title: Free fatty acid availability is closely related to myocardial lipid storage and cardiac function in hypoglycemia counterregulation.
abstract: Hypoglycemia, a major side effect of intensive glucose-lowering therapy, was recently linked to increased cardiovascular risk in patients with diabetes. Whether increased circulating free fatty acids (FFA) owing to catecholamine-induced lipolysis affect myocardial energy metabolism and thus link hypoglycemia to cardiac vulnerability is unclear. Therefore, this study investigated the impact of hypoglycemia counterregulation (± inhibition of lipolysis) on myocardial lipid content (MYCL) and left ventricular function in healthy subjects. Nine healthy men were studied in randomized order: 1) insulin/hypoglycemia test (IHT; ins+/aci-), 2) IHT during inhibition of adipose tissue lipolysis by acipimox (ins+/aci+), 3) normoglycemia with acipimox (ins-/aci+), and 4) normoglycemia with placebo (ins-/aci-). MYCL and cardiac function were assessed by employing magnetic resonance spectroscopy/imaging at baseline and at 2 and 6 h. In response to acute hypoglycemia, plasma FFA (P<0.0001) and ejection fraction (EF; from 63.2±5.5 to 69.6±6.3%, P=0.0001) increased significantly and were tightly correlated with each other (r=0.68, P=0.0002); this response was completely blunted by inhibition of adipose tissue lipolysis. In the presence of normoglycemia, inhibition of lipolysis was associated with a drop in EF (from 59.2±5.5 to 53.9±6.9%,P=0.005) and a significant decrease in plasma FFA, triglycerides, and MYCL (by 48.5%, P=0.0001). The present data indicate that an intact interorgan cross-talk between adipose tissue and the heart is a prerequisite for catecholamine-mediated myocardial contractility and preservation of myocardial lipid stores in response to acute hypoglycemia.
authors: Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria; yvonne.winhofer@meduniwien.ac.at.
authors: Yvonne
authors: Y
authors: Winhofer
authors: Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria; Centre of Excellence, High-Field MR, Department of Radiodiagnostics, Medical University of Vienna, Vienna, Austria;
authors: Martin
authors: M
authors: Krššák
authors: Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria;
authors: Peter
authors: P
authors: Wolf
authors: Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria; Mariahilf Community Pharmacy, Arnoldstein, Austria; Medical Direction, Specialized Hospital Complex Agathenhof, Micheldorf, Austria;
authors: Christian-Heinz
authors: CH
authors: Anderwald
authors: Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria;
authors: Angelika
authors: A
authors: Geroldinger
authors: Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria;
authors: Georg
authors: G
authors: Heinze
authors: Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria;
authors: Sabina
authors: S
authors: Baumgartner-Parzer
authors: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria;
authors: Rodrig
authors: R
authors: Marculescu
authors: Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy, Department of Medicine III, Medical University of Vienna, Vienna, Austria; and.
authors: Thomas
authors: T
authors: Stulnig
authors: Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors: Michael
authors: M
authors: Wolzt
authors: Centre of Excellence, High-Field MR, Department of Radiodiagnostics, Medical University of Vienna, Vienna, Austria;
authors: Siegfried
authors: S
authors: Trattnig
authors: Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria;
authors: Anton
authors: A
authors: Luger
authors: Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria;
authors: Michael
authors: M
authors: Krebs
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000328:Adult; D052636:Allostasis / Q000187:drug effects; D004837:Epinephrine / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000009:adverse effects; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007328:Insulin / Q000009:adverse effects; D050356:Lipid Metabolism / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009638:Norepinephrine / Q000097:blood; D013318:Stroke Volume / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000517:prevention & control; D055815:Young Adult
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007328:Insulin; D000262:Adenylyl Cyclases; D009638:Norepinephrine; D004837:Epinephrine
keywords: acipimox; cardiac function; cardiac magnetic resonance imaging and spectroscopy; catecholamine-mediated lipolysis; free fatty acids; hypoglycemia; insulin/hypoglycemia test; myocardial lipid content