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.