Doms № 4 -2022

Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: a glucose-independent effect through AMPK signaling
Noha F. Abdelkader, Marawan A. Elbaset, Passant E. Moustafa, Sherehan M. Ibrahim

DOI: 10.1007/s12272-022-01391-5


Abstract Diabetic peripheral neuropathy (DPN) represents a severe microvascular condition that dramatically affects diabetic patients despite adequate glycemic control, result-ing in high morbidity. Thus, recently, anti- diabetic drugs that possess glucose-independent mechanisms attracted attention. This work aims to explore the potentiality of the selective sodium-glucose cotransporter-2 inhibitor, empagli-flozin (EMPA), to ameliorate streptozotocin-induced DPN in rats with insight into its precise signaling mechanism. Rats were allocated into four groups, where control animals received vehicle daily for 2 weeks. In the remaining groups, DPN was elicited by single intraperitoneal injections of freshly prepared streptozotocin and nicotinamide (52.5 and 50 mg/kg, respectively). Then EMPA (3 mg/kg/p.o.) was given to two groups either alone or accompanied with the AMPK inhibitor dorsomorphin (0.2 mg/kg/i.p.). Despite the non-significant anti-hyperglycemic effect, EMPA improved sciatic nerve histopathological alterations, scoring, myeli-nation, nerve fibers’ count, and nerve conduction velocity. Moreover, EMPA alleviated responses to different nocicep-tive stimuli along with improved motor coordination. EMPA modulated ATP/AMP ratio, upregulated p-AMPK while reducing p-p38 MAPK expression, p-ERK1/2 and conse-quently p-NF-κB p65 as well as its downstream mediators (TNF-α and IL-1β), besides enhancing SOD activity and lowering MDA content. Moreover, EMPA downregulated mTOR and stimulated ULK1 as well as beclin-1. Likewise, EMPA reduced miR-21 that enhanced RECK, reducing MMP-2 and -9 contents. EMPA’s beneficial effects were almost abolished by dorsomorphin administration. In con-clusion, EMPA displayed a protective effect against DPN independently from its anti-hyperglycemic effect, probably via modulating the AMPK pathway to modulate oxidative and inflammatory burden, extracellular matrix remodeling, and autophagy.

Keywords: Empagliflozin, Dorsomorphin, Diabetic peripheral neuropathy, AMPK, p38 MAPK, mTOR.



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