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Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes.

ABSTRACT: Insulin action in adipose tissue is crucial for whole-body glucose homeostasis, with insulin resistance being a major risk factor for metabolic diseases such as type 2 diabetes. Recent studies have proposed mitochondrial oxidants as a unifying driver of adipose insulin resistance, serving as a signal of nutrient excess. However, neither the substrates for nor sites of oxidant production are known. Because insulin stimulates glucose utilization, we hypothesized that glucose oxidation would fuel respiration, in turn generating mitochondrial oxidants. This would impair insulin action, limiting further glucose uptake in a negative feedback loop of "glucose-dependent" insulin resistance. Using primary rat adipocytes and cultured 3T3-L1 adipocytes, we observed that insulin increased respiration, but notably this occurred independently of glucose supply. In contrast, glucose was required for insulin to increase mitochondrial oxidants. Despite rising to similar levels as when treated with other agents that cause insulin resistance, glucose-dependent mitochondrial oxidants failed to cause insulin resistance. Subsequent studies revealed a temporal relationship whereby mitochondrial oxidants needed to increase before the insulin stimulus to induce insulin resistance. Together, these data reveal that (a) adipocyte respiration is principally fueled from nonglucose sources; (b) there is a disconnect between respiration and oxidative stress, whereby mitochondrial oxidant levels do not rise with increased respiration unless glucose is present; and (c) mitochondrial oxidative stress must precede the insulin stimulus to cause insulin resistance, explaining why short-term, insulin-dependent glucose utilization does not promote insulin resistance. These data provide additional clues to mechanistically link nutrient excess to adipose insulin resistance.

SUBMITTER: Krycer JR

PROVIDER: S-EPMC6952605 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes.

Krycer James R JR Elkington Sarah D SD Diaz-Vegas Alexis A Cooke Kristen C KC Burchfield James G JG Fisher-Wellman Kelsey H KH Cooney Gregory J GJ Fazakerley Daniel J DJ James David E DE

The Journal of biological chemistry 20191119 1

Insulin action in adipose tissue is crucial for whole-body glucose homeostasis, with insulin resistance being a major risk factor for metabolic diseases such as type 2 diabetes. Recent studies have proposed mitochondrial oxidants as a unifying driver of adipose insulin resistance, serving as a signal of nutrient excess. However, neither the substrates for nor sites of oxidant production are known. Because insulin stimulates glucose utilization, we hypothesized that glucose oxidation would fuel r ...[more]

PMID: 31744882

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Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes.

Publications

Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes.

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