SLGT2 Inhibitor Rescues Myelopoiesis in G6PC3 Deficiency

Hiwarkar, Prashant; Bargir, Umair Ahmed; Pandrowala, Ambreen; Bodhanwala, Minnie; Thakker, Naresh; Taur, Prasad; Madkaikar, Manisha; Desai, Mukesh

doi:10.1007/s10875-022-01323-4

Cited by 9 publications

(8 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Improvement of neutropenia and colitis manifestations as well as of the quality of life was reported. In these patients, the dosage of empagliflozin (0.03-0.28 mg/kg/day) able to decrease plasma 1,5-AG was lower than GSDIb patients: a possible explanation could be that patients with G6PC3 deficiency do not take CS, an important source of 1,5-AG (36), therefore they may need a lower dose of empagliflozin to correct neutrophil dysfunction (35). Furthermore, mutation in other sodium-glucose transporters, such as SGLT5, might explain higher urinary excretion of 1,5-AG, milder neutropenia and a better responsiveness to empagliflozin in some patients (17).…”

Section: Evidences From Neutropenia Typementioning

confidence: 86%

“…The first evidence for the use of empagliflozin in G6PC3 deficiency were recently described in 3 patients: a 30-year old woman with neutropenia, recurrent infections and inflammatory enterocolitis (35) and 2 children with recurrent infections (17). Improvement of neutropenia and colitis manifestations as well as of the quality of life was reported.…”

Section: Evidences From Neutropenia Typementioning

confidence: 99%

See 1 more Smart Citation

Current understanding on pathogenesis and effective treatment of glycogen storage disease type Ib with empagliflozin: new insights coming from diabetes for its potential implications in other metabolic disorders

2023

View full text Add to dashboard Cite

Glycogen storage type Ib (GSDIb) is a rare inborn error of metabolism caused by glucose-6-phosphate transporter (G6PT, SLC37A4) deficiency. G6PT defect results in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa and into both glycogenolysis and gluconeogenesis impairment. Clinical features include hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia, and growth retardation. Long-term complications are liver adenoma, hepatocarcinoma, nephropathy and osteoporosis. The hallmark of GSDIb is neutropenia, with impaired neutrophil function, recurrent infections and inflammatory bowel disease. Alongside classical nutritional therapy with carbohydrates supplementation and immunological therapy with granulocyte colony-stimulating factor, the emerging role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction led to repurpose empagliflozin, an inhibitor of the renal glucose transporter SGLT2: the current literature of its off-label use in GSDIb patients reports beneficial effects on neutrophil dysfunction and its clinical consequences. Surprisingly, this glucose-lowering drug ameliorated the glycemic and metabolic control in GSDIb patients. Furthermore, numerous studies from big cohorts of type 2 diabetes patients showed the efficacy of empagliflozin in reducing the cardiovascular risk, the progression of kidney disease, the NAFLD and the metabolic syndrome. Beneficial effects have also been described on peripheral neuropathy in a prediabetic rat model. Increasing evidences highlight the role of empagliflozin in regulating the cellular energy sensors SIRT1/AMPK and Akt/mTOR, which leads to improvement of mitochondrial structure and function, stimulation of autophagy, decrease of oxidative stress and suppression of inflammation. Modulation of these pathways shift the oxidative metabolism from carbohydrates to lipids oxidation and results crucial in reducing insulin levels, insulin resistance, glucotoxicity and lipotoxicity. For its pleiotropic effects, empagliflozin appears to be a good candidate for drug repurposing also in other metabolic diseases presenting with hypoglycemia, organ damage, mitochondrial dysfunction and defective autophagy.

show abstract

Section: Evidences From Neutropenia Typementioning

confidence: 86%

Section: Evidences From Neutropenia Typementioning

confidence: 99%

Current understanding on pathogenesis and effective treatment of glycogen storage disease type Ib with empagliflozin: new insights coming from diabetes for its potential implications in other metabolic disorders

2023

View full text Add to dashboard Cite

show abstract

“…As previous reports suggest that G6PC3 deficiency can lead to death from severe infections when neutropenia is left untreated, prompt diagnosis and provision of treatments are critical 31,32 . Importantly, empagliflozin, an SGLT2 inhibitor frequently used to treat type 2 diabetes, has successfully resolved neutrophil defects in patients with G6PC3 deficiency by lowering the 1,5-AG blood concentrations 30,33,34 . Along with the use of this highly effective, safe, and easy-to-take oral alternative to granulocyte-colony-stimulating factor (G-CSF) injections, early disease diagnosis may improve outcomes of G6PC3 deficient patients 35,36 .…”

