Common Genetic Variants Near SLC2A2 and Glycemic Response to Glimepiride in the GRADE Comparative Effectiveness Clinical Trial

OBJECTIVE Optimizing second-line therapy for type 2 diabetes remains challenging because of interindividual variability in response. Current treatment selection does not consider personal genetic profiles. To address this gap, we conducted a pharmacogenomic genome-wide association study (GWAS) in a randomized comparative effectiveness trial to identify genetic predictors of glycemic response to insulin glargine, glimepiride, liraglutide, and sitagliptin when added to metformin. RESEARCH DESIGN AND METHODS In the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study (GRADE), we performed a GWAS for the time to reach primary (glycated hemoglobin [HbA1c] ≥7%) and secondary (HbA1c >7.5%) metabolic failure. We conducted replication in independent cohorts, performed fine mapping of the top variants near SLC2A2, evaluated them for physiologic impact using oral glucose tolerance testing (OGTT) and response to acute glipizide challenge, and characterized glycemic response to glimepiride in an slc2a2-mutated zebrafish model. RESULTS rs2129019 in SLC2A2 encoding GLUT2 was enriched in African/African American participants and conferred a 38% increased risk of metabolic failure per A allele on glimepiride (P = 1.55 × 10−8). Carriers had impaired β-cell function, evidenced by a lower C-peptide index during OGTT, and diminished glucose-lowering response to acute sulfonylurea challenge. Genetic manipulation in zebrafish confirmed that slc2a2 disruption attenuated the glucose-lowering effect of glimepiride. CONCLUSIONS Genetic variation influences glycemic response to glucose-lowering medications, with SLC2A2 emerging as a genetic factor that modulates sulfonylurea response. These findings warrant further study to evaluate whether low-response allele carriers would benefit from alternative glucose-lowering therapies to advance precision diabetes care.

Authors

Institutions

Publication Details

Journal
Diabetes Care
Published
2026-11-05
DOI
https://doi.org/10.2337/dc26-1633
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
NOV
article

Common Genetic Variants Near SLC2A2 and Glycemic Response to Glimepiride in the GRADE Comparative Effectiveness Clinical Trial

Sridhar Tanukonda, J. Costello, Marie Pigeyre, Stephanie Behringer-Massera et al.
Diabetes Care
Genetic Associations and Epidemiology
article

Common Genetic Variants Near SLC2A2 and Glycemic Response to Glimepiride in the GRADE Comparative Effectiveness Clinical Trial

Sridhar Tanukonda, J. Costello, Marie Pigeyre, Stephanie Behringer-Massera, Tasha Stephanie Raines, E. Gonzalez Hattery, Naji Younes, Deepak L. Bhatt, A. Ross, Alicia Huerta‐Chagoya, C.A. White, J. Brown-Friday, Katherine A. Stancil, Leah Holloway, Ruth J. F. Loos, Christian Thomas Ruff, Andrew C. Jackson, Marcel den Hoed, Adrienne Krol, S. Duran, Mabil Sibymon, Hertzel C. Gerstein, Ruchi Gaba, M. Tiktin, J. Pring, Aaron Leong, L. Colosimo, Bethany Cramer, Adrienne Ideozu, Stella Nam, C. Patel, Maggie C.Y. Ng, Entila Xhori, James B. Meigs, L. Savoye, L. Sayyed Kassem, Haiyin Liu, J. Iacoboni, Lucia Alfano, Lisa Tucker, Melissa Diane McKee, Marcin Czajkowski, J. Lukin, Anna Citko, José C. Florez, Anastasia Emmanouilidou, J.P. Crandall, Priscilla A. Hollander, Paulina Konopka, F. Morehead, C. Sanders, Elizabeth Burgess, Adam Jacek Kretowski, F. Ismail-Beigi, Tanya Kulow, Łukasz Szczerbiński, K. Ballentine-Cargill, Cynthia Adams, Adem Y. Dawed, A. Balasubramanyam, Radhika Mungara, Endrina Mújica, Kris Chionh, A. Werner, Steven E. Kahn, L.S. Phillips, Leslie S. Satin, C. Falck-Ytter, Filipe A. Moura, G. McPhee, E. Roe, H. Estrella, J. Jimenez, Polly Burt, Maria V. Kononets, M. Rhee, Robin Goland, A. Sood, S. Gonzalez de la torre, Mark Tripputi, Josephine H. Li, Ewan R. Pearson, Maxine Maher-Albertelli, S. Person, Chona Gullett, A. Maxwell, Nicholas Marston, Thinley Yidzin Wangden, Josep Maria Mercader, Maheak Vora, Lorie Estrada, J. Boers, Ashley Smiley, Darin E. Olson, G. Montes, Marc S. Sabatine, Yi-Pin Lai, C. Wright, P. Wilson, C. Newman
article en

Abstract

OBJECTIVE Optimizing second-line therapy for type 2 diabetes remains challenging because of interindividual variability in response. Current treatment selection does not consider personal genetic profiles. To address this gap, we conducted a pharmacogenomic genome-wide association study (GWAS) in a randomized comparative effectiveness trial to identify genetic predictors of glycemic response to insulin glargine, glimepiride, liraglutide, and sitagliptin when added to metformin. RESEARCH DESIGN AND METHODS In the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study (GRADE), we performed a GWAS for the time to reach primary (glycated hemoglobin [HbA1c] ≥7%) and secondary (HbA1c >7.5%) metabolic failure. We conducted replication in independent cohorts, performed fine mapping of the top variants near SLC2A2, evaluated them for physiologic impact using oral glucose tolerance testing (OGTT) and response to acute glipizide challenge, and characterized glycemic response to glimepiride in an slc2a2-mutated zebrafish model. RESULTS rs2129019 in SLC2A2 encoding GLUT2 was enriched in African/African American participants and conferred a 38% increased risk of metabolic failure per A allele on glimepiride (P = 1.55 × 10−8). Carriers had impaired β-cell function, evidenced by a lower C-peptide index during OGTT, and diminished glucose-lowering response to acute sulfonylurea challenge. Genetic manipulation in zebrafish confirmed that slc2a2 disruption attenuated the glucose-lowering effect of glimepiride. CONCLUSIONS Genetic variation influences glycemic response to glucose-lowering medications, with SLC2A2 emerging as a genetic factor that modulates sulfonylurea response. These findings warrant further study to evaluate whether low-response allele carriers would benefit from alternative glucose-lowering therapies to advance precision diabetes care.

Diabetes Care
Broad Institute (US), Uppsala University (SE), University of Copenhagen (DK), Brigham and Women's Hospital (US), Bialystok University of Technology (PL), Harvard University (US), Medical University of Białystok (PL), University of Dundee (GB), George Washington University (US), University of Michigan (US), Science for Life Laboratory (SE), Population Health Research Institute (CA), Yale University (US), VA Connecticut Healthcare System (US), Massachusetts General Hospital (US), VA Puget Sound Health Care System (US), Thrombolysis in Myocardial Infarction Study Group (US), Mass General Brigham (US), Hamilton Health Sciences (CA), Vanderbilt University Medical Center (US), McMaster University (CA), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 20%
Genetic Associations and Epidemiology
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.

Laika access coming soon