title: Pre-treatment with a DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic rats.
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.
authors.affiliation: MRC Cape Heart Centre, Cape Town, Republic of South Africa. bh3@sun.ac.za
authors.forename: Barbara
authors.initials: B
authors.lastname: Huisamen
authors.forename: Amanda
authors.initials: A
authors.lastname: Genis
authors.forename: Erna
authors.initials: E
authors.lastname: Marais
authors.forename: Amanda
authors.initials: A
authors.lastname: Lochner
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002316:Cardiotonic Agents / Q000494:pharmacology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D010770:Phosphotransferases / Q000378:metabolism; D011236:Prediabetic State / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D002316:Cardiotonic Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D010770:Phosphotransferases