Hungry for your alanine: when liver depends on muscle proteolysis

Sarabhai, Theresia; Roden, Michael

doi:10.1172/jci131931

Cited by 48 publications

(32 citation statements)

References 23 publications

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“…1b). Prolonged fasting also resulted in 60% lower rates of glucose-alanine cycling, with a 50% reduction in hepatic mitochondrial oxidation, demonstrating an interorgan link between liver and muscle during the fed-to-fasting transition in both rats 10 and humans 18,19 . Unbiased metabolomic analysis suggests that the same sequence of events occurs in ten-day fasted humans and reveals discrete starvation phases with gluconeogenic amino acid consumption and subsequent surge in lipids with a high degree of unsaturation and chain length 12,13 , reflecting increased adipocyte NEFA release.…”

Section: Fed-to-fasting Transition and Insulin Resistancementioning

confidence: 96%

The integrative biology of type 2 diabetes

Roden

Shulman²

2019

Nature

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794

632

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Obesity and type 2 diabetes are the most frequent metabolic disorders, but their causes remain largely unclear. Insulin resistance, the common underlying abnormality, results from imbalance between energy intake and expenditure favouring nutrient-storage pathways, which evolved to maximize energy utilization and preserve adequate substrate supply to the brain. Initially, dysfunction of white adipose tissue and circulating metabolites modulate tissue communication and insulin signalling. However, when the energy imbalance is chronic, mechanisms such as inflammatory pathways accelerate these abnormalities. Here we summarize recent studies providing insights into insulin resistance and increased hepatic gluconeogenesis associated with obesity and type 2 diabetes, focusing on data from humans and relevant animal models.

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Section: Fed-to-fasting Transition and Insulin Resistancementioning

confidence: 96%

The integrative biology of type 2 diabetes

Roden

Shulman²

2019

Nature

Self Cite

794

632

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show abstract

“…Liver provides gluconeogenesis activity, whereas skeletal muscle consumes glucose through glycolysis. These processes are linked through two cycles ( Dashty, 2013 ; Sarabhai and Roden, 2019 ). Alanine is transported to the liver and converted into glucose, which is then released into the circulation and taken up by skeletal muscle.…”

Section: Resultsmentioning

confidence: 99%

Trans-omic analysis reveals obesity-associated dysregulation of inter-organ metabolic cycles between the liver and skeletal muscle

et al. 2021

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Summary Systemic metabolic homeostasis is regulated by inter-organ metabolic cycles involving multiple organs. Obesity impairs inter-organ metabolic cycles, resulting in metabolic diseases. The systemic landscape of dysregulated inter-organ metabolic cycles in obesity has yet to be explored. Here, we measured the transcriptome, proteome, and metabolome in the liver and skeletal muscle and the metabolome in blood of fasted wild-type and leptin-deficient obese ( ob / ob ) mice, identifying components with differential abundance and differential regulation in ob / ob mice. By constructing and evaluating the trans-omic network controlling the differences in metabolic reactions between fasted wild-type and ob / ob mice, we provided potential mechanisms of the obesity-associated dysfunctions of metabolic cycles between liver and skeletal muscle involving glucose-alanine, glucose-lactate, and ketone bodies. Our study revealed obesity-associated systemic pathological mechanisms of dysfunction of inter-organ metabolic cycles.

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“…Protein catabolism occurs in skeletal muscles, connective tissues, and the GI tract in critical illness, allowing for increased release of amino acids into circulation 58 . Additionally, pyruvate in skeletal muscle may undergo transamination to the amino acid alanine, which can be transported to the liver in the Cahill cycle 59 . The increased amino acid efflux from endogenous sources enhances hepatic gluconeogenesis and increases synthesis of acute‐phase proteins, including haptoglobin and C‐reactive protein.…”

Section: Substrate Utilization In Critical Illnessmentioning

confidence: 99%

“…58 Additionally, pyruvate in skeletal muscle may undergo transamination to the amino acid alanine, which can be transported to the liver in the Cahill cycle. 59 The increased amino acid efflux from endogenous sources enhances hepatic gluconeogenesis and increases synthesis of acute-phase proteins, including haptoglobin and Creactive protein. Ongoing protein catabolism in critical illness results in a total-body net negative nitrogen balance that causes a loss of lean body mass and may contribute to organ dysfunction and worse outcomes.…”

Section: Protein Metabolismmentioning

confidence: 99%

Endogenous Glucose Production in Critical Illness

et al. 2021

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Regulation of endogenous glucose production (EGP) by hormonal, neuronal, and metabolic signaling pathways contributes to the maintenance of euglycemia under normal physiologic conditions. EGP is defined by the generation of glucose from substrates through glycogenolysis and gluconeogenesis, usually in fasted states, for local and systemic use. Abnormal increases in EGP are noted in patients with diabetes mellitus type 2, and elevated EGP may also impact the pathogenesis of nonalcoholic fatty liver disease and congestive heart failure. In this narrative review, we performed a literature search in PubMed to identify recently published English language articles characterizing EGP in critical illness. Evidence from preclinical and clinical studies demonstrates that critical illness can disrupt EGP through multiple mechanisms including increased systemic inflammation, counterregulatory hormone and catecholamine release, alterations in the hypothalamic-pituitary axis, insulin resistance, lactic acidosis, and iatrogenic insults such as vasopressors and glucocorticoids administered as part of clinical care. EGP contributes to hyperglycemia in critical illness when abnormally elevated and to hypoglycemia when abnormally depressed, each of which has been independently associated with increased mortality. Increased EGP may also promote protein catabolism that could worsen critical illness myopathy and impede recovery. Better understanding of the mechanisms and factors contributing to dysregulated EGP in critical illness may help in the development of therapeutic strategies that promote euglycemia, reduce intensive care unit-associated catabolism, and improve patient outcomes.

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Hungry for your alanine: when liver depends on muscle proteolysis

Cited by 48 publications

References 23 publications

The integrative biology of type 2 diabetes

The integrative biology of type 2 diabetes

Trans-omic analysis reveals obesity-associated dysregulation of inter-organ metabolic cycles between the liver and skeletal muscle

Endogenous Glucose Production in Critical Illness

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