Section: Discussionmentioning

confidence: 99%

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Zhen,

Betti,

Kars

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: G6PC3 deficiency is a rare genetic disorder that causes syndromic congenital neutropenia. It is driven by the intracellular accumulation of a metabolite named 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Objective: The G6PC3 c.210delC variant has been identified in patients of Mexican origin. We set out to study the origin and functional consequence of this mutation. Furthermore, we sought to characterize the clinical phenotypes caused by it. Methods: Using whole-genome sequencing data, we conducted haplotype analysis to estimate the age of this allele and traced its ancestral origin. We examined how this mutation affected G6PC3 protein expression and performed extracellular flux assays on patient-derived cells to characterize how this mutation impacts glycolysis. Finally, we compared the clinical presentations of patients with the c.210delC mutation relative to other G6PC3 deficient patients published to date. Results: Based on the length of haplotypes shared amongst ten carriers of the G6PC3 c.210delC mutation, we estimated that this variant originated in a common ancestor of indigenous American origin. The mutation causes a frameshift that introduces a premature stop codon, leading to a complete loss of G6PC3 protein expression. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Clinically, c.210delC carriers display all the clinical features of syndromic severe congenital neutropenia type 4 observed in prior reports of G6PC3 deficiency. Conclusion: The G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.

show abstract

“…It was demonstrated that SLC37A4 and G6PC3 collaborated to destroy 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a close structural analog of G6P and an inhibitor of low- K M hexokinases, which catalyze the first step in glycolysis in most tissues. Failure to eliminate 1,5AG6P appears to be the mechanism of neutrophil dysfunction and death in G6PC3-deficient mice ( 62 ).…”

Section: Discussionmentioning

confidence: 99%

A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype

Torabidastgerdooei,

Roy,

Annabi

2023

Front. Endocrinol.

View full text Add to dashboard Cite

BackgroundGlycogen plays an important role in glucose homeostasis and contributes to key functions related to brain cancer cell survival in glioblastoma multiforme (GBM) disease progression. Such adaptive molecular mechanism is dependent on the glycogenolytic pathway and intracellular glucose-6-phosphate (G6P) sensing by brain cancer cells residing within those highly hypoxic tumors. The involvement of components of the glucose-6-phosphatase (G6Pase) system remains however elusive.ObjectiveWe questioned the gene expression levels of components of the G6Pase system in GBM tissues and their functional impact in the control of the invasive and brain cancer stem cells (CSC) phenotypes.MethodsIn silico analysis of transcript levels in GBM tumor tissues was done by GEPIA. Total RNA was extracted and gene expression of G6PC1-3 as well as of SLC37A1-4 members analyzed by qPCR in four human brain cancer cell lines and from clinically annotated brain tumor cDNA arrays. Transient siRNA-mediated gene silencing was used to assess the impact of TGF-β-induced epithelial-to-mesenchymal transition (EMT) and cell chemotaxis. Three-dimensional (3D) neurosphere cultures were generated to recapitulate the brain CSC phenotype.ResultsHigher expression in G6PC3, SLC37A2, and SLC37A4 was found in GBM tumor tissues in comparison to low-grade glioma and healthy tissue. The expression of these genes was also found elevated in established human U87, U251, U118, and U138 GBM cell models compared to human HepG2 hepatoma cells. SLC37A4/G6PC3, but not SLC37A2, levels were induced in 3D CD133/SOX2-positive U87 neurospheres when compared to 2D monolayers. Silencing of SLC37A4/G6PC3 altered TGF-β-induced EMT biomarker SNAIL and cell chemotaxis.ConclusionTwo members of the G6Pase system, G6PC3 and SLC37A4, associate with GBM disease progression and regulate the metabolic reprogramming of an invasive and CSC phenotype. Such molecular signature may support their role in cancer cell survival and chemoresistance and become future therapeutic targets.

show abstract

SLGT2 Inhibitor Rescues Myelopoiesis in G6PC3 Deficiency

Cited by 9 publications

References 25 publications

Current understanding on pathogenesis and effective treatment of glycogen storage disease type Ib with empagliflozin: new insights coming from diabetes for its potential implications in other metabolic disorders

Current understanding on pathogenesis and effective treatment of glycogen storage disease type Ib with empagliflozin: new insights coming from diabetes for its potential implications in other metabolic disorders

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype

Contact Info

Product

Resources

About