Abstract
Lipotoxicity of the heart has been implicated as a leading cause of morbidity in Type 2 Diabetes Mellitus (T2DM). While numerous reports have demonstrated increased myocardial fatty acid (FA) utilization in obese T2DM animal models, this diabetic phenotype has yet to be demonstrated in non-obese animal models of T2DM. Therefore, the present study investigates functional, metabolic, and genomic differences in myocardial FA metabolism in non-obese type 2 diabetic rats. The study utilized Goto-Kakizaki (GK) rats at the age of 24 weeks. Each rat was imaged with small animal positron emission tomography (PET) to estimate myocardial blood flow (MBF) and myocardial FA metabolism. Echocardiograms (ECHOs) were performed to assess cardiac function. Levels of triglycerides (TG) and non-esterified fatty acids (NEFA) were measured in both plasma and cardiac tissues. Finally, expression profiles for 168 genes that have been implicated in diabetes and FA metabolism were measured using quantitative PCR (qPCR) arrays. GK rats exhibited increased NEFA and TG in both plasma and cardiac tissue. Quantitative PET imaging suggests that GK rats have increased FA metabolism. ECHO data indicates that GK rats have a significant increase in left ventricle mass index (LVMI) and decrease in peak early diastolic mitral annular velocity (E’) compared to Wistar rats, suggesting structural remodeling and impaired diastolic function. Of the 84 genes in each the diabetes and FA metabolism arrays, 17 genes in the diabetes array and 41 genes in the FA metabolism array were significantly up-regulated in GK rats. Our data suggest that GK rats’ exhibit increased genomic disposition to FA and TG metabolism independent of obesity.
Highlights
Type 2 Diabetes Mellitus (T2DM) is a complex, heterogeneous, polygenic disease that affects more than 150 million people worldwide [1]
The analysis indicated that 41 of the 84 genes involved in fatty acids (FA) metabolism were significantly altered in GK rats in comparison to Wistar rats (Figure 4)
Our data support the notion that GK rats exhibit functional, metabolic and genomic differences in FA utilization independent of obesity
Summary
Type 2 Diabetes Mellitus (T2DM) is a complex, heterogeneous, polygenic disease that affects more than 150 million people worldwide [1]. Recent epidemiological and experimental evidence suggests that there is a close link between the pathogenesis of obesity and T2DM [2], confounding the bleak outlook for T2DM. Cardiovascular disease is the leading cause of death among diabetic patients [3,4], attributed to impairment in heart muscle contraction, abnormalities in diastolic function [5]. Several theories have been put forth, evidence has emerged that severe alterations in myocardial energy metabolism may explain deficiencies in cardiac function among diabetic patients [6]. Insulin resistance in the onset of T2DM shifts the balance of substrate utilization such that the diabetic heart relies almost exclusively on fatty acids (FA) for its energy needs [7]. Notwithstanding the link between obesity and T2DM, it is often neglected that a significant fraction of the population with T2DM, by some accounts 20%, is nonobese [9]
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