Skip to main content
Erschienen in:

01.02.2011

Pre-treatment with a DPP-4 Inhibitor is Infarct Sparing in Hearts from Obese, Pre-diabetic Rats

verfasst von: Barbara Huisamen, Amanda Genis, Erna Marais, Amanda Lochner

Erschienen in: Cardiovascular Drugs and Therapy | Ausgabe 1/2011

Einloggen, um Zugang zu erhalten

Abstract

Cardiovascular risk is closely associated with insulin resistance and type 2 diabetes. Therapy based on the actions of GLP-1 is currently seen as a novel approach to treat this disease. The aims of this study was therefore to use an animal model to determine whether (i) pre-treatment of obese, insulin resistant but pre-diabetic rats with a DPP4 inhibitor, PFK275-055, could protect the heart from ischaemia/reperfusion injury and (ii) the possible mechanisms involved in such protection. Obese, pre-diabetic rats (DIO) were treated for 4 weeks with 10 mg/kg/day of the DPP4 inhibitor PFK275-055. Ex vivo perfusion was used to subject hearts to ischaemia/reperfusion to determine infarct size, functional recovery and post-ischaemic activation of proteins associated with cardiac protection. Adult ventricular cardiomyocytes were isolated to determine insulin sensitivity. Other assessments included body weight, intra-peritoneal fat weight, insulin and GLP-1 levels as well as histological evaluation of the pancreata. Results showed that DIO animals had higher body mass and intra-peritoneal fat mass than chow-fed animals. They presented with elevated plasma insulin levels and lower GLP-1 levels. Treatment with the DPP4 inhibitor resulted in smaller infarct size development in hearts from DIO rats after ischaemia/reperfusion accompanied by activation of cardioprotective kinases. GLP-1 levels were elevated and plasma insulin levels lower after treatment. In addition, the beta-cell to alpha-cell ratio of the pancreas was improved. We conclude that treatment with PFK275-055 for 4 weeks protected the heart against ischaemia/reperfusion injury, elevated GLP-1 levels and improved metabolic control in obese, pre-diabetic rats.
Literatur
1.
Zurück zum Zitat Alexander CM, Landsman PB, Teusch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes and prevalence of coronary hart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210–3.PubMedCrossRef Alexander CM, Landsman PB, Teusch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes and prevalence of coronary hart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210–3.PubMedCrossRef
2.
Zurück zum Zitat Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen D, Pyorala K, et al. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med. 2004;164:1066–76.PubMedCrossRef Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen D, Pyorala K, et al. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med. 2004;164:1066–76.PubMedCrossRef
3.
Zurück zum Zitat Rader DJ. Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am J Med. 2007;120:S12–8.PubMedCrossRef Rader DJ. Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am J Med. 2007;120:S12–8.PubMedCrossRef
4.
Zurück zum Zitat Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46–52.PubMedCrossRef Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46–52.PubMedCrossRef
5.
Zurück zum Zitat Pratley RE. Overview of glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors for type 2 diabetes. Medscape J Med. 2008;10:171.PubMed Pratley RE. Overview of glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors for type 2 diabetes. Medscape J Med. 2008;10:171.PubMed
6.
Zurück zum Zitat Tahrani AA, Piya MK, Kennedy A, Barnett AH. Glycaemic control in type 2 diabetes: targets and new therapies. Pharmacol Ther. 2009. Tahrani AA, Piya MK, Kennedy A, Barnett AH. Glycaemic control in type 2 diabetes: targets and new therapies. Pharmacol Ther. 2009.
7.
Zurück zum Zitat Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-s in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962–5.PubMedCrossRef Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-s in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962–5.PubMedCrossRef
8.
Zurück zum Zitat Mannucci E, Rotella CM. Future perspectives on glucagon-like peptide-1, diabetes and cardiovascular risk. Nutr Metab Cardiovasc Dis. 2008;18:639–45.PubMedCrossRef Mannucci E, Rotella CM. Future perspectives on glucagon-like peptide-1, diabetes and cardiovascular risk. Nutr Metab Cardiovasc Dis. 2008;18:639–45.PubMedCrossRef
