BACKGROUND AND AIMS: Recent studies suggest that empagliflozin reduces total and cardiovascular mortality in both diabetic and nondiabetic subjects. Although the exact mechanism is unclear, it is understood to positively affect myocardial energetics, including the metabolism of ketone bodies, lipids, and fatty acids. In this study, we compared empagliflozin effects on lipid metabolism in the heart and liver in a prediabetic rat model with severe dyslipidemia. MATERIALS AND METHODS: Wistar rats served as the control group, while hereditary hypertriglyceridemic (HHTg) rats were used as a nonobese, prediabetic model. Rats were treated with or without empagliflozin at a dose of 10 mg/kg body weight (BW) for 8 weeks. RESULTS: In HHTg rats, empagliflozin decreased body weight and adiposity, improved glucose tolerance, and decreased serum triacylglycerols (TAGs) (p < 0.001). Empagliflozin decreased the activity and gene expression of the lipogenic enzyme SCD-1 (p < 0.001) in the myocardium, which may have led to a decrease in the ectopic accumulation of TAGs and lipotoxic diacylglycerols and lysophosphatidylcholines (p < 0.001). Changes in the myocardial phosphatidylcholine/phosphatidylethanolamine ratio (p < 0.01) and in the fatty acid profile of myocardial phospholipids may have contributed to the antifibrotic effects of empagliflozin. The anti-inflammatory effects of empagliflozin were evidenced by an increased IL-10/TNFα ratio (p < 0.001), a marked decrease in arachidonic acid metabolites (20-HETE, p < 0.001), and an increase in PUFA metabolites (14,15-EETs, p < 0.001) in the myocardium. However, empagliflozin did not significantly affect either the concentration or utilization of ketone bodies. In the liver, empagliflozin decreased lipogenesis and the accumulation of TAGs and lipotoxic intermediates. Its effect on arachidonic acid metabolites and alterations in n-3 PUFA metabolism was less pronounced than in the myocardium. CONCLUSION: Our findings suggest that empagliflozin treatment in the heart and liver reduced the accumulation of neutral lipids and lipotoxic intermediates and altered the metabolism of n-3 PUFA. In the heart, empagliflozin altered arachidonic acid metabolism, which is likely associated with the anti-inflammatory and antifibrotic effects of the drug. We assume that these alterations in lipid metabolism contribute to the cardioprotective effects of empagliflozin in prediabetic states with severe dyslipidemia.

• Klíčová slova
• SGLT2 inhibitors, arachidonic acid, cardiovascular disease, empagliflozin, inflammation, ketone body, lipid metabolism,
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND AIM: The role of dietary protein and glycemic index on insulin resistance (based on TyG index) within a nutritional program for weight loss and weight maintenance was examined. METHODS: This study analyzed 744 adults with overweight/obesity within the DIOGenes project. Patients who lost at least 8% of their initial weight (0-8 weeks) after a low-calorie diet (LCD) were randomly assigned to one of five ad libitum diets designed for weight maintenance (8-34 weeks): high/low protein (HP/LP) and high/low glycemic index (HGI/LGI), plus a control. The complete nutritional program (0-34 weeks) included both LCD plus the randomized diets intervention. The TyG index was tested as marker of body mass composition and insulin resistance. RESULTS: In comparison with the LP/HGI diet, the HP/LGI diet induced a greater BMI loss (p < 0.05). ∆TyG was positively associated with resistance to BMI loss (β = 0.343, p = 0.042) during the weight maintenance stage. In patients who followed the HP/LGI diet, TyG (after LCD) correlated with greater BMI loss in the 8-34 weeks period (r = -0.256; p < 0.05) and during the 0-34 weeks intervention (r = -0.222, p < 0.05) periods. ΔTyG1 value was associated with ΔBMI2 (β = 0.932; p = 0.045) concerning the HP/LGI diet. CONCLUSIONS: A HP/LGI diet is beneficial not only for weight maintenance after a LCD, but is also related to IR amelioration as assessed by TyG index changes. Registration Clinical Trials NCT00390637.

