Effects of Hyperglycemia on Myocardial Perfusion in Humans With and Without Type 2 Diabetes

Effects of Hyperglycemia on Myocardial Perfusion in Humans With and Without Type 2 Diabetes: Modulation by Glucagon-Like-Peptide-1

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, United Kingdom Prospective Diabetes Study (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.

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.