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Property "Has-20abstract" (as page type) with input value "Type-202-20diabetes-20and-20insulin-20resistance-20have-20been-20associated-20with-20mitochondrial-20dysfunction,-20but-20it-20is-20debated-20whether-20this-20is-20a-20primary-20factor-20in-20the-20pathogenesis-20of-20the-20disease.-20To-20test-20the-20concept-20that-20mitochondrial-20dysfunction-20is-20secondary-20to-20the-20development-20of-20insulin-20resistance,-20we-20employed-20the-20unique-20model-20of-20prolonged-20fasting-20in-20humans.-20Prolonged-20fasting-20is-20a-20physiologic-20condition-20in-20which-20muscular-20insulin-20resistance-20develops-20in-20the-20presence-20of-20increased-20free-20fatty-20acid-20(FFA)-20levels,-20increased-20fat-20oxidation-20and-20low-20glucose-20and-20insulin-20levels.-20It-20is-20therefore-20anticipated-20that-20skeletal-20muscle-20mitochondrial-20function-20is-20maintained-20to-20accommodate-20increased-20fat-20oxidation-20unless-20factors-20secondary-20to-20insulin-20resistance-20exert-20negative-20effects-20on-20mitochondrial-20function.-0A-0AWhile-20in-20a-20respiration-20chamber,-20twelve-20healthy-20males-20were-20subjected-20to-20a-2060-20h-20fast-20and-20a-2060-20h-20normal-20fed-20condition-20in-20a-20randomized-20crossover-20design.-20Afterward,-20insulin-20sensitivity-20was-20assessed-20using-20a-20hyperinsulinemic-2Deuglycemic-20clamp,-20and-20mitochondrial-20function-20was-20quantified-20-27-27ex-20vivo-27-27-20in-20permeabilized-20muscle-20fibers-20using-20high-2Dresolution-20respirometry.-0A-0AIndeed,-20FFA-20levels-20were-20increased-20approximately-20ninefold-20after-2060-20h-20of-20fasting-20in-20healthy-20male-20subjects,-20leading-20to-20elevated-20intramuscular-20lipid-20levels-20and-20decreased-20muscular-20insulin-20sensitivity.-20Despite-20an-20increase-20in-20whole-2Dbody-20fat-20oxidation,-20we-20observed-20an-20overall-20reduction-20in-20both-20coupled-20state-203-20respiration-20and-20maximally-20uncoupled-20respiration-20in-20permeabilized-20skeletal-20muscle-20fibers,-20which-20could-20not-20be-20explained-20by-20changes-20in-20mitochondrial-20density.-0A-0AThese-20findings-20confirm-20that-20the-20insulin-2Dresistant-20state-20has-20secondary-20negative-20effects-20on-20mitochondrial-20function.-20Given-20the-20low-20insulin-20and-20glucose-20levels-20after-20prolonged-20fasting,-20hyperglycemia-20and-20insulin-20action-20per-20se-20can-20be-20excluded-20as-20underlying-20mechanisms,-20pointing-20toward-20elevated-20plasma-20FFA-20and-2For-20intramuscular-20fat-20accumulation-20as-20possible-20causes-20for-20the-20observed-20reduction-20in-20mitochondrial-20capacity." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

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