9.
Zurück zum Zitat Zhao T, Parikh P, Bhashyam S, Bolukoglu H, Poornima I, Shen Y-T, et al. The direct effects of Glucagon-like peptide-1 (GLP-1) on myocardial contractility and glucose uptake in normal and post-ischemic isolated rat hearts. J Pharmacol Exp Ther. 2006;317:1106–13.PubMedCrossRef Zhao T, Parikh P, Bhashyam S, Bolukoglu H, Poornima I, Shen Y-T, et al. The direct effects of Glucagon-like peptide-1 (GLP-1) on myocardial contractility and glucose uptake in normal and post-ischemic isolated rat hearts. J Pharmacol Exp Ther. 2006;317:1106–13.PubMedCrossRef
10.
Zurück zum Zitat Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2005;54:146–50.PubMedCrossRef Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2005;54:146–50.PubMedCrossRef
11.
Zurück zum Zitat Huisamen B, Genade S, Webster I, Lochner A. Signalling pathways activated by glucagon-like peptide-1 (7-36) amide in the heart and their role in protection against ischemia. Cardiovasc J Afr. 2008;19:77–83.PubMed Huisamen B, Genade S, Webster I, Lochner A. Signalling pathways activated by glucagon-like peptide-1 (7-36) amide in the heart and their role in protection against ischemia. Cardiovasc J Afr. 2008;19:77–83.PubMed
12.
Zurück zum Zitat Montrose-Rafizadeh C, Egan JM, Roth J. Incretin hormones regulate glucose-dependent insulin secretion in RIN 1046-38 cells: mechanism of action. Enocrinology. 1994;135:589–94.CrossRef Montrose-Rafizadeh C, Egan JM, Roth J. Incretin hormones regulate glucose-dependent insulin secretion in RIN 1046-38 cells: mechanism of action. Enocrinology. 1994;135:589–94.CrossRef
13.
Zurück zum Zitat Egan JM, Montrose-Rafizadeh C, Wang Y, Bernier M, Roth J. Glucagon-like peptide-1 (7-36) amide (GLP-1) enhances insulin-stimulated glucose metabolism in 3T3-L1 adipocytes: one of several potential extrapancreatic sites of GLP-1 action. Endocrinology. 1994;135:2070–5.PubMedCrossRef Egan JM, Montrose-Rafizadeh C, Wang Y, Bernier M, Roth J. Glucagon-like peptide-1 (7-36) amide (GLP-1) enhances insulin-stimulated glucose metabolism in 3T3-L1 adipocytes: one of several potential extrapancreatic sites of GLP-1 action. Endocrinology. 1994;135:2070–5.PubMedCrossRef
14.
Zurück zum Zitat Valverde I, Morales M, Clementi F, Lopez-Delgado MI, Delgado E, Perea A, et al. Glucagon-like peptide-I: a potent glycogenic hormone. FEBS Lett. 1994;349:313–6.PubMedCrossRef Valverde I, Morales M, Clementi F, Lopez-Delgado MI, Delgado E, Perea A, et al. Glucagon-like peptide-I: a potent glycogenic hormone. FEBS Lett. 1994;349:313–6.PubMedCrossRef
15.
Zurück zum Zitat Deacon CF. What do we know about the secretion and degradation of incretin hormones? Regul Pept. 2005;128:117–24.PubMedCrossRef Deacon CF. What do we know about the secretion and degradation of incretin hormones? Regul Pept. 2005;128:117–24.PubMedCrossRef
16.
Zurück zum Zitat Barnett A. DPP4 inhibitors and their potential role in the manegement of type 2 diabetes. Int J Clin Pract. 2006;60:1454–70.PubMedCrossRef Barnett A. DPP4 inhibitors and their potential role in the manegement of type 2 diabetes. Int J Clin Pract. 2006;60:1454–70.PubMedCrossRef
17.
Zurück zum Zitat Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–705.PubMedCrossRef Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–705.PubMedCrossRef
18.
Zurück zum Zitat Ahrén B, Foley JE. The islet inhancer cildagliptin: mechanisms of improved glucose metabolism. Int J Clin Pract Suppl. 2008;159:8–14.PubMedCrossRef Ahrén B, Foley JE. The islet inhancer cildagliptin: mechanisms of improved glucose metabolism. Int J Clin Pract Suppl. 2008;159:8–14.PubMedCrossRef
19.
Zurück zum Zitat Vilsbøll T. The effects of glucagon-like peptide-1 on the beta cell. Diab Obes Metab. 2009;11:11–8.CrossRef Vilsbøll T. The effects of glucagon-like peptide-1 on the beta cell. Diab Obes Metab. 2009;11:11–8.CrossRef
20.
Zurück zum Zitat Mafong DD, Henry RR. The role of incretins in cardiovascular control. Curr Hypertens Rep. 2009;11:18–22.PubMedCrossRef Mafong DD, Henry RR. The role of incretins in cardiovascular control. Curr Hypertens Rep. 2009;11:18–22.PubMedCrossRef
21.
Zurück zum Zitat Pickavance LC, Tadayyon M, Widdowson PS, Buckinham RE, Wilding JPH. Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution. Br J Pharmacol. 1999;128:1570–6.PubMedCrossRef Pickavance LC, Tadayyon M, Widdowson PS, Buckinham RE, Wilding JPH. Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution. Br J Pharmacol. 1999;128:1570–6.PubMedCrossRef
