Endothelial and Metabolic Effects of Glucagon-like Peptide-1 (GLP-1) in Coronary Circulation in Patients With Type 2 Diabetes Mellitus

Condition(s) targeted: Type 2 Diabetes Mellitus

Intervention: Glucagon like peptide-1 (Drug); Adenosine (Drug)

Phase: N/A

Status: Completed

Sponsored by: University Hospital, Gentofte, Copenhagen

Official(s) and/or principal investigator(s):
Jan S Jensen, MD, DMSc, Study Chair, Affiliation: University hospital Gentofte, Department of Cardiology
Jaya Rosenmeier, MD, Ph.D., Principal Investigator, Affiliation: University hospital Gentofte, Department of Cardiology

GLP-1 is an incretin hormone which is discharged from the intestines after food intake. The hormone is known for its powerful insulinotropic and trophic effects on the beta cells in the pancreas and is currently used as an anti-diabetic agent in patients with type 2 diabetes (T2DM). GLP-1 receptors are widely distributed including on the endothelial cells in both coronary and skeletal muscle circulation and on the myocardium. GLP-1-receptor studies on knock-out mice have shown that they exhibit a reduced myocardial contractility and reduced diastolic heart function. GLP-1 also shows beneficial cardiovascular effects in patients with acute myocardial infarctions and dogs with dilated cardiomyopathy in that the left ventricle function and endothelial dysfunction improves after GLP-1 treatment via insulin-independent mechanisms. Preclinical studies indicate that exogenous administrated GLP-1 in physiological concentrations can improve perfusion but this has never been tested in humans. It is also unknown whether GLP-1 can directly increase the glucose/metabolite uptake across both cardiac and skeletal muscle in an insulin independent manner. Unpublished studies do however indicate that the improvement in the cardiovascular system is largely dependent upon a high blood glucose level and only partially dependent upon the antiglycemic effects of GLP-1. In the proposed studies the investigators wish to examine the physiological role of GLP-1 receptor stimulation both with regard to perfusion, metabolic improvement as well as cardiac inotropic. These studies will be conducted in both healthy and in T2DM patients.

Official title: Endothelial and Metabolic Effects of GLP-1 in Coronary Circulation in Patients With Type 2 Diabetes Mellitus

Study design: Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Primary outcome:

Coronary blood flow

Coronary metabolite uptake

Minimum age: 18 Years. Maximum age: 75 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Caucasians over 18

- Emitted for non-acute coronary arteriography (CAG) in Gentofte hospital

- BMI 23-35 kg/m2

- Normal hemoglobin

- Who gives informed consent

- Those with type 2 diabetes: HbA1c 6-10%

- Those without type 2 diabetes: Normal oral glucose tolerance test (OGTT) according to

WHO criteria Exclusion Criteria:

- Liver disease (ALAT > 2x normal)

- Diabetic nefropati (Creatinine > 130 µM or albuminuria)

- Treatment with medicine that cannot be paused 12 hours before intervention

- Pregnancy or breastfeeding

- Insulin- or glitazone treatment

- Healthy controls: close family history with diabetes

- Unstable angina pectoris

- Non-STEMI

- Atrial fibrillation

- Valvular disease

- LVEF < 50%

- Severe systemic disease

- Type 1 diabetes

University Hospital Gentofte, Department of Cardiology, Gentofte 2900, Denmark

Related publications:

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Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW, Bax JJ, Romijn JA, de Roos A, Radder JK. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol. 2003 Jul 16;42(2):328-35.

Edwards CM, Todd JF, Mahmoudi M, Wang Z, Wang RM, Ghatei MA, Bloom SR. Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes. 1999 Jan;48(1):86-93.

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Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, Shannon RP. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004 Mar 2;109(8):962-5. Epub 2004 Feb 23.

Yu M, Moreno C, Hoagland KM, Dahly A, Ditter K, Mistry M, Roman RJ. Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats. J Hypertens. 2003 Jun;21(6):1125-35.

Nyström T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahrén B, Sjöholm A. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1209-15. Epub 2004 Sep 7.

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Nikolaidis LA, Elahi D, Shen YT, Shannon RP. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2401-8. Epub 2005 Jul 15.

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Nyström T, Gonon AT, Sjöholm A, Pernow J. Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept. 2005 Feb 15;125(1-3):173-7.

Starting date: June 2009
Last updated: September 17, 2012