Examining Genetic Influence on Response to Beta-Blocker Medications in People With Type 2 Diabetes

Beta-blockers are medications used to treat cardiovascular disease (CVD) symptoms, including high blood pressure and chest pain. People with diabetes who receive beta-blockers may experience adverse health effects, but the exact cause of why this happens remains unknown. This study will examine the genetic factors that may influence how atenolol, a beta-blocker medication, affects fat breakdown, blood sugar levels, and heart function in people with type 2 diabetes.

People with diabetes who develop CVD have worse health outcomes than people without diabetes who develop CVD. Beta-blockers are medications used to treat high blood pressure, angina (i.e., chest pain), arrhythmias, and other CVD conditions. While beta-blockers are effective at treating these conditions, they may also have damaging effects on cholesterol or glucose levels, thereby possibly lessening their ability to prevent CVD events in people with diabetes. It is important to identify which patients may not benefit from receiving beta-blocker medications. Genetic factors may influence how people respond to beta-blocker medications. The purpose of this study is to evaluate the influence of genetic variation on beta-blocker-induced changes in insulin sensitivity, fat breakdown, and heart function in people with type 2 diabetes. This study will enroll people with type 2 diabetes. At a series of up to three baseline study visits, participants will have a blood collection, a glucose tolerance test, an echocardiogram to obtain images of the heart, and biopsies of muscle from the thigh and fat from the stomach. All participants will then receive atenolol once a day for 8 weeks. During Week 1, participants will receive a low dose of atenolol. They will then attend a study visit at the end of Week 1, and study researchers will examine how well participants are tolerating the medication. If the atenolol is well tolerated, the dose will be increased. Study researchers will call participants 1 week after any dosage changes to monitor for side effects. Blood collection will occur again at a study visit at Week 4. At Week 8, participants will then attend up to three study visits for repeat baseline testing. Participants will then be slowly tapered off of atenolol over a 1-week period.

12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated

Estimate of peripheral lipolysis using modeling of free fatty acid levels collected during an IV glucose tolerance test. The change in threshold for insulin action (post-atenolol minus pre-atenolol) is the primary variable from this modeling that we analyzed.

As measured by the Homeostatic model assessment of insulin resistance (HOMA2-IR) (post atenolol - pre atenolol). he Homeostatic model assessment (HOMA) is a method for assessing insulin sensitivity from fasting glucose and insulin. A higher HOMA value indicates higher insulin resistance. The widely-used formulae available for HOMA1 provide only linear approximations of HOMA_%B and HOMA_IR, the inverse of HOMA_%S. These are: HOMA1_IR = [FPI (uU/ml) x FPG (mmol/l) ]/22.5 HOMA1_%B = (20 x FPI)/(FPG - 3.5) The results obtained for HOMA2 may differ considerably from HOMA1 computer-calculated values, especially for more extreme glucose and insulin values. For this reason, no attempt has been made to provide linear approximations of HOMA2 calculated values of HOMA_%B, HOMA_IR and HOMA_%S. The software needed to calculate HOMA2 values is available on this website: https://www.dtu.ox.ac.uk/homacalculator/download.php, subject to the conditions specified on the downloads page.

Glucose effectiveness as measured by insulin-modified IV glucose tolerance test using the MINMOD model.

Inclusion Criteria: Type 2 diabetes Pre-Diabetes Exclusion Criteria: Insulin therapy Treatment with any beta-blocker in the 30 days before study entry Asthma Chronic obstructive pulmonary disease (COPD) Greater than first degree heart block Heart rate less than 60 bpm Systolic blood pressure less than 90 mm Hg Raynaud's phenomenon Known history of angina, heart attack, heart failure, coronary revascularization, or automatic implantable cardioverter defibrillators Pregnant Creatinine clearance less than 35 ml/min Hematologic dysfunction (white blood cell [WBC] count less than 3000 or hematocrit less than 28%) Allergy to amide anesthetics