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Burkart, Alison

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Burkart

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Alison

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Burkart, Alison
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    Metabolic modeling of muscle metabolism identifies key reactions linked to insulin resistance phenotypes
    (Elsevier, 2014) Nogiec, Christopher; Burkart, Alison; Dreyfuss, Jonathan M.; Lerin, Carles; Kasif, Simon; Patti, Mary-Elizabeth
    Objective: Dysregulated muscle metabolism is a cardinal feature of human insulin resistance (IR) and associated diseases, including type 2 diabetes (T2D). However, specific reactions contributing to abnormal energetics and metabolic inflexibility in IR are unknown. Methods: We utilize flux balance computational modeling to develop the first systems-level analysis of IR metabolism in fasted and fed states, and varying nutrient conditions. We systematically perturb the metabolic network to identify reactions that reproduce key features of IR-linked metabolism. Results: While reduced glucose uptake is a major hallmark of IR, model-based reductions in either extracellular glucose availability or uptake do not alter metabolic flexibility, and thus are not sufficient to fully recapitulate IR-linked metabolism. Moreover, experimentally-reduced flux through single reactions does not reproduce key features of IR-linked metabolism. However, dual knockdowns of pyruvate dehydrogenase (PDH), in combination with reduced lipid uptake or lipid/amino acid oxidation (ETFDH), does reduce ATP synthesis, TCA cycle flux, and metabolic flexibility. Experimental validation demonstrates robust impact of dual knockdowns in PDH/ETFDH on cellular energetics and TCA cycle flux in cultured myocytes. Parallel analysis of transcriptomic and metabolomics data in humans with IR and T2D demonstrates downregulation of PDH subunits and upregulation of its inhibitory kinase PDK4, both of which would be predicted to decrease PDH flux, concordant with the model. Conclusions: Our results indicate that complex interactions between multiple biochemical reactions contribute to metabolic perturbations observed in human IR, and that the PDH complex plays a key role in these metabolic phenotypes.
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    Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function
    (Nature Publishing Group, 2016) Burkart, Alison; Tan, Kelly; Warren, Laura; Iovino, Salvatore; Hughes, Katelyn J.; Kahn, C.; Patti, Mary-Elizabeth
    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.