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.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Alzheimer Disease*/metabolism ; Diabetes Mellitus, Type 2*/drug therapy ; Diabetes Mellitus, Type 2*/metabolism ; Ketosis*/metabolism ; Sodium-Glucose Transporter 2 Inhibitors*/pharmacology; Female ; Humans ; Middle Aged ; Blood Glucose/metabolism ; Brain/metabolism ; Glutamic Acid/metabolism ; Insulin/metabolism ; Insulin, Regular, Human/metabolism ; Insulin-Like Growth Factor I/metabolism ; Neurons/metabolism ; Neurotransmitter Agents/metabolism ; Placenta Growth Factor/metabolism ; Placenta Growth Factor/pharmacology ; Receptor, Insulin/metabolism ; Signal Transduction

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 not 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-h 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.

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United States AG NIA NIH HHS

Keywords: empagliflozin; glutamate; glutamine; insulin signaling; magnetic resonance spectroscopy; neuronal-origin extracellular vesicles; β-hydroxybutyrate

0 (Blood Glucose)
HDC1R2M35U (empagliflozin)
3KX376GY7L (Glutamic Acid)
0 (Insulin)
0 (Insulin, Regular, Human)
67763-96-6 (Insulin-Like Growth Factor I)
0 (Neurotransmitter Agents)
144589-93-5 (Placenta Growth Factor)
EC 2.7.10.1 (Receptor, Insulin)
0 (Sodium-Glucose Transporter 2 Inhibitors)

Date Created: 20221111 Date Completed: 20221116 Latest Revision: 20221211

20240829

PMC9657243

10.3390/cells11213372

36359767