title: Glucagon-like peptide-1 protects against ischemic left ventricular dysfunction during hyperglycemia in patients with coronary artery disease and type 2 diabetes mellitus.
abstract: BACKGROUND
  Enhancement of myocardial glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7-36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)-one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments.
  
  
  RESULTS
  In study 1, the HHC (compared with control) increased glucose (13.0 ± 1.9 versus 4.8 ± 0.5 mmol/l, p < 0.0001) and insulin (1,212 ± 514 versus 114 ± 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 ± 175 versus 1,001 ± 333 μmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 ± 5.0 versus 71.3 ± 4.3%, p = 0.004) and regional (peak systolic strain -18.1 ± 6.6 versus -15.5 ± 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia.
  
  
  CONCLUSIONS
  In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM.
  
  
  BACKGROUND
  http://www.isrctn.org . Unique identifier ISRCTN69686930.
authors.affiliation: Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK. drliammccormick@doctors.org.uk.
authors.forename: Liam M
authors.initials: LM
authors.lastname: McCormick
authors.affiliation: Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK. pmheck@doctors.org.uk.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Heck
authors.affiliation: Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK. liamring@doctors.org.uk.
authors.forename: Liam S
authors.initials: LS
authors.lastname: Ring
authors.affiliation: Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK. annakydd@doctors.org.uk.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Kydd
authors.affiliation: Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK. sophie.j.clarke@gmail.com.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Clarke
authors.affiliation: Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK. stevieh@doctors.org.uk.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hoole
authors.affiliation: Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK. dpd24@medschl.cam.ac.uk.|Department of Cardiovascular Medicine, ACCI Level 6, Addenbrooke's Hospital, Box 110, Hills Rd, Cambridge, CB2 0QQ, UK. dpd24@medschl.cam.ac.uk.
authors.forename: David P
authors.initials: DP
authors.lastname: Dutka
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003324:Coronary Artery Disease / Q000150:complications* / Q000175:diagnosis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000175:diagnosis; D058065:Diabetic Cardiomyopathies / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D018618:Echocardiography, Doppler, Color; D025401:Echocardiography, Stress; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage*; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000150:complications* / Q000175:diagnosis; D054795:Incretins / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage*; D013318:Stroke Volume / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D054795:Incretins; D007328:Insulin; D010446:Peptide Fragments; C055453:glucagon-like peptide 1 (7-36)amide; D052216:Glucagon-Like Peptide 1