes in type 2 diabetes.

Published
2023

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