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

NCT00923962 | Completed

• 1 other identifier: GLP-1 Coronary circulation 01
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

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 Unpublished studies do however indicate that the improvement in the cardiovascular system is largely dependent upon a high blood glucose level and only partially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

Conditions

Type 2 Diabetes Mellitus

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Coronary blood flow

  10 minutes after I.A. GLP-1

• Coronary metabolite uptake

  10 minutes after I.A. GLP-1

Study Arms (3)

Type 2 Diabetes patients

ACTIVE COMPARATOR

Drug: Glucagon like peptide-1; Drug: Adenosine

Healthy

ACTIVE COMPARATOR

Drug: Glucagon like peptide-1; Drug: Adenosine

Artherosclerosis

ACTIVE COMPARATOR

Drug: Glucagon like peptide-1; Drug: Adenosine

Interventions

Glucagon like peptide-1 DRUG

0,1 pmol/kg/min

Artherosclerosis; Healthy; Type 2 Diabetes patients

Adenosine DRUG

20-40 microgram/minute

Artherosclerosis; Healthy; Type 2 Diabetes patients

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Gentofte, Copenhagen: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

University Hospital Gentofte, Department of Cardiology

Gentofte Municipality, 2900, Denmark

Location

Related Publications (16)

• Bjallmark 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. doi: 10.1016/j.echo.2006.11.024.

  PMID: 17617311 BACKGROUND

• 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. doi: 10.1016/s0735-1097(03)00625-9.

  PMID: 12875772 BACKGROUND

• 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. doi: 10.2337/diabetes.48.1.86.

  PMID: 9892226 BACKGROUND

• 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. doi: 10.1016/s0167-0115(01)00300-7.

  PMID: 11730979 BACKGROUND

• Luque MA, Gonzalez N, Marquez L, Acitores A, Redondo A, Morales M, Valverde I, Villanueva-Penacarrillo ML. Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes. J Endocrinol. 2002 Jun;173(3):465-73. doi: 10.1677/joe.0.1730465.

  PMID: 12065236 BACKGROUND

• 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.

  PMID: 19176536 BACKGROUND

• 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. doi: 10.2337/diacare.24.9.1614.

  PMID: 11522708 BACKGROUND

• 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. doi: 10.1161/01.CIR.0000120505.91348.58. Epub 2004 Feb 23.

  PMID: 14981009 BACKGROUND

• 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. doi: 10.1097/00004872-200306000-00012.

  PMID: 12777949 BACKGROUND

• Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, Sjoholm 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. doi: 10.1152/ajpendo.00237.2004. Epub 2004 Sep 7.

  PMID: 15353407 BACKGROUND

• 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. doi: 10.1210/endo.137.7.8770921.

  PMID: 8770921 BACKGROUND

• 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. doi: 10.1016/0014-5793(94)01430-9.

  PMID: 7843404 BACKGROUND

• Wei Y, Mojsov S. Distribution of GLP-1 and PACAP receptors in human tissues. Acta Physiol Scand. 1996 Jul;157(3):355-7. doi: 10.1046/j.1365-201X.1996.42256000.x. No abstract available.

  PMID: 8830893 BACKGROUND

• 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. doi: 10.1152/ajpheart.00347.2005. Epub 2005 Jul 15.

  PMID: 16024574 BACKGROUND

• 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.

  PMID: 18427132 BACKGROUND

• Nystrom T, Gonon AT, Sjoholm 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. doi: 10.1016/j.regpep.2004.08.024.

  PMID: 15582729 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Glucagon-Like Peptide 1; Adenosine

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Jan S Jensen, MD, DMSc

  University hospital Gentofte, Department of Cardiology

  STUDY CHAIR

• Jaya Rosenmeier, MD, Ph.D.

  University hospital Gentofte, Department of Cardiology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 18, 2009
• Study Start: June 1, 2009
• Primary Completion: January 1, 2012
• Study Completion: January 1, 2012
• Last Updated: September 18, 2012

Record last verified: 2012-09

Locations

DK (1)