Effects of Hyperglycemia on Myocardial Perfusion in Humans With and Without Type 2 Diabetes (GLP-1)

Purpose
The overall goal of this proposal is to determine the effects of acute hyperglycemia and its modulation by Glucagon-like Peptide-1 (GLP-1) on myocardial perfusion in type 2 diabetes (DM). This study plan utilizes myocardial contrast echocardiography (MCE) to explore a) the effects of acute hyperglycemia on myocardial perfusion and coronary flow reserve in individuals with and without DM; and b) the effects of GLP-1 on myocardial perfusion and coronary flow reserve during euglycemia and hyperglycemia in DM. The investigators will recruit individuals with and without DM matched for age, gender and degree of obesity. The investigators will measure myocardial perfusion at rest and during vasodilator stress (to ascertain coronary flow reserve) while subjects are under controlled pancreatic clamp conditions during euglycemia (glucose ~100 mg/dl) and hyperglycemia (glucose ~250 mg/dl) in the presence and absence of concomitant GLP-1 infusion. The investigators believe that the translational significance of their studies is immense, impacting upon both acute and chronic cardiovascular disease manifestations. The effect of glycemic control on cardiovascular outcomes, morbidity and mortality remains an area of active investigation, fueled by the recent conflicting results of several large clinical trials (ACCORD, UKPDS, ADVANCE, VADT). If the investigators find that hyperglycemia is associated with altered myocardial perfusion, the mechanistic implications in the prevention and management of acute and chronic cardiovascular diseases in DM will be groundbreaking. Furthermore, if GLP-1 augments myocardial perfusion (as it does in the peripheral vasculature), the therapeutic benefits for prevention of cardiovascular events in this predisposed population are clear.

Further study details as provided by Mayo Clinic:
Primary Outcome Measures:

• To determine whether hyperglycemia alters myocardial perfusion in subjects with type 2 diabetes [ Time Frame: Nov 2009-2011 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

• To determine whether GLP-1 modulates myocardial perfusion in subjects with type 2 diabetes. [ Time Frame: Nov 2009-2011 ] [ Designated as safety issue: No ]

Estimated Enrollment: 50
Study Start Date: February 2010
Estimated Study Completion Date: May 2012
Estimated Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)

Eligibility
Ages Eligible for Study: 40 Years to 60 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: Yes
Sampling Method: Non-Probability Sample

Study Population
25 subjects with type 2 diabetes and 25non-diabetic subjects matched for age, gender and degree of obesity will be studied.

The diabetic subjects will be between 40 and 60 years of age and will have a body mass index of < or =35 kg/m2. Diabetic subjects treated according to ADA guidelines will be eligible for study including a blood pressure < 140/90, LDL cholesterol < 130 mg/dl, HDL cholesterol >40 mg/dl and triglycerides <200 mg/dl.

All nondiabetic subjects will not have a history of diabetes in their first degree family members. None of the subjects will have any overt evidence of cardiac, renal, pulmonary or hepatic disorder nor will they be engaging in regular vigorous physical activities. All subjects will undergo a resting ECG and a treadmill ECG test to ensure that they do not have active or occult coronary artery disease unless such testing had been completed within six months of enrollment and reported as normal.

Criteria
Inclusion Criteria:

• Males and females
• Age 40-60 years BMI< or = 35 kg/m2
• Diabetic subjects with HbA1c concentrations of < or = 8%.
• Diabetic subjects will be either on diet and lifestyle therapy alone, or monotherapy with metformin or sulphonylureas (except glyburide).
• All diabetic subjects should be on stable dose oral agent therapy for 3 months prior to enrollment.

Exclusion Criteria:

• Subjects with cerebrovascular or peripheral vascular disease.
• Subjects with suspected or overt autonomic neuropathy.
• Diabetic subject on thiazolidinediones, insulin, GLP-1 based therapies (exenatide or sitagliptin), alpha-glucosidase inhibitors, glyburide or combination antidiabetic drug therapies.
• Diabetics with microalbuminuria.