Abstract P2067: Depleted Cardiac Energy Reservoirs And Type 2 Diabetes: The Unfulfilled Role Of Endogenous Creatine

Abstract

To maintain contractility, the heart turns over the cellular ATP pool six times per minute, with up to half replenished via the creatine:phosphocreatine system (Cr:PCr). This ‘safe’ energy reservoir arises from endogenous sources, through biosynthesis in the kidney and liver for delivery to the heart. Exogenous PCr drastically improves contractility following myocardial ischemia/reperfusion injury (I/R), as exemplified by cardioplegic PCr supplements provided during coronary artery bypass surgery. Considering clinical outcomes following I/R are typically worse in patients with Type 2 Diabetes (T2D), we hypothesized that T2D comorbidities that impact physiology of the kidney and liver may impair endogenous production of Cr and limit cardiac Cr:PCr. We employed a rat model that combined obesity and steatosis (high-fat diet), with pancreatic insufficiency (streptozotocin), to produce elevated blood glucose, serum triglycerides and reduced insulin sensitivity, consistent with a T2DM phenotype. Heart, liver, kidney and blood were sampled from T2D rats for histology and metabolomics by targeted mass spectrometry. Renal microanatomy showed little variation in response to T2D, while nuclear displacement and vacuolation was apparent in liver sections. We identified no change in renal Cr substrate guanidinoacetate (GAA) (0.7996±0.09; n -fold±SEM, p -value=0.524) or the serum GAA levels (0.95±0.13; n -fold±SEM, p -value=0.993). In the liver, GAA levels were depleted (0.468±0.04; p <0.0001), with a comparable reduction of hepatic creatine abundance (0.391±0.07; p =0.003). Cardiac levels of both Cr and PCr were significantly depleted in the heart (Cr: 0.392±0.02, p <0.0001; and PCr: 0.642±0.07, p =0.02). To confirm that this decrease in cardiac Cr:PCr did not simply reflect increased metabolism, we monitored cardiac creatinine and found only a modest decrease in T2D hearts (0.783±0.05; p =0.003), confirming a depletion in Cr bioavailability. In summary, hepatic derangement indicative of steatosis promoted impaired creatine biosynthesis to limit availability of Cr:PCr for restoration of ATP in the diabetic heart. In the absence of adequate ‘safe’ energy reservoirs, such hearts are compromised further following I/R injury.