Empagliflozin Induced Ketosis, Upregulated IGF-1/Insulin Receptors and the Canonical Insulin Signaling Pathway in Neurons, and Decreased the Excitatory Neurotransmitter Glutamate in the Brain of Non-Diabetics

Abstract

Sodium-glucose cotransporter-2 inhibitors (SGLT2is), such as empagliflozin, lower blood glucose in type 2 diabetes mellitus and improve cardiorenal outcomes regardless of diabetes presence. Whether SGLT2is exert any effects on the brain's metabolism has 6not been studied. We conducted a single-arm clinical trial to investigate the effects of once daily administration of oral empagliflozin (25 mg) for 14 days on systemic and brain metabolism in 21 non-diabetics aged 55 years old or older. Empagliflozin lowered circulating insulin and elevated β-hydroxybutyrate over 34-hour periods, both following its first administration and after 14 days of daily administration, with minor alterations in glucose homeostasis. Levels of phosphorylated insulin-like growth factor-1 receptor (pIGF-1R), phosphorylated insulin receptor (pIR), phosphorylated-in-tyrosine insulin receptor substrate-1 (pY-IRS-1), and phosphorylated protein kinase B or AKT (pAKT) were increased in extracellular vesicles enriched for neuronal origin (NEVs) following the first empagliflozin administration, but not after 14 days. Our finding of IGF-1R upregulation in NEVs is promising because several post-mortem and epidemiological studies support the idea that upregulation of IGF signaling may protect against Alzheimer’s disease (AD). Moreover, our finding showing activation of insulin signaling and, in particular, the canonical pathway (pIR, pY-IRS-1, pAKT) in NEVs is important because such changes have been repeatedly associated with neuronal survival. Using brain magnetic resonance spectroscopy (MRS), we detected decreased concentrations of the excitatory neurotransmitter glutamate and its precursor glutamine after empagliflozin administration. This finding is also encouraging since glutamatergic excitotoxicity has long been implicated in AD pathology. Overall, our findings may motivate the repurposing of SGLT2is for use in AD and other, related diseases that are characterized by downregulation of IGF-1/insulin signaling in neurons and excitotoxicity.

Efficacy of empagliflozin as adjunctive therapy to citalopram in major depressive disorder: a randomized double-blind, placebo-controlled clinical trial

“…This outcome can be attributed to the various properties of empagliflozin as an SGLT2 inhibitor, particularly its ability to inhibit the oxidative-inflammatory-apoptosis pathway, and other hormonal effects such as a decrease in serum ACTH levels. Additionally, empagliflozin has neurotransmitter effects such as reducing glutamate concentration [ 60 ]. To the best of our knowledge, this study is the first clinical trial that investigates the effect of add-on treatment of empagliflozin with its complex set of neuroreceptor, neuroinflammatory and neurohormonal effects on clinical depression symptoms.…”

Profiling and Cellular Analyses of Obesity-Related circRNAs in Neurons and Glia under Obesity-like In Vitro Conditions

“…In microglia, scavenger receptor-related genes, such as macrophage scavenger receptor 1 ( Msr1 ) and CD36, are related to low-density Chol uptake [ 72 ], amyloid beta phagocytosis [ 80 ], and lipid metabolism homeostasis [ 81 ]. In microglia and astrocytes, fatty acid oxidation-related genes, such as Ppara and Pgc1a , are associated with autophagy, neuronal proliferation, memory formation [ 82 , 83 ], microglia polarization [ 84 ], and apoptosis [ 85 ]. In astrocytes, glutamate transporter-related genes, such as Gls , are related to excitatory neurotransmitter secretion and synapse transmission [ 86 ].…”

Targeting immunometabolic pathways for combination therapy in Alzheimer's disease

“…In human studies, a recent report of >11,000 cases with T2D and dementia compared with >46,000 T2D controls found that SGLT2i treatment was associated with a 42% reduced risk of dementia, the largest effect of any anti‐diabetic medication 44 . A recent open label study in cognitively normal older non‐diabetic adults also showed that empagliflozin reduced cerebral glutamate levels assessed with magnetic resonance spectroscopy, and acutely increased markers of insulin signaling in neuronal origin‐enriched extracellular vesicles 46 …”