The SGLT2-inhibitor dapagliflozin improves neutropenia and neutrophil dysfunction in a mouse model of the inherited metabolic disorder GSDIb

Resaz, Roberta; Raggi, Federica; Segalerba, Daniela; Lavarello, Chiara; Gamberucci, Alessandra; Bosco, Maria Carla; Astigiano, Simonetta; Assunto, Antonia; Melis, Daniela; D’Acierno, Mariavittoria; Veiga‐da‐Cunha, Maria; Petretto, Andrea; Marcolongo, Paola; Trepiccione, Francesco; Eva, Alessandra

doi:10.1016/j.ymgmr.2021.100813

Cited by 8 publications

(9 citation statements)

References 17 publications

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“…9,28 The glycosuria induced by SGLT2 inhibition is expected to compete with 1,5AG at the site of the SGLT4 transporter and favor its urinary excretion. 29,30 This, in turn, reduces the systemic level of 1,5AG and is beneficial to neutrophils' function as demonstrated in the experimental models 8,9 and in a small cohort of patients with GSD1b. 28 Because there is no evidence that SGLT2 can transport 1,5AG and the activity of HK-1 in PT cells is negligible in basal conditions, a pathogenetic mechanism that interferes with glycolysis seems unlikely to be crucial for the PT cells.…”

Section: Discussionmentioning

confidence: 91%

“…As additional mechanism, the SGLT2 inhibitors play a crucial role on renal reabsorption of the 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a noncanonical metabolite that results from the phosphorylation of 1,5AG. 1,5AG6P is responsible of neutropenia in G6PT and G6Pase- β KO mice 8 , 9 , 28 . Indeed, 1,5AG6P accumulation in neutrophil cytosol inhibits glucose phosphorylation by hexokinases and, thus, glycolysis 9 , 28 .…”

Section: Discussionmentioning

confidence: 99%

“…1,5AG6P is responsible of neutropenia in G6PT and G6Pase-b KO mice. 8,9,28 Indeed, 1,5AG6P accumulation in neutrophil cytosol inhibits glucose phosphorylation by hexokinases and, thus, glycolysis. 9,28 The glycosuria induced by SGLT2 inhibition is expected to compete with 1,5AG at the site of the SGLT4 transporter and favor its urinary excretion.…”

Section: Discussionmentioning

confidence: 99%

“…Gliflozins constitute a new class of drugs used for treating type 2 diabetes mellitus, because they reduce the renal threshold for glucose reabsorption and consequently facilitate glucose clearance. Empagliflozin, a SGLT2 inhibitor, improved neutrophils’ function in mice 8 and patients with GSD1b, 9 but the lack of data on its effect on the kidney (the target organ) imposed cautions on its usage.…”

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confidence: 99%

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Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b

D’Acierno

Resaz

Iervolino

et al. 2022

JASN

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Background: Mutations in SLC37A4, which encodes the intracellular glucose transporter G6PT, cause the rare glycogen storage disease type 1b (GSD1b). A long-term consequence of GSD1b is kidney failure, which requires kidney replacement therapy. The main protein markers of proximal tubule function, including NaPi2A, NHE3, SGLT2, GLUT2, and AQP1, are downregulated as part of the disease phenotype. Methods: We utilized an inducible mouse model of GSD1b, TM-G6PT-/-, to show that glycogen accumulation plays a crucial role in altering proximal tubule morphology and function. To limit glucose entry into proximal tubule cells and, thus, to prevent glycogen accumulation, we administered a SGLT2-inhibitor, dapagliflozin, to TM-G6PT-/- mice. Results: In proximal tubule cells, G6PT suppression stimulates the upregulation and activity of hexokinase I, which increases availability of the reabsorbed glucose for intracellular metabolism. Dapagliflozin prevented glycogen accumulation and improved kidney morphology by promoting a metabolic switch from glycogen synthesis towards lysis and restored expression levels of the main proximal tubule functional markers. Conclusion: We provide proof of concept for the efficacy of dapagliflozin in preserving kidney function in GSD1b mice. Our findings could represent the basis for repurposing this drug to treat GSD1b patients.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b

D’Acierno

Resaz

Iervolino

et al. 2022

JASN

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“…We also did not measure levels of 1,5AG6P or neutrophil oxygen burst. The optimal dose of empagliflozin and the use of other potential SGLT-2 inhibitors have not been established [ 15 ]. These issues may be resolved by the results of ongoing clinical trials, such as a large study (NCT04930627) conducted in Poland by the Children’s Memorial Health Institute in collaboration with the Medical University of Warsaw.…”

Section: Discussionmentioning

confidence: 99%

The overall benefits of empagliflozin treatment in adult siblings with glycogen storage disease type Ib: one year experience

2022

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IntroductionRecently published case reports suggest the benefit of empagliflozin use in subjects with glycogen storage disease Ib (GSD Ib).Material and methodsWe present the clinical and laboratory data of 2 adult brothers with GSD Ib treated with empagliflozin for 12 months.ResultsThere was no severe infection during administration of empagliflozin. The improvement of clinical symptoms of inflammatory bowel disease and arthritis along with reduction in serum CRP levels and urinary albumin excretion were noted. Neutrophil count increased allowing for reduction or temporary withdrawal of G-CSF treatment.ConclusionsEmpagliflozin may be new safe treatment in GSD Ib patients with advanced stage of the disease.

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Biochemical characterization of the human ubiquitous glucose‐6‐phosphatase in neutrophil granulocytes

Lédeczi,

Németh,

Kardon

2024

FEBS Open Bio

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Glucose‐6‐phosphatase‐β (G6PC3) is a ubiquitous phosphatase present in the endoplasmic reticulum, which, unlike G6PC1, is not responsible for maintaining blood glucose level under starvation. Recently, G6PC3 has been shown to play an important role in neutrophil granulocytes, eliminating the toxic metabolite 1,5‐anhydroglucitol‐6‐phosphate. The present study aimed to look for alternative substrates for the enzyme and outline the expression changes in the parts of this multicomponent system during neutrophil granulocyte differentiation. We determined the kinetic characteristics of recombinant human G6PC3 towards different sugar phosphates, and the transport of these compounds was also measured in rat liver microsomes. We found that all investigated sugar phosphates are substrates for G6PC3, although their microsomal transport is much slower than that of glucose‐6‐phosphate. Using the HL‐60 promyelocytic leukemia cell line as an in vitro model system for myeloid differentiation, we found no significant differences in enzyme expression and phosphatase activity latency between undifferentiated and differentiated cells. Our results provide novel insights into the possible role of G6PC3 in the dephosphorylation of alternative sugar phosphates or their metabolites synthesized in the endoplasmic reticulum and confirm the potential feature of the enzyme in the promyelocytic stage as well. These findings contribute to our knowledge of intracellular carbohydrate metabolism of neutrophil granulocytes, which facilitates further research directions to better understand the underlying mechanisms of neutropenias.

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The SGLT2-inhibitor dapagliflozin improves neutropenia and neutrophil dysfunction in a mouse model of the inherited metabolic disorder GSDIb

Cited by 8 publications

References 17 publications

Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b

Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b

The overall benefits of empagliflozin treatment in adult siblings with glycogen storage disease type Ib: one year experience

Biochemical characterization of the human ubiquitous glucose‐6‐phosphatase in neutrophil granulocytes

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