Effects of Sitagliptin Combined with GTS-21 on Improving Glycemic Control and Diabetic Nephropathy by Anti-Apoptosis in Lepr^db/db Mice.

Authors

Weikun Tian, Wenzhao Wang, Shuo Tang, Liye Su, Robert Cooney, Xinghan Tian, Qinghe Meng

Published in

European journal of pharmacology. Pages 179426. Oct 14, 2026. Epub Oct 14, 2026.

Abstract

Activation of α7 nicotinic acetylcholine receptor (α7nAChR) by GTS-21 engages the cholinergic anti-inflammatory pathway (CAP). This study investigated adding GTS-21 to sitagliptin, a DPP-4 inhibitor used to increase endogenous GLP-1, confers additional benefit over sitagliptin monotherapy on glycemic control and diabetic nephropathy (DN) in Leprdb/db mice, focusing on anti-apoptotic mechanisms.
Leptin receptor-deficient (Lepr^db/db, 8-week-old) mice were randomized into control (saline), sitagliptin (20 mg/kg), or combination (sitagliptin 20 mg/kg + GTS-21 4 mg/kg) groups for 4 weeks. Oral glucose tolerance test (OGTT), serum creatinine (Scr), blood urea nitrogen (BUN), and IL-6 were measured. Renal histology was evaluated by H&E staining. Apoptosis was assessed by TUNEL staining and cleaved caspase-3 expression. In vitro, HK-2 cells exposed to high glucose (30 mM) were treated with liraglutide (100 nM) and/or GTS-21 (20 nM) to examine apoptosis.
Combination therapy significantly improved glucose tolerance at weeks 1 and 4 (AUC reduction, P=0.0366 and P=0.0435 vs control), whereas sitagliptin alone showed no effect. Both treatments reduced Scr (P=0.0002 for combination; P=0.0101 for monotherapy), but only combination therapy attenuated renal histological injury (P=0.002) and decreased IL-6 in serum and kidney (P=0.0433 and P=0.0041). Renal apoptosis was also suppressed, with reduced TUNEL-positive cells (P=0.0043) and cleaved caspase-3 (P=0.0122). In HK-2 cells, high glucose increased cleaved caspase-3 (P=0.0324), which was attenuated by liraglutide plus GTS-21 (P=0.0320).
Add-on GTS-21 to sitagliptin improved glycemic control and attenuated diabetic nephropathy beyond sitagliptin monotherapy in Leprdb/db mice, with reduced renal inflammation and suppressed apoptosis. These findings suggest that combined activation of GLP-1 receptor and α7nAChR signaling warrants further investigation as a renoprotective strategy in diabetic nephropathy.

PMID:
42874910
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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