Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells

Haythorne, Elizabeth; Lloyd, Matthew; Walsby-Tickle, John; Tarasov, Andrei I.; Sandbrink, Jonas B.; Portillo, Idoia; Expósito, Raúl Terrón; Sachse, G.; Cyranka, Małgorzata; Rohm, Maria; Rorsman, Patrik; McCullagh, James; Ashcroft, Frances M.

doi:10.1038/s41467-022-34095-x

Cited by 42 publications

(38 citation statements)

References 71 publications

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“…shown to impair glucose oxidation and beta-cell function (43). Collectively, these findings may suggest that hyperglycemia stimulate mTORC1 in a timeand cell-type dependent manner.…”

Section: Implications Of Mtorc1 Inhibition For Diabetes Complications...mentioning

confidence: 87%

“…We have previously shown that, in diabetes, mTORC1 is specifically activated in KPTCs and that the development of DKD in this model is strictly dependent on mTORC1 activation in these cells ( 23 ). Similarly, in pancreatic islets, stimulation of mTORC1 by hyperglycemia has been recently shown to impair glucose oxidation and β cell function ( 43 ). Collectively, these findings may suggest that hyperglycemia stimulates mTORC1 in a time- and cell type–dependent manner.…”

Section: Discussionmentioning

confidence: 99%

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Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition

Kogot-Levin¹,

Riahi²,

Abramovich³

et al. 2023

JCI Insight

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Diabetes is associated with increased risk for kidney and liver diseases, congestive heart failure, and mortality. Urinary glucose excretion using sodiumglucose cotransporter 2 (SGLT2) inhibitors prevents these adverse outcomes, however the mechanisms involved are not clear. Herein, we generated a roadmap of the metabolic alterations that occur in the kidney, liver, and heart in diabetes and in response to SGLT2 inhibition. We performed in vivo metabolic labeling with 13 C-glucose in normoglycemic and diabetic mice treated with or without the SGLT2 inhibitor dapagliflozin, followed by simultaneous metabolomics and metabolic flux analyses in different organs and the plasma.We found that in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis and further inhibited pyruvate kinase activity in the liver. SGLT2 inhibition increased glucose oxidation in all organs; in the kidney, this effect was associated with modulation of the redox state, which may protect against oxidative stress. In addition, diabetes was associated with altered methionine cycle metabolism, evident by decreased betaine and methionine levels, whereas treatment with SGLT2i increased hepatic betaine along with decreased homocysteine levels. mTORC1 activity was inhibited by SGLT2i along with stimulation of AMPK in both normoglycemic and diabetic animals, possibly explaining the protective effects against kidney, liver, and heart diseases. Collectively, our findings suggest that SGLT2i induces metabolic reprogramming orchestrated by AMPK-mTORC1 signaling with common and distinct effects in various tissues with implications for diabetes and aging.

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“…shown to impair glucose oxidation and beta-cell function (43). Collectively, these findings may suggest that hyperglycemia stimulate mTORC1 in a timeand cell-type dependent manner.…”

Section: Implications Of Mtorc1 Inhibition For Diabetes Complications...mentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition

Kogot-Levin¹,

Riahi²,

Abramovich³

et al. 2023

JCI Insight

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show abstract

“…157 Notably, glycolytic metabolites between PFK and GAPDH were identified as culprits for impaired mitochondrial function. 158 Additionally, enhanced glycolysis is implicated in βcell dysfunction during aging, which is relevant to T2D. 159 Identifying specific metabolites causing glycolysis-related mitochondrial damage, offers a potential therapeutic avenue for preserving healthy β cells.…”

Section: And Perspectivesmentioning

confidence: 99%

Unique features of β‐cell metabolism are lost in type 2 diabetes

Muñoz,

Fex,

Moritz

et al. 2024

Acta Physiologica

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Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin‐sensitive tissues post‐prandially, this anabolic hormone restores blood glucose levels to pre‐prandial levels. Maintaining physiological glucose levels thus relies on proper β‐cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type‐specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (GCK), whereas other genes are selectively “disallowed”, including lactate dehydrogenase A (LDHA) and monocarboxylate transporter 1 (MCT1). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life‐threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply‐driven rather than demand‐driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β‐cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients.

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“…Meanwhile, inhibition of glucokinase prevented the changes in metabolic gene expressions induced by chronic hyperglycaemia and regained insulin content. 57 The underlying mechanisms of β-cell impairment by hyperglycemia has been unclear for decades, and, restricting glucose metabolism would be a solution to control β-cells impairment under diabetic condition.…”

Section: Risk Factors For β-Cell Dysfunction In Type 2 Diabetesmentioning

confidence: 99%

Pancreatic Beta-cell Dysfunction in Type 2 Diabetes

Khin

Lee

2023

Eur J Inflamm

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Pancreatic β-cells produce and secrete insulin to maintain blood glucose levels within a narrow range. Defects in the function and mass of β-cells play a significant role in the development and progression of diabetes. Increased β-cell deficiency and β-cell apoptosis are observed in the pancreatic islets of patients with type 2 diabetes. At an early stage, β-cells adapt to insulin resistance, and their insulin secretion increases, but they eventually become exhausted, and the β-cell mass decreases. Various causal factors, such as high glucose, free fatty acids, inflammatory cytokines, and islet amyloid polypeptides, contribute to the impairment of β-cell function. Therefore, the maintenance of β-cell function is a logical approach for the treatment and prevention of diabetes. In this review, we provide an overview of the role of these risk factors in pancreatic β-cell loss and the associated mechanisms. A better understanding of the molecular mechanisms underlying pancreatic β-cell loss will provide an opportunity to identify novel therapeutic targets for type 2 diabetes.

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Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells

Cited by 42 publications

References 71 publications

Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition

Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition

Unique features of β‐cell metabolism are lost in type 2 diabetes

Pancreatic Beta-cell Dysfunction in Type 2 Diabetes

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