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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.

Our understanding of the genetics of type 2 diabetes mellitus (T2DM) has changed, in part owing to implementation of genome-wide association studies as a method for unraveling the genetic architecture of complex traits. These studies enable a global search throughout the nuclear genome for variants that are associated with specific phenotypes. Currently, single nucleotide polymorphisms in about 24 different genetic loci have been associated with T2DM. Most of these genetic loci are associated with the insulin secretion pathway rather than insulin resistance. Study design, heritability differences and the intrinsic properties of in vivo insulin resistance measures might partially explain why only a few loci associated with insulin resistance have been detected through genome-wide association approaches. Despite the success of these approaches at detecting loci associated with T2DM, currently known associations explain only a small amount of the genetic variance involved in the disease. Compared with previous studies, larger cohorts might be needed to identify variants of smaller effect sizes and lower allele frequencies. Finally, the current list of genetic loci that are related to T2DM does not seem to offer greater predictive value in determining diabetes risk than do commonly used phenotypic risk factors and family history.