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

Purpose

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 Unpublished studies do however indicate that the improvement in the cardiovascular system is largely dependent upon a high blood glucose level and only partially dependent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.

Condition	Intervention
Type 2 Diabetes Mellitus	Drug: Glucagon like peptide-1 Drug: Adenosine


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacodynamics Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Official Title:	Endothelial and Metabolic Effects of GLP-1 in Coronary Circulation in Patients With Type 2 Diabetes Mellitus

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Type 2

Drug Information available for: Adenosine Glucagon

U.S. FDA Resources

Further study details as provided by University Hospital, Gentofte, Copenhagen:

Primary Outcome Measures:

Coronary blood flow [ Time Frame: 10 minutes after I.A. GLP-1 ] [ Designated as safety issue: No ]
Coronary metabolite uptake [ Time Frame: 10 minutes after I.A. GLP-1 ] [ Designated as safety issue: No ]


Enrollment:	35
Study Start Date:	June 2009
Study Completion Date:	January 2012
Primary Completion Date:	January 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Type 2 Diabetes patients	Drug: Glucagon like peptide-1 0,1 pmol/kg/min Drug: Adenosine 20-40 microgram/minute
Active Comparator: Healthy	Drug: Glucagon like peptide-1 0,1 pmol/kg/min Drug: Adenosine 20-40 microgram/minute
Active Comparator: Artherosclerosis	Drug: Glucagon like peptide-1 0,1 pmol/kg/min Drug: Adenosine 20-40 microgram/minute

Eligibility


Ages Eligible for Study:	18 Years to 75 Years (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00923962

Locations


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

Sponsors and Collaborators

University Hospital, Gentofte, Copenhagen

Merck Sharp & Dohme Corp.

Investigators


Study Chair:	Jan S Jensen, MD, DMSc	University hospital Gentofte, Department of Cardiology
Principal Investigator:	Jaya Rosenmeier, MD, Ph.D.	University hospital Gentofte, Department of Cardiology

More Information

Publications:

Bjällmark A, Larsson M, Winter R, Westholm C, Jacobsen P, Lind B, Brodin LA. Velocity tracking--a novel method for quantitative analysis of longitudinal myocardial function. J Am Soc Echocardiogr. 2007 Jul;20(7):847-56.

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.

Golpon HA, Puechner A, Welte T, Wichert PV, Feddersen CO. Vasorelaxant effect of glucagon-like peptide-(7-36)amide and amylin on the pulmonary circulation of the rat. Regul Pept. 2001 Dec 15;102(2-3):81-6.

Luque MA, González N, Márquez L, Acitores A, Redondo A, Morales M, Valverde I, Villanueva-Peñacarrillo ML. Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes. J Endocrinol. 2002 Jun;173(3):465-73.

Mogelvang R, Sogaard P, Pedersen SA, Olsen NT, Schnohr P, Jensen JS. Tissue Doppler echocardiography in persons with hypertension, diabetes, or ischaemic heart disease: the Copenhagen City Heart Study. Eur Heart J. 2009 Mar;30(6):731-9. doi: 10.1093/eurheartj/ehn596. Epub 2009 Jan 27.

Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care. 2001 Sep;24(9):1614-9.

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.

Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology. 1996 Jul;137(7):2968-78.

Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett. 1995 Jan 30;358(3):219-24.

Wei Y, Mojsov S. Distribution of GLP-1 and PACAP receptors in human tissues. Acta Physiol Scand. 1996 Jul;157(3):355-7. Review.

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.

Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008 May 6;117(18):2340-50. doi: 10.1161/CIRCULATIONAHA.107.739938. Epub 2008 Apr 21. Erratum in: Circulation. 2008 Jul 22;118(4):e81.

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.


Responsible Party:	Jacob Christian Sivertsen, MD, University Hospital, Gentofte, Copenhagen
ClinicalTrials.gov Identifier:	NCT00923962 History of Changes
Other Study ID Numbers:	GLP-1 Coronary circulation 01
Study First Received:	June 17, 2009
Last Updated:	September 17, 2012
Health Authority:	Denmark: The Regional Committee on Biomedical Research Ethics Denmark: National Board of Health

Keywords provided by University Hospital, Gentofte, Copenhagen:


Basic science Type 2 Diabetes mellitus Glucagon like peptid-1 Coronary Bloodflow Metabolite uptake

Additional relevant MeSH terms:


Diabetes Mellitus Diabetes Mellitus, Type 2 Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Glucagon Glucagon-Like Peptide 1 Adenosine Gastrointestinal Agents Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs	Incretins Analgesics Sensory System Agents Peripheral Nervous System Agents Anti-Arrhythmia Agents Vasodilator Agents Purinergic P1 Receptor Agonists Purinergic Agonists Purinergic Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 28, 2016