Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[¹⁸F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer

Abstract

-Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[ 18 F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([ 11 C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin ϩ glucose euglycemic clamp conditions (120 mU·m Ϫ2 ·min Ϫ1 ) to 3-h saline infusion. Lean controls (n ϭ 10) were compared with glycemically controlled volunteers with T2DM (n ϭ 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P Ͻ 0.01) and significantly increased myocardial oxygen consumption (P ϭ 0.04) and perfusion (P ϭ 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P Ͻ 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P Ͻ 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P Ͻ 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P ϭ 0.003). Myocardial work efficiency was lower in T2DM (P ϭ 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P ϭ 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM. myocardial; heart; diabetes; metabolism; metabolic flexibility; positron emission tomography ALTERATIONS IN METABOLIC SUBSTRATE uptake and metabolism are part of the phenotype that defines type 2 diabetes mellitus (T2DM) (3,4,33,39,74). The phenomenon of "metabolic flexibility" is the capacity of an organism, a tissue bed, or a cell system to switch readily among fuel types. Impaired metabolic flexibility is another phenotypic feature of T2DM (33, 66).Impaired metabolic flexibility has been demonstrated in skeletal muscle in human diabetes (32,66). This whole body effect likely arises due to effects of impaired insulin-stimulated glucose uptake, together with abnormalities in availability, uptake, and metabolism of fatty acid fuels (33,66,75).The myocardium is also affected by T2DM. The fuel needs of the heart are dramatically different than those of skeletal muscle, supporting continuous work even under resting conditions. Abnormalities in myocardial fuel selection in animal models of diabetes have been described (42,54,75), including impairments in insulin-stimulated glucose uptake and impaired suppression of myocardial fatty acid u...

Cardiovascular consequences of metabolic syndrome

“…(109, 110) Such abnormalities have been shown in animal models of insulin resistance,(111-113) in humans with obesity/insulin resistance,(46, 114, 115) and in obese humans with Type 2 diabetes. (116) This lipotoxicity effect is in addition to the previously described adverse effects of hyperglycemia on myocardial fuel selection (which combined exert ‘glucolipotoxicity’) (117), although the hyperglycemia is modest in MetS in the absence of concurrent diabetes. Notably, emerging data suggests a sexual dimorphism, with increased rates of fatty acid uptake and utilization in female animal models(110, 118) and in women.…”

Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation

“…when oxygen is restricted. Published data suggest that the diabetic heart has limited metabolic flexibility to change metabolism in response to stimuli, 18 , 19 and decreased mitochondrial energetics in response to anoxia 20 , 21 . To acutely adapt to low oxygen availability the heart must downregulate fatty acid metabolism and increase anaerobic glycolysis, mediated in part by AMP-activated protein kinase (AMPK) activation 22 .…”

Imaging of myocardial fatty acid oxidation

“…Indeed, the 6-thia LCFA analog, 14- 18 F-fluoro-6-thia-heptadecanoic acid (FTHA, Figure 1) was shown to exhibit >100 heart:blood concentration ratio with prolonged myocardial retention. 18 F-labeling at the ω-3 position was developed to minimize in vivo defluorination in rodent models, but subsequent studies in pigs [30] and humans [31] showed that terminally 18 F-labeled thia fatty acids do not exhibit appreciable metabolic defluorination in these higher mammals. Inhibition of MFAO with a CPT-1 inhibitor caused an 81% reduction in murine heart uptake of FTHA, indicating specificity of uptake for imaging of MFAO [29].…”

“…Many of these observations have been uniquely made possible by the availability of non-invasive quantitative assessments of fuel flux using radiolabeled glucose [95, 103, 113–116] and fatty acid tracers [78, 92, 95, 98, 103, 105, 109, 114, 117–121], showing augmented fatty acid uptake and utilization under fasting conditions, and importantly impaired capacity to switch among fuel sources (i.e. metabolic inflexibility)[31, 105, 113, 115, 122] (Figure 4). …”

“…Insulin induced major shifts in all of these parameters; this effect of insulin was statistically different between the two groups only for the suppression of NEFA, but the steady state values achieved under insulin stimulation differed for both FAO and FAO/MVO2. From [31]…”