title: Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function.
abstract: Insulin resistance, a critical component of type 2 diabetes (T2D), precedes and predicts T2D onset. T2D is also associated with mitochondrial dysfunction. To define the cause-effect relationship between insulin resistance and mitochondrial dysfunction, we compared mitochondrial metabolism in induced pluripotent stem cells (iPSC) from 5 healthy individuals and 4 patients with genetic insulin resistance due to insulin receptor mutations. Insulin-resistant iPSC had increased mitochondrial number and decreased mitochondrial size. Mitochondrial oxidative function was impaired, with decreased citrate synthase activity and spare respiratory capacity. Simultaneously, expression of multiple glycolytic enzymes was decreased, while lactate production increased 80%. These perturbations were accompanied by an increase in ADP/ATP ratio and 3-fold increase in AMPK activity, indicating energetic stress. Insulin-resistant iPSC also showed reduced catalase activity and increased susceptibility to oxidative stress. Thus, insulin resistance can lead to mitochondrial dysfunction with reduced mitochondrial size, oxidative activity, and energy production.
authors.affiliation: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Burkart
authors.affiliation: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Tan
authors.affiliation: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Warren
authors.affiliation: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Iovino
authors.affiliation: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Katelyn J
authors.initials: KJ
authors.lastname: Hughes
authors.affiliation: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.affiliation: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Mary-Elizabeth
authors.initials: ME
authors.lastname: Patti
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D007333:Insulin Resistance; D019344:Lactic Acid; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology*; D053142:Mitochondrial Size; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D017382:Reactive Oxygen Species; D019344:Lactic Acid; D002950:Citrate (si)-Synthase; C435941:INSR protein, human; D011972:Receptor, Insulin