Title Metabolic utilization of free fatty acids and carbohydrates in diabetic hearts Title (croatian) Metaboličko korištenje slobodnih masnih kiselina i ugljikohidrata u dijabetičkom srcu Author Michael Lem Mentor Marko Ljubković (mentor)Committee member Zoran Valić (predsjednik povjerenstva)Committee member Joško Božić (član povjerenstva)Committee member Anita Markotić (član povjerenstva)Granter University of Split Defense date and country 2019-07-18, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Abstract Objectives: The main goal of the present study was to investigate directly the ability of heart mitochondria to oxidize fatty acids and carbohydrates in patients suffering from DM2. Since DM2 is a metabolic disease which disturbs normal metabolic processes in the entire body, we wanted to explore the potential impact on utilization of the main substrates in metabolically very active organ, such as heart. Although some studies had been performed in animal models of diabetes, investigation conducted on the tissue derived from human DM2 patients enables a direct insight into clinically relevant aspects of the disease.
Patients and Methods: Thirty-seven patients who had been previously diagnosed with Coronary Artery Disease (CAD), were hemodynamically stable and were scheduled for elective Coronary Artery Bypass Grafting (CABG) surgery. Emergency patients, patients with LV ejection fraction (LVEF) below 50%, patients with type 1 diabetes mellitus, concomitant valve replacement, and severe renal, hepatic or pulmonary disease were excluded from our investigation. The included patients were subdivided into two categories. One group of nondiabetic patients (labelled as nonDM group) and the second the diabetic group (labelled DM). The diabetic group were patients defined on the clinical diagnosis of Type 2 Diabetes (DM2), chronic use of diabetic medication, having a fasting plasma glucose (> 7 mml/L) or a glycosylated hemoglobin (HbA1c >6.5%). Pre, intra- and post-surgical procedures were performed according to the standard clinical routines of the Department of Cardiac Surgery. This experiment and all subsequent processes follow the Declaration of Helsinki and was approved by the Ethical Committees of the University Hospital of Split (2181-147-01). All patients were explained the planned procedures and study objectives in detail prior to giving the signed informed consent for their enrollment.
Results: Examination of mitochondrial oxidation of the main energy substrates revealed significant alterations in the ability to process fatty acid in DM heart. Upon addition of palmitoyl-carnitine, respiration in the presence of ADP was significantly lower in LV myocardium from DM patients as compared to nonDM. Cardiac mitochondrial ability to oxidize carbohydrates (pyruvate) was not affected in diabetic patients.
Conclusion: The study shows that LV myocardium of DM2 patients undergoing CABG surgery has significantly altered mitochondrial function, with decreased capacity to oxidize long chain fatty acids and unaffected capacity to oxidize carbohydrates. This, combined with increased load of fatty acids and decreased cardiomyocytes’ uptake of glucose (demonstrated in a number of previous studies), may result in excessive accumulation of fat in cardiac cells. The fact that these changes are found without significant disruption of cardiac contractile function points toward importance of aggressive management of insulin resistance in order to prevent cardiac complications of the disease, as well as potential intracellular targets for prevention of diabetic cardiomyopathy. Lastly, since this study was performed on LV myocardial tissue of living patients, clinical relevance and applicability of the current data to the real-life setting is immediate.
Abstract (croatian) Ciljevi: Glavni cilj ove studije je bio ispitati sposobnost srčanih mitohondrija za oksidaciju masnih kiselina i ugljikohidrata kod pacijenata koji boluju od šećerne bolesti tipa 2. Obzirom da u toj bolest ujedno dolazi do poremećaja metabolizma u čitavom tijelu, namjera nam je bila ispitati njen mogući utjecaj na korištenje energetskih metaboličkih supstrata u metabolički vrlo aktivnom organu, poput srca. Iako su ranije napravljene neke slične studije na životinjskim modelima dijabetesa, ispitivanje sprovedeno na tkivu ljudskih pacijenata koji boluju od dijabetesa tipa 2 omogućuje izravni uvid u klinički relevantni aspekt bolesti.
