title: The detrimental effects of acute hyperglycemia on myocardial glucose uptake.
abstract: OBJECTIVE
  Although acute hyperglycemic (AHG) episodes are linked to lower glucose uptake, underlying mechanisms remain unclear. We hypothesized that AHG triggers reactive oxygen species (ROS) production and increases non-oxidative glucose pathway (NOGP) activation, i.e. stimulation of advanced glycation end products (AGE), polyol pathway (PP), hexosamine biosynthetic pathway (HBP), PKC; thereby decreasing cardiac glucose uptake.
  
  
  METHODS
  H9c2 cardiomyoblasts were exposed to 25 mM glucose for 24h vs. 5.5mM controls ± modulating agents during the last hour of glucose exposure: a) antioxidant #1 for mitochondrial ROS (250 μM 4-OHCA), b) antioxidant #2 for NADPH oxidase-generated ROS (100 μM DPI), c) NOGP inhibitors - 100 μM aminoguanidine (AGE), 5 μM chelerythrine (PKC); 40 μM DON (HBP); and 10 μM zopolrestat (PP). ROS levels (mitochondrial, intracellular) and glucose uptake were evaluated by flow cytometry.
  
  
  RESULTS
  AHG elevated ROS, activated NOGPs and blunted glucose uptake. Transketolase activity (pentose phosphate pathway [PPP] marker) did not change. Respective 4-OHCA and DPI treatment blunted ROS production, diminished NOGP activation and normalized glucose uptake. NOGP inhibitory studies identified PKCβII as a key downstream player in lowering insulin-mediated glucose uptake. When we employed an agent (benfotiamine) known to shunt flux away from NOGPs (into PPP), it decreased ROS generation and NOGP activation, and restored glucose uptake under AHG conditions.
  
  
  CONCLUSIONS
  This study demonstrates that AHG elicits maladaptive events that function in tandem to reduce glucose uptake, and that antioxidant treatment and/or attenuation of NOGP activation (PKC, polyol pathway) may limit the onset of insulin resistance.
authors.affiliation: Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa.
authors.forename: Danzil
authors.initials: D
authors.lastname: Joseph
authors.affiliation: Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa.
authors.forename: Charlene
authors.initials: C
authors.lastname: Kimar
authors.affiliation: Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa.
authors.forename: Burger
authors.initials: B
authors.lastname: Symington
authors.affiliation: Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa.
authors.forename: Robyn
authors.initials: R
authors.lastname: Milne
authors.affiliation: Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa. Electronic address: mfessop@sun.ac.za.
authors.forename: M Faadiel
authors.initials: MF
authors.lastname: Essop
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D053119:Benzophenanthridines; D052160:Benzothiazoles; D002460:Cell Line; D003373:Coumaric Acids; D003980:Diazooxonorleucine; D005434:Flow Cytometry; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006146:Guanidines; D006595:Hexosamines / Q000096:biosynthesis; D006943:Hyperglycemia / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009861:Onium Compounds; D010793:Phthalazines; D011108:Polymers / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D053119:Benzophenanthridines; D052160:Benzothiazoles; D003373:Coumaric Acids; D017127:Glycation End Products, Advanced; D006146:Guanidines; D006595:Hexosamines; D009861:Onium Compounds; D010793:Phthalazines; D011108:Polymers; D017382:Reactive Oxygen Species; C024617:polyol; D003980:Diazooxonorleucine; C067172:zopolrestat; C007175:alpha-cyano-4-hydroxycinnamate; C007517:diphenyleneiodonium; C016299:chelerythrine; D005947:Glucose; C004479:pimagedine
keywords: Acute hyperglycemia; Antioxidants; Insulin resistance; Non-oxidative glucose pathways; PKCβII; Reactive oxygen species