Liver alanine catabolism promotes skeletal muscle atrophy and hyperglycaemia in type 2 diabetes

Okun, Jürgen G.; Rusu, Patricia M.; Chan, Andrea Y.; Wu, Yuqin; Yap, Yann Wan; Sharkie, Thomas; Schumacher, Jonas; Schmidt, Kathrin V.; Roberts-Thomson, Katherine; Russell, Ryan; Zota, Annika; Hille, Susanne; Jungmann, Andreas; Maggi, Ludovico; Lee, Young; Blüher, Matthias; Herzig, Stephan; Keske, Michelle A.; Heikenwälder, Mathias; Müller, Oliver; Rose, Adam J.

doi:10.1038/s42255-021-00369-9

Cited by 62 publications

(54 citation statements)

References 80 publications

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“…We found that loss of ALT2 had little effect on blood glucose concentrations in lean mice, but ALT2 suppression in obese, db/db mice produced a robust glucose-lowering effect independent of changes in liver fat or insulin sensitivity. These findings are consistent with another recent study demonstrating that suppression of both ALT enzymes in liver lowered plasma glucose concentrations in mouse models of diabetes (Okun et al, 2021). Thus, although ALT activity is primarily considered a circulating biomarker for liver or muscle injury, these data collectively demonstrate that it also plays important roles in intermediary metabolism and may contribute to dysregulated glucose production by diabetic liver.…”

Section: Introductionsupporting

confidence: 93%

“…ALT2 is abundant in human liver and GPT2 expression is down-regulated with marked weight loss. A recently published study suggested that hepatic expression of the gene encoding ALT2 is induced in people with type 2 diabetes and in mouse models of the disease (Okun et al, 2021), but other work has questioned whether ALT2 protein is expressed in human liver (Glinghammar et al, 2009). To confirm that ALT2 is abundant in human liver, hepatic protein lysates from biopsies collected during Roux-en-Y gastric bypass surgery (RYGBS) from patients with obesity were probed with antibodies for ALT1 and ALT2.…”

Section: Resultsmentioning

confidence: 99%

“…While this manuscript was in preparation, Okun and colleagues also demonstrated that ALT2 abundance was increased in liver of humans with type 2 diabetes and in several mouse models of obesity and diabetes (Okun et al, 2021). Consistent with the present studies, they showed that concomitant silencing of Gpt and Gpt2 in db/db liver attenuated hyperglycemia, led to reduced blood glucose excursions in ATT, and increased plasma alanine concentrations.…”

Section: Discussionmentioning

confidence: 97%

“…Previous work has indicated that ATF4 null mice are protected from diet-induced obesity and hyperglycemia (Seo et al, 2009), which is consistent with the effects of ATF4 on activating Gpt2 expression and gluconeogenesis from amino acids. On the other hand, Okun and colleagues found that glucocorticoid signaling was involved in the induction of Gpt2 expression in their studies (Okun et al, 2021). It remains to be determined whether the ATF4 and glucocorticoid receptor-mediated effects operate in parallel or in series to control Gpt2 expression.…”

Section: Discussionmentioning

confidence: 98%

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Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Martino

Gutiérrez‐Aguilar

Yiew

et al. 2021

Preprint

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Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We found that ALT2 was overexpressed in liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) was downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver was mediated by activating transcription factor 4; an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuated incorporation of 13C-alanine into newly synthesized glucose by hepatocytes. In vivo Gpt2 knockdown or knockout in liver had no effect on glucose concentrations in lean mice, but Gpt2 suppression alleviated hyperglycemia in db/db mice. These data suggest that ALT2 plays a significant role in hepatic gluconeogenesis from amino acids in diabetes.

