P507DPP-4 inhibition is cardioprotective and restores pancreatic function in obese, insulin resistant rats

Therapy based on GLP-1 is currently one of the most promising treatments for type 2 diabetes, also because GLP-1 is cardioprotective in animals and humans. Because GLP-1 is rapidly degraded by dipeptidylpeptidase IV (DPP-4), research focused on DPP-4 inhibitors to raise levels of GLP-1 which are attenuated in type 2 diabetes. We aimed to determine the effect of treatment of obese, pre-diabetic rats presenting with cardiovascular pathology, with a DPP-4 inhibitor (PFK275-055) on (i) cardioprotection, (ii) glucose homeostasis and (iii) pancreatic function. Methods: Obesity was induced in Wistar rats (DIO) by supplementing the diet with sucrose and condensed milk for 12 weeks where after half of control-fed & DIO rats were treated orally with 10mg/kg/day PFK275-055. After 4 weeks animals were sacrificed, trunk blood collected for biochemical analyses, body weight and intra peritoneal (IP) fat weight recorded, pancreata harvested and isolated hearts perfused. Langendorff perfused hearts were subjected to regional ischaemia/reperfusion to determine infarct development. The kinase profile during reperfusion was established in snap-frozen tissue using standard Western blotting techniques. Ventricular myocytes were prepared (standard collagenase perfusion) to determine insulin sensitivity via [3H]-2-deoxyglucose accumulation. Results: GLP-1 levels: attenuated in DIO and restored after DPP-4 treatment. Insulin levels: 49% higher in DIO and lowered by treatment. DIO suppressed pancreatic beta vs alpha cell ratio and the DPP-4 inhibitor partially corrected this. No effects on weight, IP fat or blood glucose levels were observed. Infarct size: DIO animals: 47.7±4.6% infarct of area at risk vs control = 30.0±3.7% and DIO treated = 29.8±3.1%; P<0.05, n=6. The ratio of phospho/total PKB/Akt and ERK42 was attenuated in DIO and improved after treatment. DIO resulted in a blunted glucose uptake response induced by insulin stimulation but this was not improved after treatment with PFK275-055. We conclude that treatment of prediabetic animals with a DPP-4 inhibitor elevated GLP-1 levels, improved glucose homeostasis, restored pancreatic function, and was cardioprotective.