Endothelial and Metabolic Effects of Glucagon-like Peptide-1 (GLP-1) in Coronary Circulation in Patients With Type 2 Diabetes Mellitus
Endothelial and Metabolic Effects of GLP-1 in Coronary Circulation in Patients With Type 2 Diabetes Mellitus
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 Unpublished studies do however indicate that the improvement in the cardiovascular system is largely dependent upon a high blood glucose level and only partially dependent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.
調査の概要
研究の種類
入学 (実際)
段階
- 適用できない
連絡先と場所
研究場所
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Gentofte、デンマーク、2900
- University Hospital Gentofte, Department of Cardiology
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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
研究計画
研究はどのように設計されていますか?
デザインの詳細
- 割り当て:ランダム化
- 介入モデル:並列代入
- マスキング:4倍
武器と介入
参加者グループ / アーム |
介入・治療 |
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アクティブコンパレータ:健康
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0,1 pmol/kg/min
20-40 microgram/minute
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アクティブコンパレータ:Type 2 Diabetes patients
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0,1 pmol/kg/min
20-40 microgram/minute
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アクティブコンパレータ:Artherosclerosis
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0,1 pmol/kg/min
20-40 microgram/minute
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この研究は何を測定していますか?
主要な結果の測定
結果測定 |
時間枠 |
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Coronary blood flow
時間枠:10 minutes after I.A. GLP-1
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10 minutes after I.A. GLP-1
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Coronary metabolite uptake
時間枠:10 minutes after I.A. GLP-1
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10 minutes after I.A. GLP-1
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協力者と研究者
捜査官
- スタディチェア:Jan S Jensen, MD, DMSc、University Hospital Gentofte, Department of Cardiology
- 主任研究者:Jaya Rosenmeier, MD, Ph.D.、University Hospital Gentofte, Department of Cardiology
出版物と役立つリンク
一般刊行物
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- GLP-1 Coronary circulation 01
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