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Section: Introductionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

See 2 more Smart Citations

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Martino

Gutiérrez‐Aguilar

Yiew

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…A recent study revealed that alanine aminotransferase is increased in the liver of mice with obesity and diabetes, as well as in humans with T2D. Furthermore, silencing of alanine aminotransferase in hepatocytes in mice with obesity and diabetes abrogated hyperglycaemia and restored skeletal muscle protein synthesis improving insulin sensitivity, which suggests that liver aminotransferase has a key role in inducing skeletal muscle atrophy in T2D (Okun et al, 2021). Although, aberrant PFAA concentrations have been reported previously in people with T2D in different countries, no comprehensive study was conducted to assess the PFAA concentrations in T2D with normal BMI, in Jordanian cohorts, who were only taking metformin (Al-Abbasi, 2012;Yamaguchi et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Plasma Amino Acids Metabolomics' Important in Glucose Management in Type 2 Diabetes

et al. 2021

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The perturbation in plasma free amino acid metabolome has been observed previously in diabetes mellitus, and is associated with insulin resistance as well as the onset of cardiovascular disease in this population. In this study, we investigated, for the first time, changes in the amino acid profile in a group of people with and without type 2 diabetes (T2D) with normal BMI, from Jordan, who were only managed on metformin. Twenty one amino acids were evaluated in plasma samples from 124 people with T2D and 67 healthy controls, matched for age, gender and BMI, using amino acids analyser. Total amino acids, essential amino acids, non-essential amino acids and semi-essential amino acids were similar in T2D compared to healthy controls. Plasma concentrations of four essential amino acids were increased in the presence of T2D (Leucine, p < 0.01, Lysine, p < 0.001, Phenylalanine, p < 0.01, Tryptophan, p < 0.05). On the other hand, in relation to non-essential amino acids, Alanine and Serine were reduced in T2D (p < 0.01, p < 0.001, respectively), whereas Aspartate and Glutamate were increased in T2D compared to healthy controls (p < 0.001, p < 0.01, respectively). A semi-essential amino acid, Cystine, was also increased in T2D compared to healthy controls (p < 0.01). Citrulline, a metabolic indicator amino acid, demonstrated lower plasma concentration in T2D compared to healthy controls (p < 0.01). These amino acids were also correlated with fasting blood glucose and HbA1c (p < 0.05). Glutamate, glycine and arginine were correlated with the duration of metformin treatment (p < 0.05). No amino acid was correlated with lipid profiles. Disturbances in the metabolism of these amino acids are closely implicated in the pathogenesis of T2D and associated cardiovascular disease. Therefore, these perturbed amino acids could be explored as therapeutic targets to improve T2D management and prevent associated cardiovascular complications.

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Research on the effects of intestinal FXR agonists and antibiotics on the regulation of red kidney bean polysaccharides in the liver metabolism in mice with type 2 diabetes

Zhang,

Qi,

et al. 2024

eFood

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Our previous study revealed that red kidney bean polysaccharides (RKB) exhibit a pronounced hypoglycemic effect on type 2 diabetic rats, while simultaneously exerting a significant ameliorative impact on hepatic damage in these animals. However, the precise mechanism underlying the effects of RKB on diabetes and liver metabolism remains unproven. In this study, we utilized a mouse model of type 2 diabetes induced by a high‐fat diet combined with streptozotocin to investigate the impact of RKB. We administered a combined intervention involving antibiotics, fexaramine, and RKB to elucidate the mechanism underlying RKB's effects. Our findings demonstrated that RKB significantly ameliorated liver function indices and histopathological injuries. Nevertheless, when antibiotics and fexaramine were introduced as interventions, they hindered the beneficial effects of RKB on liver function in type 2 diabetic mice. Furthermore, our nontargeted metabolomics analysis revealed that antibiotics and fexaramine exerted their inhibitory actions on RKB efficacy through modulation of distinct metabolites involved in glycerophospholipid and purine metabolic pathways.

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Liver alanine catabolism promotes skeletal muscle atrophy and hyperglycaemia in type 2 diabetes

Cited by 62 publications

References 80 publications

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Plasma Amino Acids Metabolomics' Important in Glucose Management in Type 2 Diabetes

Research on the effects of intestinal FXR agonists and antibiotics on the regulation of red kidney bean polysaccharides in the liver metabolism in mice with type 2 diabetes

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