title: Differential effects of insulin on peripheral diabetes-related changes in mitochondrial bioenergetics: involvement of advanced glycosylated end products.
abstract: Large scale clinical trials have demonstrated that an intensive antihyperglycemic treatment in diabetes mellitus (DM) in individuals reduces the incidence of micro- and macrovascular complications, e.g. nephropathy, retinopathy, DM-accelerated atherosclerosis, myocardial infarction, or limb amputations. Here, we investigated the effect of short- and long-term insulin administration on mitochondrial function in peripheral tissues of streptozotocin (STZ)-induced hyperglycemic rats. In addition, the in vitro effect of methylglyoxal (MG), advanced glycation end products (AGEs) and human diabetic plasma on mitochondrial activity was investigated in skeletal muscle and liver mitochondria and in rat skin primary fibroblasts. Hyperglycemic STZ rats showed tissue-specific patterns of energy deficiency, evidenced by reduced activities of complexes I, II and/or IV after 30 days of hyperglycemia in heart, skeletal muscle and liver; moreover, cardiac tissue was found to be the most sensitive to the diabetic condition, since energy metabolism was impaired after 10 days of the hyperglycemia. Insulin-induced tight glycemic control was effective in protecting against the hyperglycemia-induced inhibition of mitochondrial enzyme activities. Furthermore, the long-term hormone replacement (30 days) also increased these activities in kidney from STZ-treated animals, where the hyperglycemic state did not modify the electron transport activity. Results from in vitro experiments indicate that mitochondrial impairment could result from oxidative stress-induced accumulation of MG and/or AGEs. Further investigations demonstrated that human plasma AGE accumulation elicits reduced mitochondrial function in skin fibroblast. These data suggest that persistent hyperglycemia results in tissue-specific patterns of energy deficiency and that early and continuous insulin therapy is necessary to maintain proper mitochondrial metabolism.
authors.affiliation: Laboratório de Bioenergética e Estresse Oxidativo, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis/SC, Brazil.
authors.forename: Aline Pertile
authors.initials: AP
authors.lastname: Remor
authors.forename: Filipe José
authors.initials: FJ
authors.lastname: de Matos
authors.forename: Karina
authors.initials: K
authors.lastname: Ghisoni
authors.forename: Thiago Lenoir
authors.initials: TL
authors.lastname: da Silva
authors.forename: Greici
authors.initials: G
authors.lastname: Eidt
authors.forename: Marília
authors.initials: M
authors.lastname: Búrigo
authors.forename: Andreza Fabro
authors.initials: AF
authors.lastname: de Bem
authors.forename: Paulo César Lock
authors.initials: PC
authors.lastname: Silveira
authors.forename: Andrés
authors.initials: A
authors.lastname: de León
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Sanchez
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hohl
authors.forename: Viviane
authors.initials: V
authors.lastname: Glaser
authors.forename: Carlos-Alberto
authors.initials: CA
authors.lastname: Gonçalves
authors.forename: André
authors.initials: A
authors.lastname: Quincozes-Santos
authors.forename: Rafael
authors.initials: R
authors.lastname: Borba Rosa
authors.forename: Alexandra
authors.initials: A
authors.lastname: Latini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004579:Electron Transport; D004734:Energy Metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006321:Heart / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption; D011765:Pyruvaldehyde / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism; D013311:Streptozocin / Q000633:toxicity
chemical_list: D000903:Antibiotics, Antineoplastic; D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D007328:Insulin; D017382:Reactive Oxygen Species; D013311:Streptozocin; D011765:Pyruvaldehyde