• Klíčová slova
• Glycemic index, Insulin resistance, Metabolic improvement, Precision nutrition, Protein diet, TyG index,
• Publikační typ
• časopisecké články MeSH

Metformin can reduce cardiovascular risk independent of glycemic control. The mechanisms behind its non-glycemic benefits, which include decreased energy intake, lower blood pressure and improved lipid and fatty acid metabolism, are not fully understood. In our study, metformin treatment reduced myocardial accumulation of neutral lipids-triglycerides, cholesteryl esters and the lipotoxic intermediates-diacylglycerols and lysophosphatidylcholines in a prediabetic rat model (p < 0.001). We observed an association between decreased gene expression and SCD-1 activity (p < 0.05). In addition, metformin markedly improved phospholipid fatty acid composition in the myocardium, represented by decreased SFA profiles and increased n3-PUFA profiles. Known for its cardioprotective and anti-inflammatory properties, metformin also had positive effects on arachidonic acid metabolism and CYP-derived arachidonic acid metabolites. We also found an association between increased gene expression of the cardiac isoform CYP2c with increased 14,15-EET (p < 0.05) and markedly reduced 20-HETE (p < 0.001) in the myocardium. Based on these results, we conclude that metformin treatment reduces the lipogenic enzyme SCD-1 and the accumulation of the lipotoxic intermediates diacylglycerols and lysophosphatidylcholine. Increased CYP2c gene expression and beneficial effects on CYP-derived arachidonic acid metabolites in the myocardium can also be involved in cardioprotective effect of metformin.

• Klíčová slova
• arachidonic acid, cytochrome P450, fatty acid profile, lipotoxic intermediates, metformin, myocardial function, myocardial phospholipids, stearoyl-CoA desaturase,
• MeSH
• bazální metabolismus účinky léků   MeSH
• biologické markery krev   MeSH
• desaturasy mastných kyselin metabolismus   MeSH
• hyperlipoproteinemie typ IV farmakoterapie   metabolismus   MeSH
• hypoglykemika farmakologie   MeSH
• kardiotonika farmakologie   MeSH
• krysa rodu Rattus MeSH
• kyselina arachidonová metabolismus   MeSH
• mediátory zánětu krev   MeSH
• metabolismus lipidů účinky léků   MeSH
• metformin farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myokard metabolismus   MeSH
• potkani Wistar MeSH
• prediabetes farmakoterapie   metabolismus   MeSH
• rizikové faktory MeSH
• srdce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• desaturasy mastných kyselin MeSH
• hypoglykemika MeSH
• kardiotonika MeSH
• kyselina arachidonová MeSH
• mediátory zánětu MeSH
• metformin MeSH

Cardiometabolic disorders are among the leading causes of mortality in the human population. Dietary polyphenols exert beneficial effects on cardiometabolic health in humans. Molecular mechanisms, however, are not completely understood. Aiming to conduct in-depth integrative bioinformatic analyses to elucidate molecular mechanisms underlying the protective effects of polyphenols on cardiometabolic health, we first conducted a systematic literature search to identify human intervention studies with polyphenols that demonstrate improvement of cardiometabolic risk factors in parallel with significant nutrigenomic effects. Applying the predefined inclusion criteria, we identified 58 differentially expressed genes at mRNA level and 5 miRNAs, analyzed in peripheral blood cells with RT-PCR methods. Subsequent integrative bioinformatic analyses demonstrated that polyphenols modulate genes that are mainly involved in the processes such as inflammation, lipid metabolism, and endothelial function. We also identified 37 transcription factors that are involved in the regulation of polyphenol modulated genes, including RELA/NFKB1, STAT1, JUN, or SIRT1. Integrative bioinformatic analysis of mRNA and miRNA-target pathways demonstrated several common enriched pathways that include MAPK signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, focal adhesion, or PPAR signaling pathway. These bioinformatic analyses represent a valuable source of information for the identification of molecular mechanisms underlying the beneficial health effects of polyphenols and potential target genes for future nutrigenetic studies.

• Klíčová slova
• cardiometabolic health, human, integrative bioinformatics, nutrigenomics, polyphenols, systematic literature search,
• MeSH
• dospělí MeSH
• fyziologie výživy genetika   MeSH
• kardiometabolické riziko MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA krev   MeSH
• metabolický syndrom genetika   prevence a kontrola   MeSH
• mikro RNA krev   MeSH
• nutrigenomika MeSH
• ochranné látky farmakologie   MeSH
• polyfenoly farmakologie   MeSH
• signální transdukce genetika   MeSH
• výpočetní biologie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH
• Názvy látek
• messenger RNA MeSH
• mikro RNA MeSH
• ochranné látky MeSH
• polyfenoly MeSH