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

Abstract

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.

Empagliflozin in children with glycogen storage disease-associated inflammatory bowel disease: a prospective, single-arm, open-label clinical trial

“…Recently, after Wortmann et al reported the use of empagliflozin for treating neutropenia and neutrophil dysfunction in GSD-Ib patients 18 , more than 230 adult or paediatric patients with GSD-Ib who received empagliflozin have been reported in more than 20 pieces of literature, including two international questionnaire studies 20 , 31 and some case reports 21 , 32 – 36 . The efficacy in these studies was assessed by clinical symptoms and the PCDAI 6 , 28 , empagliflozin has been recommended for the treatment of neutrophil dysfunction in GDS-Ib patients with or without IBD.…”

Glycogen storage disease type Ib: modern understanding of the pathogenesis of neutropenia and prospects for its treatment with empagliflozin

“…Диетотерапия при БНГ Ia и БНГ Ib идентична, но последним в связи с предрасположенностью к ВЗК необходимы дополнительные ограничения. Отказ от голодания -это первая линия лечения путем частого употребления высокоуглеводной диеты с низким содержанием жира, дополненной сырым кукурузным крахмалом [2,12]. На первом году жизни ночные приемы пищи могут быть заменены непрерывным энтеральным питанием через назогастральный зонд или гастростому.…”

“…Эмпаглифлозин потенциально может быть использован также у пациентов с БНГ Ia с целью улучшения метаболических показателей, профилактики митохондриального стресса, инсулинорезистентности, неалкогольной жировой болезни печени (НАЖБП) и нефропатии [12].…”

“…Единственным эффективным методом лечения кардиомиопатии является кетогенная диета, но результат сильно зависит от приверженности пациентов [46]. Использование эмпаглифлозина возможно ввиду его благоприятного воздействия на печень и сердце [12].…”

Osteoporotic osseointegration: therapeutic hallmarks and engineering strategies

“…Other drugs that inhibit bone resorption include monoclonal antibodies targeting the receptor activator of nuclear factor-κB ligand (RANKL), calcitonin, and estrogen 9 . Bone formation-promoting drugs, as well as bifunctional drugs such as parathyroid hormone analogs, active vitamin D and its analogs, vitamin K, and romosozumab, have been widely recognized for clinical application 10 . However, systemic therapy has limitations, such as the need for treatment continuation for more than one year and the risk of osteoporotic fractures before and after discontinuation of treatment.…”