Fatty Acids and Insulin Modulate Myocardial Substrate Metabolism in Humans With Type 1 Diabetes

Abstract

OBJECTIVE-Normal human myocardium switches substrate metabolism preference, adapting to the prevailing plasma substrate levels and hormonal milieu, but in type 1 diabetes, the myocardium relies heavily on fatty acid metabolism for energy. Whether conditions that affect myocardial glucose use and fatty acid utilization, oxidation, and storage in nondiabetic subjects alter them in type 1 diabetes is not well known.RESEARCH DESIGN AND METHODS-To test the hypotheses that in humans with type 1 diabetes, myocardial glucose and fatty acid metabolism can be manipulated by altering plasma free fatty acid (FFA) and insulin levels, we quantified myocardial oxygen consumption (MVO 2 ), glucose, and fatty acid metabolism in nondiabetic subjects and three groups of type 1 diabetic subjects (those studied during euglycemia, hyperlipidemia, and a hyperinsulinemic-euglycemic clamp) using positron emission tomography.RESULTS-Type 1 diabetic subjects had higher MVO 2 and lower myocardial glucose utilization rate/insulin than control subjects. In type 1 diabetes, glucose utilization increased with increasing plasma insulin and decreasing FFA levels. Myocardial fatty acid utilization, oxidation, and esterification rates increased with increasing plasma FFA. Increasing plasma insulin levels decreased myocardial fatty acid esterification rates but increased the percentage of fatty acids going into esterification. CONCLUSIONS-Type 1 diabetes myocardium has increasedMVO 2 and is insulin resistant during euglycemia. However, its myocardial glucose and fatty acid metabolism still responds to changes in plasma insulin and plasma FFA levels. Moreover, insulin and plasma FFA levels can regulate the intramyocardial fate of fatty acids in humans with type 1 diabetes. Diabetes 57: [32][33][34][35][36][37][38][39][40] 2008 A growing literature suggests that impaired cardiac metabolism in diabetes contributes to cardiac dysfunction, leading to overt heart failure, a so-called "diabetic cardiomyopathy" (1-4). Results from studies in animal models of type 1 diabetes show that myocardial substrate metabolic alterations may play a key role in the development of diabetic cardiomyopathy (5). Specifically, in diabetes, there is increased lipid delivery to the myocardium, myocardial fatty acid utilization and oxidation, and decreased myocardial glucose uptake and triglyceride hydrolysis (2,6,7). This excessive myocardial fatty acid utilization may be detrimental to cardiac function via impairing glucose utilization (particularly when glucose is required, e.g., ischemia), decreasing transsarcolemmal calcium flux-induced contractility and/or increasing free radical production (8 -11). Moreover, decreasing free fatty acid (FFA) delivery to the myocardium in animal models decreases its fat storage and improves function (12). These results suggest that metabolic modulation of myocardial substrate metabolism may be a new paradigm for treatment of diabetic cardiomyopathy (12,13).There is little data on the effects of altering FFA or hormonal delivery to the ...

p53 Promotes Cardiac Dysfunction in Diabetic Mellitus Caused by Excessive Mitochondrial Respiration-Mediated Reactive Oxygen Species Generation and Lipid Accumulation

“…8 These human and animal studies have shown that increased oxidative stress correlates with lipid overload, suggesting a role for FA in the generation of ROS, 7,8 whereas an involvement of ROS generated by high glucose concentrations in metabolic abnormalities in diabetic cardiomyopathy remains to be determined. 7 Tumor suppressor, p53, has a well-characterized role in regulating apoptosis and the cell cycle in response to genomic stress; however, its broader roles in organ homeostasis are just beginning to be understood.…”

“…8 These human and animal studies have shown that increased oxidative stress correlates with lipid overload, Received February 9, 2011; accepted October 31, 2011. From the Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan (H.N., S.M., E.I.-K., M. Kimata, A.H., M. Katamura, Y.O., M.A., Y.M., K.I., M.O., H.M.); the Department of Cardiovascular Medicine, Meiji University of Integrative Medicine, Hiyoshi-cho, Nantan-shi, Kyoto, Japan (E.I.-K.); the Department of Pediatrics, Graduate School of Medicine, Kyoto University, Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan (S.S.); and the Department of Pathology and Cell Regulation, Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan (H.T., T.T.…”

“…Because the increase of mitochondrial respiration and FA influx caused myocardial lipid accumulation, 6,8,15 we evaluated the functional change in mitochondrial oxidative respiration of diabetic hearts. Basal respiration (state 2, Vo), ADP-stimulated respiration (state 3, V ADP ), and oligomycin-administered respiration after ADP stimulation (state 4, Voligomycin) were compared in p53 (ϩ/ϩ) and p53 (Ϫ/Ϫ) mice.…”

Rodent models of diabetic cardiomyopathy

“…They also demonstrated that the hearts of individuals with type 1 diabetes exhibited increased myocardial oxygen consumption (MVO 2 ) and impaired insulin-mediated glucose uptake. The increase in fatty acid utilization was proportional to serum fatty acid levels, which increased in proportion to the severity of hyperglycemia (Peterson et al, 2008).…”

Measuring plasma fatty acid oxidation with intravenous bolus injection of 3H- and 14C-fatty acid

“…Rapid intravenous injection of an FFA tracer is useful when aspects of nonoxidative FA metabolism are investigated. Examples include the incorporation of plasma FAs into VLDL-triglyceride (TG) ( 15,16 ) or the storage/uptake of plasma FAs into tissues (17)(18)(19)(20). In addition, intravenous injections can be more convenient than a continuous infusion, because bolus injections obviate the need to keep the volunteers connected to an infusion pump, thus offering greater mobility and freedom during experimental days.…”