Model analysis of effect of canagliflozin (Invokana), a sodium–glucose cotransporter 2 inhibitor, to alter plasma 1,5-anhydroglucitol

Fortuna, Danielle; McCloskey, Laura J.; Stickle, Douglas F.

doi:10.1016/j.cca.2015.11.010

Cited by 22 publications

(20 citation statements)

References 17 publications

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“…If 1,5AG6P is responsible for the toxicity observed in neutrophils, then 1,5AG administration to G6PC3-deficient mice should exacerbate their neutropenia. On the other hand, depletion of 1,5AG in the blood by treatment with an inhibitor of the renal glucose transporter SGLT2 (29, 30) should raise neutrophil numbers in these mice. To test these predictions, we turned to a mouse model of G6PC3 deficiency.…”

Section: Resultsmentioning

confidence: 99%

Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency

Veiga‐da‐Cunha

Chevalier

Stéphenne

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

127

193

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SignificanceNeutropenia presents an important clinical problem in patients with G6PC3 or G6PT deficiency, yet why neutropenia occurs is unclear. We discovered that G6PC3 and G6PT collaborate to dephosphorylate a noncanonical metabolite (1,5-anhydroglucitol-6-phosphate; 1,5AG6P) which is produced when glucose-phosphorylating enzymes erroneously act on 1,5-anhydroglucitol, a food-derived polyol present in blood. In patients or mice with G6PC3 or G6PT deficiency, 1,5AG6P accumulates and inhibits the first step of glycolysis. This is particularly detrimental in neutrophils, since their energy metabolism depends almost entirely on glycolysis. Consistent with our findings, we observed that treatment with a 1,5-anhydroglucitol-lowering drug treats neutropenia in G6PC3-deficient mice. Our findings highlight that the elimination of noncanonical side products by metabolite-repair enzymes makes an important contribution to mammalian physiology.

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Section: Resultsmentioning

confidence: 99%

Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency

Veiga‐da‐Cunha

Chevalier

Stéphenne

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

127

193

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“…SGLT2 inhibitors such as empagliflozin are anti-diabetic drugs that inhibit renal glucose reabsorption resulting in an increased urinary excretion of glucose [ 13 ]. Glucosuria decreases renal 1,5-AG reabsorption and thereby lowers its serum concentrations [ 12 , 14 ]. Treating patients with a disorder associated with fasting hypoglycemia with a glucose-lowering drug might be counterintuitive, however, no severe side effects have been reported in the first few treated patients so far [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Improved inflammatory bowel disease, wound healing and normal oxidative burst under treatment with empagliflozin in glycogen storage disease type Ib

Grünert

Elling

Maag

et al. 2020

Orphanet J Rare Dis

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Background: Glycogen storage disease type Ib (GSD Ib) is a rare inborn error of glycogen metabolism due to mutations in SLC37A4. Besides a severe form of fasting intolerance, the disorder is usually associated with neutropenia and neutrophil dysfunction causing serious infections, inflammatory bowel disease, oral, urogenital and perianal lesions as well as impaired wound healing. Recently, SGLT2 inhibitors such as empagliflozin that reduce the plasma levels of 1,5-anhydroglucitol have been described as a new treatment option for the neutropenia and neutrophil dysfunction in patients with GSD Ib. Results: We report on a 35-year-old female patient with GSD Ib who had been treated with G-CSF for neutropenia since the age of 9. She had a large chronic abdominal wound as a consequence of recurrent operations due to complications of her inflammatory bowel disease. Treatment with 20 mg empagliflozin per day resulted in normalisation of the neutrophil count and neutrophil function even after termination of G-CSF. The chronic abdominal wound that had been unchanged for 2 years before the start of empagliflozin nearly closed within 12 weeks. No side effects of empagliflozin were observed. Conclusion: SGLT2 inhibitors are a new and probably safe treatment option for GSD Ib-associated neutropenia and neutrophil dysfunction. We hypothesize that restoration of neutrophil function and normalisation of neutrophil apoptosis leads to improvement of wound healing and ameliorates symptoms of inflammatory bowel disease.

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“…A decrease of 1,5-AG has also been observed after treatment with SGLT2 inhibitor canagliflozin. 9 Wortman et al treated nondiabetic patients suffering from glycogen storage disease type Ib with empagliflozin. Empagliflozin reduced levels of 1,5-AG and prevented formation of 1,5-AG-6-phosphate, which has been suspected to cause neutropenia in these patients.…”

Section: E T T E R T O E D I T O Rmentioning

confidence: 99%

Human and mouse non‐targeted metabolomics identify 1,5‐anhydroglucitol as SGLT2‐dependent glycemic marker

Kappel

Moellmann

Thiele

et al. 2021

Clinical & Translational Med

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Model analysis of effect of canagliflozin (Invokana), a sodium–glucose cotransporter 2 inhibitor, to alter plasma 1,5-anhydroglucitol

Cited by 22 publications

References 17 publications

Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency

Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency

Improved inflammatory bowel disease, wound healing and normal oxidative burst under treatment with empagliflozin in glycogen storage disease type Ib

Human and mouse non‐targeted metabolomics identify 1,5‐anhydroglucitol as SGLT2‐dependent glycemic marker

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