Abstract
Understanding and assessing diabetic metabolism is vital for monitoring disease progression and improving treatment of patients. In vivo assessments, using MRI and MRS, provide non‐invasive and accurate measurements, and the development of hyperpolarized 13C spectroscopy in particular has been demonstrated to provide valuable metabolic data in real time. Until now, studies have focussed on individual organs. However, diabetes is a systemic disease affecting multiple tissues in the body. Therefore, we have developed a technique to simultaneously measure metabolism in both the heart and liver during a single acquisition.A hyperpolarized 13C MRS protocol was developed to allow acquisition of metabolic data from the heart and liver during a single scan. This protocol was subsequently used to assess metabolism in the heart and liver of seven control male Wistar rats and seven diabetic rats (diabetes was induced by three weeks of high‐fat feeding and a 30 mg/kg injection of streptozotocin).Using our new acquisition, we observed decreased cardiac and hepatic pyruvate dehydrogenase flux in our diabetic rat model. These diabetic rats also had increased blood glucose levels, decreased insulin, and increased hepatic triglycerides. Decreased production of hepatic [1‐13C]alanine was observed in the diabetic group, but this change was not present in the hearts of the same diabetic animals.We have demonstrated the ability to measure cardiac and hepatic metabolism simultaneously, with sufficient sensitivity to detect metabolic alterations in both organs. Further, we have non‐invasively observed the different reactions of the heart and liver to the metabolic challenge of diabetes.
Highlights
Type II diabetes is currently a worldwide concern, with an increasing patient population.[1]
The diabetic heart has an increased ratio of fatty acid to glucose metabolism, and the diabetic liver is gluconeogenic. Pyruvate handling in both the heart and liver is altered in diabetes, driven by an insensitivity to insulin, elevated circulating fatty acid levels and an increase in the presence of the products of fatty acid metabolism
Expression of increased levels of cardiac pyruvate dehydrogenase kinase 4 (PDK4), decreased cardiac glucose transporter 4 (GLUT4), and increased hepatic triglycerides was observed, as seen in 2013 in diabetic animals induced by a high‐fat diet and 30 mg/kg STZ by Mansor et al.[16]. These measures are indicative of decreased glucose metabolism typical of the diabetic phenotype, probably due to increased fatty acid metabolism. Using this model of diabetes, we successfully demonstrated that decreased cardiac pyruvate dehydrogenase (PDH) flux can be visualized with hyperpolarized pyruvate in our diabetic rat model, and this is mediated by increased PDK4,19 as expected and in agreement with ex vivo work using a 65 mg/kg STZ diabetic model by Seymour and Chatham,[20] and in vivo data from a 50 mg/kg STZ diabetic model in work by Schroeder et al.[3]
Summary
Type II diabetes is currently a worldwide concern, with an increasing patient population.[1]. A combination of in vitro, ex vivo, and in vivo techniques has enabled us to understand that two major organs that undergo these changes are the heart and liver. The diabetic heart has an increased ratio of fatty acid to glucose metabolism, and the diabetic liver is gluconeogenic. Pyruvate handling in both the heart and liver is altered in diabetes, driven by an insensitivity to insulin, elevated circulating fatty acid levels and an increase in the presence of the products of fatty acid metabolism. To obtain an accurate, dynamic, systemic metabolic picture, a technique is required to non‐invasively assess the changes occurring in multiple organs
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