22.
Zurück zum Zitat Du Toit EF, Nabben M, Lochner A. A potential role for angiotensin II in obesity induced cardiac hypertrophy and ischaemic/reperfusion injury. Basic Res Cardiol. 2005;100:346–54.PubMedCrossRef Du Toit EF, Nabben M, Lochner A. A potential role for angiotensin II in obesity induced cardiac hypertrophy and ischaemic/reperfusion injury. Basic Res Cardiol. 2005;100:346–54.PubMedCrossRef
23.
Zurück zum Zitat Villhauer EB, Brinkman JA, Naderi GA, et al. 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem. 2005;46:2774–89.CrossRef Villhauer EB, Brinkman JA, Naderi GA, et al. 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem. 2005;46:2774–89.CrossRef
24.
Zurück zum Zitat Lochner A, Genade S, Moolman JA. Ischemic preconditioning: infarct size is a more reliable endpoint than functional recovery. Basic Res Cardiol. 2003;98:337–46.PubMedCrossRef Lochner A, Genade S, Moolman JA. Ischemic preconditioning: infarct size is a more reliable endpoint than functional recovery. Basic Res Cardiol. 2003;98:337–46.PubMedCrossRef
25.
Zurück zum Zitat Marais E, Genade S, Salie R, Huisamen B, Maritz S, Moolman JA, et al. The temporal relationship between p38 MAPK and HSP27 activation in ischaemic and pharmacological preconditioning. Basic Res Cardiol. 2005;100:35–47.PubMedCrossRef Marais E, Genade S, Salie R, Huisamen B, Maritz S, Moolman JA, et al. The temporal relationship between p38 MAPK and HSP27 activation in ischaemic and pharmacological preconditioning. Basic Res Cardiol. 2005;100:35–47.PubMedCrossRef
26.
Zurück zum Zitat Donthi R, Huisamen B, Lochner A. The effect of vanadate and insulin on glucose transport in isolated adult rat cardiomyocytes. Cardiovasc Drugs Ther. 2000;14:463–70.PubMedCrossRef Donthi R, Huisamen B, Lochner A. The effect of vanadate and insulin on glucose transport in isolated adult rat cardiomyocytes. Cardiovasc Drugs Ther. 2000;14:463–70.PubMedCrossRef
27.
Zurück zum Zitat Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265–75.PubMed Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265–75.PubMed
28.
Zurück zum Zitat Holst JJ, Deacon CF. Glucagon-like peptide-1 mediates the therapeutic actions of DPPIV inhibitors. Diabetologia. 2005;48:612–5.PubMedCrossRef Holst JJ, Deacon CF. Glucagon-like peptide-1 mediates the therapeutic actions of DPPIV inhibitors. Diabetologia. 2005;48:612–5.PubMedCrossRef
29.
Zurück zum Zitat Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res. 2004;15:448–60.CrossRef Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res. 2004;15:448–60.CrossRef
30.
Zurück zum Zitat Ban K, Noyan-Ashraf H, Hoefer J, Bolz S-B, 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;117:2340–50.PubMedCrossRef Ban K, Noyan-Ashraf H, Hoefer J, Bolz S-B, 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;117:2340–50.PubMedCrossRef
31.
Zurück zum Zitat Naderali EK, Pickavance LC, Wilding JPH, Williams G. Diet-induced endothelial dysfunction in the rat is independent of the degree of increase in total body weight. Clin Sci. 2001;100:635–41.PubMedCrossRef Naderali EK, Pickavance LC, Wilding JPH, Williams G. Diet-induced endothelial dysfunction in the rat is independent of the degree of increase in total body weight. Clin Sci. 2001;100:635–41.PubMedCrossRef
32.
Zurück zum Zitat Ahrén B. Inhibition of depeptidyl peptidase-4 (DPP-4)—a novel approach to treat type 2 diabetes. Curr Enzyme Inhib. 2005;1:65–73.CrossRef Ahrén B. Inhibition of depeptidyl peptidase-4 (DPP-4)—a novel approach to treat type 2 diabetes. Curr Enzyme Inhib. 2005;1:65–73.CrossRef
33.
Zurück zum Zitat Augstein P, Berg S, Heinke P, et al. Diab Obes Metab. 2008;10:850–61.CrossRef Augstein P, Berg S, Heinke P, et al. Diab Obes Metab. 2008;10:850–61.CrossRef
34.
Zurück zum Zitat Pospisilik JA, Martin J, Dory T, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes. 2003;52:741–50.PubMedCrossRef Pospisilik JA, Martin J, Dory T, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes. 2003;52:741–50.PubMedCrossRef
Metadaten
Titel
Pre-treatment with a DPP-4 Inhibitor is Infarct Sparing in Hearts from Obese, Pre-diabetic Rats
verfasst von
Barbara Huisamen
Amanda Genis
Erna Marais
Amanda Lochner
Publikationsdatum
01.02.2011
Verlag
Springer US
Erschienen in
Cardiovascular Drugs and Therapy / Ausgabe 1/2011
Print ISSN: 0920-3206
Elektronische ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-010-6271-7

