title: 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.
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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01762046.
authors: 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.
authors: Geoffrey A
authors: GA
authors: Walford
authors: 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.
authors: Natalia
authors: N
authors: Colomo
authors: 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.
authors: Jennifer N
authors: JN
authors: Todd
authors: 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.
authors: Liana K
authors: LK
authors: Billings
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Marlene
authors: M
authors: Fernandez
authors: 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.
authors: Bindu
authors: B
authors: Chamarthi
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: A Sofia
authors: AS
authors: Warner
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Jaclyn
authors: J
authors: Davis
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Katherine R
authors: KR
authors: Littleton
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Alicia M
authors: AM
authors: Hernandez
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Rebecca R
authors: RR
authors: Fanelli
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Amelia
authors: A
authors: Lanier
authors: Joslin Diabetes Center, Boston, Massachusetts, United States of America.
authors: Corinne
authors: C
authors: Barbato
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Rachel J
authors: RJ
authors: Ackerman
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Sabina Q
authors: SQ
authors: Khan
authors: Joslin Diabetes Center, Boston, Massachusetts, United States of America.
authors: Rosa
authors: R
authors: Bui
authors: Joslin Diabetes Center, Boston, Massachusetts, United States of America.
authors: Laurel
authors: L
authors: Garber
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Elliot S
authors: ES
authors: Stolerman
authors: 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.
authors: Allan F
authors: AF
authors: Moore
authors: Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Chunmei
authors: C
authors: Huang
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Varinderpal
authors: V
authors: Kaur
authors: Genomics Platform, Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Maegan
authors: M
authors: Harden
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Andrew
authors: A
authors: Taylor
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Ling
authors: L
authors: Chen
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Alisa K
authors: AK
authors: Manning
authors: Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Paul
authors: P
authors: Huang
authors: 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.
authors: Deborah
authors: D
authors: Wexler
authors: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Rita M
authors: RM
authors: McCarthy
authors: Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Janet
authors: J
authors: Lo
authors: 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.
authors: Melissa K
authors: MK
authors: Thomas
authors: Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America.
authors: Richard W
authors: RW
authors: Grant
authors: Harvard Medical School, Boston, Massachusetts, United States of America; Joslin Diabetes Center, Boston, Massachusetts, United States of America.
authors: Allison
authors: A
authors: Goldfine
authors: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Margo S
authors: MS
authors: Hudson
authors: 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.
authors: Jose C
authors: JC
authors: Florez
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D015415:Biomarkers; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005913:Glipizide / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D008687:Metformin; D005913:Glipizide