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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. Since insulin stimulates glucose utilisation, we hypothesised 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, glucosedependent 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 fuelled from non-glucose 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 utilisation does not promote insulin resistance. These data provide additional clues to mechanistically link nutrient excess to adipose insulin resistance. Adipose tissue is a key nutrient sensor in mammals (1). Being highly sensitive to insulin, adipocytes respond to nutrient replete conditions by increasing energy intake and storage as lipid. Conversely, under nutrient excess, adipocytes become insulin resistant, leading to increased lipid utilisation and reduced glucose intake. Indeed, impaired glucose uptake into adipose tissue is one of the earliest defects observed in whole-body insulin resistance, in both rodents and humans (e.g., (2

In Figure 7B of the originally published version of this article, the authors sourced some data from a previously published paper (Krycer et al., 2020). However, they inadvertently failed to acknowledge this and cite the source. This has since been corrected online, and the source is now cited in the legend of Figure 7B. The reference has also been added. The authors sincerely apologize for this oversight. Figure 7. Insulin Altered the Profile of Substrates' Fates (B) The partitioning of radiolabelled glucose into end products CO 2 , glycerol (TAG-Gly) and fatty acyl. These pools constituted a small fraction of the glucose consumed compared to lactate efflux determined by enzymatic assay. The rates for glucose, lactate, and CO 2 were sourced from Krycer et al. (2020), showing glucose uptake, lactate production, and glucose oxidation into CO 2 rates from adipocytes cultured in 10 mM glucose with and without 100 nM insulin.