Weitere Artikel der Ausgabe 1/2011

Cardiovascular Drugs and Therapy 1/2011 Zur Ausgabe

Neu im Fachgebiet Kardiologie

Herzrhythmusstörungen – neue Verfahren für langfristige Erfolge

16.07.2024 Vorhofflimmern Podcast

Prof. Markus Lerch wirft gemeinsam mit dem Herzspezialisten Prof. Gerd Hasenfuß aus Göttingen einen Blick auf neue Entwicklungen in der Diagnostik und Therapie von Herzrhythmusstörungen. Hören Sie in dieser Folge, warum fast jedes Vorhofflimmern therapiert werden sollte, wieso die Ablationsbehandlung auch bei Herzinsuffizienz gute Effekte zeigt und vor und nach welchen Medikamenten Sie ein EKG schreiben sollten.

Deutsche Gesellschaft für Innere Medizin

Kongestive Herzinsuffizienz: Wie die Diurese am besten gelingt

15.07.2024 Herzinsuffizienz Nachrichten

Ein effektives Flüssigkeitsmanagement ist bei schwerer kongestiver Herzinsuffizienz essenziell. Ein gutes Therapieregime im ambulanten Setting scheint die Kombination aus Furosemid und Metolazon zu sein; im Vergleich gelang damit die stärkste Natriurese.

Vorhofflimmern: Auftreten schon in jüngeren Jahren ist kein gutes Zeichen

15.07.2024 Vorhofflimmern Nachrichten

Tritt Vorhofflimmern schon in jüngeren Jahren auf, geht dies mit einem höheren Risiko für kardiovaskuläre Erkrankungen und einer verkürzten Lebenserwartung einher, zeigt eine landesweite Studie aus Dänemark.

Bempedoinsäure bei gleicher LDL-Senkung klinisch so wirksam wie Statine

15.07.2024 Lipidstoffwechselstörungen Nachrichten

Der Lipidsenker Bempedoinsäure reduziert das Risiko für kardiovaskuläre Ereignisse pro Senkung des LDL-Cholesterins um 1 mmol/l ebenso wirksam wie Statine, so das Ergebnis eines indirekten Vergleichs beider Therapien.

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.