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1. 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.

Author

Geoffrey A Walford, Natalia Colomo, Jennifer N Todd, Liana K Billings, Marlene Fernandez, Bindu Chamarthi, A Sofia Warner, Jaclyn Davis, Katherine R Littleton, Alicia M Hernandez, Rebecca R Fanelli, Amelia Lanier, Corinne Barbato, Rachel J Ackerman, Sabina Q Khan, Rosa Bui, Laurel Garber, Elliot S Stolerman, Allan F Moore, Chunmei Huang, Varinderpal Kaur, Maegan Harden, Andrew Taylor, Ling Chen, Alisa K Manning, Paul Huang, Deborah Wexler, Rita M McCarthy, Janet Lo, Melissa K Thomas, Richard W Grant, Allison Goldfine, Margo S Hudson, and Jose C Florez

Subjects
Medicine, Science
Abstract

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.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.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.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.ClinicalTrials.gov NCT01762046.

Published
2015
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2. 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

Author

Jennifer N. Todd, Andrew W. Taylor, Geoffrey A. Walford, Maegan Harden, Deborah J. Wexler, Jaclyn Davis, Melissa K. Thomas, Janet Lo, Varinderpal Kaur, Jose C. Florez, Ling Chen, Katherine R. Littleton, Rachel J. Ackerman, Rebecca R. Fanelli, Bindu Chamarthi, Paul L. Huang, Corinne Barbato, Liana K. Billings, Allison B. Goldfine, A. Sofia Warner, Elliot S. Stolerman, Alisa K. Manning, Allan F. Moore, Sabina Q. Khan, Richard W. Grant, Rita M. McCarthy, Margo S. Hudson, Chunmei Huang, Marlene Fernandez, Alicia M. Hernandez, Rosa Bui, Laurel Garber, Amelia Lanier, Natalia Colomo, [Walford,GA, Colomo,N, Todd,JN, Billings,LK, Fernandez,M, Warner,AS, Davis,J, Littleton,KR, Hernandez,AM, Fanelli,RR, Lanier,A, Ackerman,RJ, Khan,SQ, Stolerman,ES, Moore,AF, Kaur,V, Taylor,A, Chen,L, Manning,AK, Florez,JC] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America. [Walford,GA, Wexler,D, Thomas,MK, Florez,JC] Diabetes Research Center, Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America. [Walford,GA, Huang,C, Huang,P, Lo,J, Goldfine,A, Florez,JC] Harvard Medical School, Boston, Massachusetts, United States of America. [Colomo,N] Department of Endocrinology and Nutrition. Hospital Universitario Regional de Málaga. Instituto de Investigación Biomédica de Málaga (IBIMA). Málaga, Spain. [Todd,JN] Boston Children’s Hospital, Boston, Massachusetts, United States of America. [Billings,LK, ] Division of Endocrinology and Metabolism, NorthShore University Health System, Evanston, Illinois, United States of America. [Chamarthi,B] Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America. [Chamarthi,B, McCarthy,RM, Hudson,MS] Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America. [Barbato,C, Bui,R, Garber,L, Goldine,A] Joslin Diabetes Center, Boston, Massachusetts, United States of America. [Harden,M] Genomics Platform, Broad Institute, Cambridge, Massachusetts, United States of America. [Grant,RW] Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America., This work was conducted with support from National Institutes of Health/NIDDK awards R01 DK088214, R03 DK077675, and P30 DK036836, from the Joslin Clinical Research Center from its philanthropic donors, and and the Harvard Catalyst: The Harvard Clinical and translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH Awards M01-RR-01066, 1 UL1 RR025758-04 and 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers).

Subjects
Blood Glucose, Male, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], medicine.medical_treatment, lcsh:Medicine, Type 2 diabetes, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Hipoglicemiantes, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Insulina, Insulin, lcsh:Science, Genetics, Glucose tolerance test, Prueba de tolerancia a la glucosa, Multidisciplinary, medicine.diagnostic_test, Predisposición genética a la enfermedad, Middle Aged, Polimorfismo de nucleótido único, Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease [Medical Subject Headings], Metformin, 3. Good health, Phenotype, Treatment Outcome, Chemicals and Drugs::Organic Chemicals::Amidines::Guanidines::Biguanides::Metformin [Medical Subject Headings], Female, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Pharmacology::Pharmacogenetics [Medical Subject Headings], Alelos, Fenotipo, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Clinical Laboratory Techniques::Clinical Chemistry Tests::Blood Chemical Analysis::Glucose Tolerance Test [Medical Subject Headings], Transcription Factor 7-Like 2 Protein, medicine.drug, Research Article, Adult, Blood sugar, Check Tags::Male [Medical Subject Headings], Hypoglycemia, Polymorphism, Single Nucleotide, Diabetes mellitus, medicine, Chemicals and Drugs::Biological Factors::Biological Markers [Medical Subject Headings], Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Proteína 2 similar al factor de transcripción 7, Humans, Hypoglycemic Agents, Genetic Predisposition to Disease, Named Groups::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings], Alleles, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Pancreatic Hormones::Insulins [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome [Medical Subject Headings], Aged, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], business.industry, lcsh:R, Diseases::Endocrine System Diseases::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], glipicida, Glucose Tolerance Test, medicine.disease, Biomarcadores, Check Tags::Female [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors::TCF Transcription Factors::Transcription Factor 7-Like 2 Protein [Medical Subject Headings], Diabetes Mellitus, Type 2, Pharmacogenetics, Diabetes Mellitus, Tipo II, Chemicals and Drugs::Organic Chemicals::Sulfur Compounds::Sulfones::Sulfonylurea Compounds::Glipizide [Medical Subject Headings], Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Hypoglycemic Agents [Medical Subject Headings], lcsh:Q, Resultado del tratamiento, business, Biomarkers, Glipizide, Glucosa sanguínea, Chemicals and Drugs::Carbohydrates::Monosaccharides::Hexoses::Glucose::Blood Glucose [Medical Subject Headings]
Abstract

ClinicalTrials.gov NCT01762046; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; 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. Yes

Published
2015

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