Pacijenti i metode: Trideset i sedam pacijenata kojima je ranije dijagnosticirana ishemijska bolest srca (CAD), hemodinamski stabilni i na rasporedu za elektivni zahvat postavljanja aorto-srčane premosnice je bilo uključeno u studiju. Hitni pacijenti, oni s ejekcijskom frakcijom lijevog ventrikula ispod 50 %, s dijabetesom tip 1, pratećom zamjenom zaliska i teško oštećenom bubrežnom, jetrenom ili plućnom funkcijom su bili isključeni iz istraživanja. Uključeni pacijenti su podijeljeni u dvije skupine; pacijenti s dijabetesom tipa 2 (DM) i oni bez dijabetesa (nonDM). Dijabetičku su skupinu činili pacijenti s kliničkom dijagnozom dijabetesa tipa 2, kroničnom upotrebom antidijabetika, s koncentracijom glukoze natašte višom od 7 mml/l ili glikoziliranim hemoglobinom višim od 6.6 %. Svi postupci prije, za vrijeme i nakon operativnog zahvata su bili provedeni u skladu sa standardnim postupnikom Zavoda za kardijalnu kirurgiju. Svi eksperimentalni postupci su bili u sklada s Helsinškom deklaracijom i odobreni od strane Etičkog povjerenstva KBC-a Split (2181-147-01). Svim pacijentima je detaljno objašnjena planirana procedura i ciljevi studije prije nego im je dano na izbor potpisivanje obrasca informiranog pristanka.
Rezultati: Ispitivanje mitohondrijske oksidacije glavnih energetskih supstrata je otkrilo značajno smanjenu sposobnost srčanog mišića pacijenata s dijabetesom tipa 2 za procesuiranjem masnih kiselina. Nakon dodatka palmitoil-karnitina u sustav, mitohondrijska respiracija u prisutnosti ADP-a je bila značajno niža u miokardu lijevog ventrikula pacijenata s dijabetesom nego onih bez. Istovremeno, sposobnost srčanih mitohondrija za oksidaciju ugljikohidrata (piruvata) nije bila smanjena.
Zaključak: Istraživanje je pokazalo da miokard lijevog ventrikula kod pacijenata s dijabetesom tipa 2 koji su podvrgnuti operaciji postavljanja aortokoronarne premosnice ima značajno promijenjenu mitohondrijsku funkciju, koja se očituje u smanjenoj sposobnosti za oksidaciju dugolančanih masnih kiselina, uz nepromijenjenu sposobnost za oksidaciju ugljikohidrata. Ovakav poremećaj, ako je praćen povećanim utokom masnih kiselina u stanice miokarda i smanjenim utokom glukoze (kao što je ranije pokazano), može dovesti do prekomjernog nakupljanja masnoće u srčanim stanicama. Činjenica da su opisane promjene pronađene u srcu u kojem još nije došlo do značajnijeg poremećaja funkcije ukazuje na važnost potrebe intenzivne terapije smanjene inzulinske osjetljivosti u svrhu prevencije srčanih komplikacija bolesti, kao i na potencijalne unutarstanične puteve za prevenciju dijabetičke kardiomiopatije. Na kraju, obzirom da je opisano istraživanje provedeno na tkivu lijevog ventrikula živućih pacijenata, klinička važnost i primjenjivost prikupljenih podataka u svakodnevnoj praksi je očita.
Keywords
Diabetes Mellitus Type 2
Diabetic Cardiomyopathies
Heart Failure
Coronary Artery Disease
Fatty Acids
Keywords (croatian)
Šećerna bolest tipa 2
Dijabetičke kardiomiopatije
Zatajenje srca
Bolest koronarnih arterija
Masne kiseline
Language english URN:NBN urn:nbn:hr:171:582584 Study programme Title: Medical Studies in English Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2019-10-17 12:37:27
