title: 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 + glucose euglycemic clamp conditions (120 mU·m(-2)·min(-1)) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 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.
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana; and kmather@iu.edu.
authors.forename: K J
authors.initials: KJ
authors.lastname: Mather
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: G D
authors.initials: GD
authors.lastname: Hutchins
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: K
authors.initials: K
authors.lastname: Perry
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: W
authors.initials: W
authors.lastname: Territo
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: R
authors.initials: R
authors.lastname: Chisholm
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: A
authors.initials: A
authors.lastname: Acton
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: B
authors.initials: B
authors.lastname: Glick-Wilson
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: R V
authors.initials: RV
authors.lastname: Considine
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: S
authors.initials: S
authors.lastname: Moberly
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana; and Mayo Clinic, Rochester, Minnesota.
authors.forename: T R
authors.initials: TR
authors.lastname: DeGrado
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000000981:diagnostic imaging / Q000378:metabolism*; D004526:Efficiency; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006321:Heart / Q000000981:diagnostic imaging* / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D010168:Palmitates; D049268:Positron-Emission Tomography; D013871:Thiones
chemical_list: C515150:16-fluoro-4-thiapalmitic acid; D005227:Fatty Acids; D005462:Fluorine Radioisotopes; D007328:Insulin; D010168:Palmitates; D013871:Thiones; D005947:Glucose
keywords: diabetes; heart; metabolic flexibility; metabolism; myocardial; positron emission tomography