Effects of Sitagliptin Combined with GTS-21 on Improving Glycemic Control and Diabetic Nephropathy by Anti-Apoptosis in Leprdb/db Mice
- Design
- Animal study · Mixed outcome
- Match to healthy normal-weight adults aged 55–75
- Not human evidenceVERY_INDIRECT: diabetic (Leprdb/db) mice and high-glucose kidney cells; no human data.
- Could weight loss explain it?
- PossiblyNo body-weight or HbA1c data and no mediation analysis are reported; the kidney findings are not separated from the improved glucose tolerance.
- Study tier
- Study tier 4VERY_LOW: preclinical mouse and cell study.
- Assessment
- Version 2 · Two reviewers differed; settled by a recorded ruling · Oct 19, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
In diabetic mice, researchers compared saline, the DPP-4 inhibitor sitagliptin (which raises the body's own GLP-1) and sitagliptin plus GTS-21 for 4 weeks. Sitagliptin alone did not improve glucose tolerance but lowered serum creatinine; adding GTS-21 improved glucose tolerance, kidney tissue injury and inflammation markers. In kidney cells, liraglutide with GTS-21 reduced a cell-death marker. These are animal and cell results, not evidence in people.
01Findings
What the study reported
- Drugs
- Sitagliptin, Liraglutide
- Dose
- sitagliptin 20 mg/kg (mice, alone or with GTS-21 4 mg/kg); liraglutide 100 nM (HK-2 cells)
- Treatment duration
- 4 weeks
- Comparator
- control (saline); sitagliptin monotherapy
- Primary outcome
- glycaemic control (OGTT) and diabetic nephropathy markers (serum creatinine, BUN, IL-6, renal histology, apoptosis)
- Effect
- Combination therapy improved glucose tolerance at weeks 1 and 4 (P=0.0366 and P=0.0435 vs control) while sitagliptin alone showed no effect; both reduced serum creatinine (P=0.0002 combination; P=0.0101 monotherapy); only the combination attenuated renal histological injury (P=0.002) and lowered IL-6.
- 95% confidence interval
- Not extracted
- P value
- P=0.0366 and P=0.0435 (combination vs control, glucose tolerance); P=0.0002 (combination) and P=0.0101 (sitagliptin monotherapy), serum creatinine
- Follow-up
- Not stated
- Adverse events
- not reported in abstract
- Limitations
- Mouse and cell study of 4 weeks' treatment with group sizes not stated; the GLP-1 receptor agonist was tested only in cells, and the in vivo exposure is a DPP-4 inhibitor.
Who was studied
- Obesity status
- not reported in abstract
- Diabetes status
- diabetes required (Leprdb/db diabetic mouse model)
- Cvd status
- not reported in abstract
- Ckd status
- diabetic nephropathy required (Leprdb/db mouse model)
- Baseline condition
- diabetic nephropathy in leptin receptor-deficient (Leprdb/db) mice; high-glucose HK-2 cells
- Inclusion exclusion
- 8-week-old Leprdb/db mice
Study quality details
- Study design
- Preclinical (animal)
- Sample size
- not extracted
- Randomization
- yes
- Blinding
- not stated
- Comparator
- control (saline); sitagliptin monotherapy
- Follow up duration
- not stated
- Outcome type
- mixed
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- VERY_INDIRECT
- Statistical precision
- P values reported; no CI reported; group sizes not stated
- Risk of bias
- not assessed
- Funding conflicts
- unclear
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- not stated in source
- Sponsor role
- not reported in abstract
- Author conflicts
- One author reports employment by SUNY Upstate Medical University; the other authors declare no competing interests.
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[OBJECTIVE] 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. [METHODS] Leptin receptor-deficient (Leprdb/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. [RESULTS] 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). [CONCLUSIONS] 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.