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ObjectiveGenome-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.MethodsAll 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.ResultsApproximately 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.ConclusionsSUGAR-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 RegistrationClinicalTrials.gov NCT01762046

Objective Higher hemoglobin A1c (HbA1c) is associated with lower cognitive function in type 2 diabetes. To determine if associations persist at lower levels of dysglycemia in patients who have established cardiovascular disease, cognitive performance was assessed in the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial. Research Design and Methods The age-adjusted relationships between HbA1c and cognitive performance measured by the Mini-mental State Examination (MMSE), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT), and Categorical Verbal Fluency (CVF) were assessed in 226 men with metabolic syndrome and established stable coronary artery disease. Results 61.5% of participants had normoglycemia, 20.8% impaired fasting glucose, and 17.7% type 2 diabetes. HbA1c was associated with cognitive function tests of DSST, RAVLT, TMT and CVF (all P<0.02), but not MMSE. In an age-adjusted model, a 1% (11 mmol/mol) higher HbA1c value was associated with a 5.9 lower DSST score (95%CI: −9.58 to −2.21; P<0.0001); a 2.44 lower RAVLT score (95%CI: −4.00 to −0.87; P<0.0001); a 15.6 higher TMT score (95%CI: 5.73 to 25.6; P<0.0001); and a 3.71 lower CVF score (95%CI: −6.41 to −1.01; P<0.02). In multivariate model adjusting for age, education and cardiovascular covariates, HbA1c remains associated with cognitive function tests of RAVLT (R2=0.27, P<0.0001), TMT (R2=0.18, P<0.0001), and CVF (R2=0.20, P<0.0001) although association with DSST was reduced. Conclusion Higher HbA1c is associated with lower cognitive function performance scores across multiple domain tests in men with metabolic syndrome and coronary artery disease. Future studies may demonstrate whether glucose lowering within the normative range improves cognitive health.