The role of α-ketoglutarate and the hypoxia sensing pathway in the regulation of pancreatic β-cell function

Hoang, Monica; Joseph, Jamie W.

doi:10.1080/19382014.2020.1802183

Cited by 10 publications

(16 citation statements)

References 118 publications

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“…One interesting glucose phenotype is that both acute and chronic AKG treatments increase blood insulin but not glucagon levels in DIO and db/db mice. These findings are consistent with previous reports that AKG stimulates insulin secretion through hypoxia-inducible factor-prolyl hydroxylases (PHDs) in clonal β-cells as well as rodent and human islets 21,43 . Glucose-induced secretion of insulin is wellknown to inhibit hepatic glucose production 44 , suggesting a possibility that AKG increases insulin secretion to indirectly inhibit hepatic gluconeogenesis.…”

Section: Discussionsupporting

confidence: 93%

Alpha-ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling

Shu

Yuan

Jia

et al. 2020

Preprint

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While resistance exercise effectively improves overall health in diabetic patients, the underlying biological mechanism by which resistance exercise improves metabolic function and glucose homeostasis remain mostly unknown. Previously, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial effects of resistance exercise on metabolic function. We found that resistance exercise-induced α-ketoglutaric acid (AKG) stimulates muscle hypertrophy and fat loss through 2-oxoglutarate receptor 1 (OXGR1)-dependent adrenal activation. Here, we provided evidence for the beneficial effects of AKG on glucose homeostasis in a diet-induced obesity (DIO) mouse model, which are independent of OXGR1. We showed that circulating AKG levels are negatively correlated with the fraction of blood glycated hemoglobin (HbA1c) in both humans and mice and significantly decreased in DIO mice. Consistently, pharmacological elevation of AKG effectively decreased body weight, blood glucose, and hepatic gluconeogenesis without changing insulin sensitivity and glucose tolerance in DIO mice. Notably, OXGR1KO blocked the inhibitory effects of AKG on body weight but failed to affect AKG’s suppression on blood glucose and hepatic gluconeogenesis, indicating distinct mechanisms for AKG’s regulation on energy balance and glucose homeostasis. In supporting this view, we showed that serpina1e, a member of protease inhibitor serpins superfamily, mediates the direct inhibitory effects of AKG on gluconeogenesis in both in vitro hepatocytes and liver slice. By using a liver-specific serpina1e deletion mouse model, we further demonstrated that liver serpina1e is required for the inhibitory effects of AKG on hepatic gluconeogenesis and hyperglycemia in DIO mice. Finally, we provided in vitro evidence to support a model in which AKG decreases hepatic gluconeogenesis by targeting trimethylation of lysine 27 on histone 3 (H3K27me3) in seprina1e promoter region. Our studies established an important role of AKG in glucose homeostasis, and identified the AKG-serpina1e pathway as potential therapeutic targets to attenuate hyperglycemia.

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Section: Discussionsupporting

confidence: 93%

Alpha-ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling

Shu

Yuan

Jia

et al. 2020

Preprint

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“…Previously, it has been reported that PC suppression might activate compensatory responses in β-cells either through increasing flux of downstream pyruvate cycling fluxes such as ICD c or through a separate pathway involving acetyl-CoA [43]–[45]; these effects are not explicitly included in our model. As a further extension, the model could be expanded to describe the role of α-ketogulutarate in insulin regulation [46], [47].…”

Section: Discussionmentioning

confidence: 99%

“…[45]; these effects are not explicitly included in our model. As a further extension, the model could be expanded to describe the role of αketogulutarate in insulin regulation [46], [47]. .…”

Section: Cytosolic Isocitrate Dehydrogenase Sensitivity Rankingsmentioning

confidence: 99%

Kinetic modelling of β-cell metabolism reveals control points in the insulin-regulating pyruvate cycling pathways

Rahul

Stinchcombe

Joseph

et al. 2021

Preprint

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Insulin, a key hormone in the regulation of glucose homeostasis, is secreted by pancreatic β-cells in response to elevated glucose levels. Insulin is released in a biphasic manner in response to glucose metabolism in β-cells. The first phase of insulin secretion is triggered by an increase in the ATP:ADP ratio; the second phase occurs in response to both a rise in ATP:ADP as well as other key metabolic signals, including a rise in the NADPH:NADP+ ratio. Experimental evidence indicates that pyruvate-cycling pathways play an important role in the elevation of the NADPH:NADP+ ratio in response to glucose. In this work we developed a kinetic model for the tricarboxylic acid cycle and pyruvate cycling pathways. We successfully validated our model against recent experimental observations and performed local and global sensitivity analysis to identify key regulatory interactions in the system. The model predicts that the dicarboxylate carrier (DIC) and pyruvate transporter (PYC) are the most important regulators of pyruvate cycling and NADPH production. In contrast, our analysis showed that variation in the pyruvate carboxylase (PC) flux was compensated by a response in the activity of mitochondrial isocitrate dehydrogenase (ICDm) resulting in minimal effect on overall pyruvate cycling flux. The model predictions suggest starting points for further experimental investigation, as well as potential drug targets for treatment of type 2 diabetes.

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“…Mitochondrial metabolites, transported by the citrate carrier (CIC), dicarboxylate carrier (DIC), oxoglutarate carrier (OGC), and mitochondrial pyruvate carrier (MPC) play important roles in the regulation of glucose-stimulated insulin secretion (GSIS). A recent review discusses a possible link between defective anaplerotic-derived α-ketoglutarate (αKG), hypoxia-inducible factor-prolyl hydroxylases (PDHs), and the development of T2DM [ 57 ].…”

Section: Metabolite Supply For Liver Function and Energy Supply Fomentioning

confidence: 99%

Mitochondria at Work: New Insights into Regulation and Dysregulation of Cellular Energy Supply and Metabolism

Schirrmacher¹

2020

Biomedicines

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Mitochondria are of great relevance to health, and their dysregulation is associated with major chronic diseases. Research on mitochondria—156 brand new publications from 2019 and 2020—have contributed to this review. Mitochondria have been fundamental for the evolution of complex organisms. As important and semi-autonomous organelles in cells, they can adapt their function to the needs of the respective organ. They can program their function to energy supply (e.g., to keep heart muscle cells going, life-long) or to metabolism (e.g., to support hepatocytes and liver function). The capacity of mitochondria to re-program between different options is important for all cell types that are capable of changing between a resting state and cell proliferation, such as stem cells and immune cells. Major chronic diseases are characterized by mitochondrial dysregulation. This will be exemplified by cardiovascular diseases, metabolic syndrome, neurodegenerative diseases, immune system disorders, and cancer. New strategies for intervention in chronic diseases will be presented. The tumor microenvironment can be considered a battlefield between cancer and immune defense, competing for energy supply and metabolism. Cancer cachexia is considered as a final stage of cancer progression. Nevertheless, the review will present an example of complete remission of cachexia via immune cell transfer. These findings should encourage studies along the lines of mitochondria, energy supply, and metabolism.

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The role of α-ketoglutarate and the hypoxia sensing pathway in the regulation of pancreatic β-cell function

Cited by 10 publications

References 118 publications

Alpha-ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling

Alpha-ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling

Kinetic modelling of β-cell metabolism reveals control points in the insulin-regulating pyruvate cycling pathways

Mitochondria at Work: New Insights into Regulation and Dysregulation of Cellular Energy Supply and Metabolism

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