👤 Fabien De Meester

Obesity and Type 2 diabetes mellitus (DM) induce left ventricular (LV) diastolic dysfunction, which contributes to an increasing prevalence of heart failure with a preserved LV ejection fraction. We investigated the effects of sitagliptin (SITA), an inhibitor of dipeptidylpeptidase-4 (DPP-4) and anti-diabetic drug, on LV structure and function of obese mice with Type 2 DM. Obese Type 2 diabetic mice (Lepr(db/db), BKS.Cg-Dock7(m)+/+ Lepr(db)/J), displaying increased cardiomyocyte and LV stiffness at the age of 16 weeks, were treated with SITA (300 mg/kg/day) or vehicle for 8 weeks. SITA severely impaired serum DPP-4 activity, but had no effect on glycaemia. Invasive haemodynamic recordings showed that SITA reduced LV passive stiffness and increased LV stroke volume; LV end-systolic elastance remained unchanged. In addition, SITA reduced resting tension of isolated single cardiomyocytes and intensified phosphorylation of the sarcomeric protein titin. SITA also increased LV concentrations of cGMP and increased activity of protein kinase G (PKG). In vitro activation of PKG decreased resting tension of cardiomyocytes from vehicle-treated mice, but had no effect on resting tension of cardiomyocytes from SITA-treated mice. In obese Type 2 diabetic mice, in the absence of hypoglycaemic effects, inhibition of DPP-4 decreases LV passive stiffness and improves global LV performance. These effects seem at least partially mediated by stimulatory effects on the myocardial cGMP-PKG pathway and, hence, on the phosphorylation status of titin and the hereto coupled cardiomyocyte stiffness modulus. Show less

The impact of diet and environmental factors on genes concerned with epigenetic inheritance and the mechanism of evolution has grown significantly beyond the Modern Synthesis period. Epigenetic inheritance is the passing of phenotypic change to subsequent generations in ways that are outside the genetic code of DNA. Recently, polymorphisms of the human Delta-5 (fatty acid desaturase, FADS1) and Delta-6 (FADS2) desaturase genes have been described as being associated with the level of several long-chain n-3 and n-6 polyunsaturated fatty acids (PUFAs) in serum phospholipids. Increased consumption of refined starches and sugar increases the generation of superoxide anion in the tissues and free fatty acids (FFA) in the blood. There is an increased amount and activity of nuclear factor-κB (NF-κB), a transcriptional factor regulating the activity of at least 125 genes, most of which are pro-inflammatory. The consumption of glucose may be associated with an increase in 2 other pro-inflammatory transcription factors: activating protein-1 (AP-1), and early growth response protein-1 (Egr-1). AP-1 regulates the transcription of matrix metallo-proteinases and Egr-1 modulates the transcription of tissue factor and plasminogen activator inhibitor-1. It is possible that a complex set of factors, including nutritional factors, come into play during epigenetic inheritance. Show less