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The study to understand the genetics of the acute response to metformin and glipizide in humans (SUGAR-MGH): design of a pharmacogenetic resource for type 2 diabetes.

Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Diabetes Research Center, Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Endocrinology and Nutrition. Hospital Universitario Regional de Málaga. Instituto de Investigación Biomédica de Málaga (IBIMA). Málaga, Spain. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America; Boston Children's Hospital, Boston, Massachusetts, United States of America. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Diabetes Research Center, Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America; Division of Endocrinology and Metabolism, NorthShore University Health System, Evanston, Illinois, United States of America. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts, United States of America. Joslin Diabetes Center, Boston, Massachusetts, United States of America. Harvard Medical School, Boston, Massachusetts, United States of America. Genomics Platform, Broad Institute, Cambridge, Massachusetts, United States of America. Diabetes Research Center, Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts, United States of America. Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America. Harvard Medical School, Boston, Massachusetts, United States of America; Joslin Diabetes Center, Boston, Massachusetts, United States of America.

PloS one. 2015;(3):e0121553
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Abstract

OBJECTIVE Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH, NCT01762046) is a novel resource of genetic and biochemical data following glipizide and metformin administration. We describe recruitment, enrollment, and phenotyping procedures and preliminary results for the first 668 of our planned 1,000 participants enriched for individuals at risk of requiring anti-diabetic therapy in the future. METHODS All individuals are challenged with 5 mg glipizide × 1; twice daily 500 mg metformin × 2 days; and 75-g oral glucose tolerance test following metformin. Genetic variants associated with glycemic traits and blood glucose, insulin, and other hormones at baseline and following each intervention are measured. RESULTS Approximately 50% of the cohort is female and 30% belong to an ethnic minority group. Following glipizide administration, peak insulin occurred at 60 minutes and trough glucose at 120 minutes. Thirty percent of participants experienced non-severe symptomatic hypoglycemia and required rescue with oral glucose. Following metformin administration, fasting glucose and insulin were reduced. Common genetic variants were associated with fasting glucose levels. CONCLUSIONS SUGAR-MGH represents a viable pharmacogenetic resource which, when completed, will serve to characterize genetic influences on pharmacological perturbations, and help establish the functional relevance of newly discovered genetic loci to therapy of type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT01762046.

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Publication Type : Clinical Trial

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