Early Treatment with Empagliflozin and GABA Improves β-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice

Abstract EN

While the autoimmune character of T1D (type 1 diabetes) is being challenged, it is currently recognized that inflammation plays a key role in its development.

We hypothesized that glucotoxicity could contribute to β-cell mass destruction through participation in islet inflammation.

We evaluated the potential of empagliflozin (EMPA) and GABA (gamma-aminobutyric acid) to protect β-cell mass against glucotoxicity and to increase β-cell mass after diagnosis of T1D.

Empagliflozin is a SGLT2 (sodium-dependent glucose cotransporter) inhibitor which thereby blocks glucose recapture by the kidney and promotes glucose excretion in urine.

GABA is an inhibitory neurotransmitter, which stimulates α-to-β cell transdifferentiation.

In streptozotocin-treated mice, empagliflozin and/or GABA were delivered for a period of five days or three weeks.

As compared to untreated T1D mice, EMPA-treated T1D mice had decreased FFA (free fatty acid) levels and improved glucose homeostasis.

EMPA-treated T1D mice had higher islet density, with preserved architecture, compared to T1D mice, and EMPA-treated T1D mice also differed from T1D mice by the total absence of immune cell infiltration within islets.

Islets from EMPA-treated mice were also less subjected to ER (endoplasmic reticulum) stress and inflammation, as shown by qPCR analysis.

Glucose homeostasis parameters and islet area/pancreas area ratio improved, as compared to diabetic controls, when T1D mice were treated for three weeks with GABA and EMPA.

T1D EMPA+GABA mice had higher glucagon levels than T1D mice, without modifications of glucagon area/islet area ratios.

In conclusion, empagliflozin and GABA, used in monotherapy in streptozotocin-induced diabetic mice, have positive effects on β-cell mass preservation or proliferation through an indirect effect on islet cell inflammation and ER stress.

Further research is mandatory to evaluate whether empagliflozin and GABA may be a potential therapeutic target for the protection of β-cell mass after new-onset T1D.