INTRODUCTON:
Sitagliptin, an orally available DPP-IV inhibitor developed to be used as a once daily treatment for T2DM. DPP-4 inhibitors are an oral drug class with a mode of action based on incretin physiology. The gastrointestinal hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are secreted from the intestinal L- and K-cells after a meal, respectively. They enhance insulin secretion under hyperglycemic conditions and are responsible for around 70% of the postprandial insulin secretion [1]. Inhibiton of dipeptidyl peptidase-4 (DPP-4) the key enzyme involved in the initial cleavage of both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1).The prevention of GLP-1 degradation by DPP-4 inhibition leads to an elevation of endogenous GLP-1 plasma concentrations that contributes significantly to the stimulation of insulin secretion and inhibition of glucagon secretion in a glucose dependent manner[2].Diabetic nephropathy is a major cause of end‐stage renal disease worldwide and a major indication for dialysis and transplantation[3].
The present work was carried out to study the effect of sitagliptin on experimentally induced diabetic nephropathy in rats.
MATERIAL AND METHODS
To study the effect of sitagliptin on renal functions in a model of type II diabetes mellitus, 18 male adult rats were used .They were divided into 3 groups (n=6 for each) as follows:Group I: control normal rats which received saline vehicle. Group II: diabetic group:non treated diabetic rats. Noninsulin-dependent diabetes mellitus was induced in overnight fasted rats by a single (i.p) injection of 65 mg/kg body weight STZ, 15 minute (min) after (i.p) administration of 110 mg/kg body weight of nicotinamide. STZ was dissolved in citrate buffer (pH 4.5) and nicotinamide was dissolved in normal saline. Hyperglycemia was confirmed by the elevated glucose levels in plasma, determined at 72 h and then on day 7 after injection. Animals with blood glucose concentration more than 250 mg/dl were used for the study. The rats examined on the 4th week to determine diabetic nephropathy by measuring the level of serum urea, serum creatinine and 24-h UAE [5].Group (III): diabetic rats treated by oral sitagliptin once a day by gastric tube at a dose of (10 mg/kg dissolved in distilled water) for 6 weeks from induction of diabetes mellitus [6]. Fasting blood glucose (F.B.G) was measured every week, serum urea, serum creatinine &24-h UAE were measured on the 4th & on the 7th week, finally renal blood flow by Doppler blood flowmeter & histopathologial examination of the kidney were studied at the end of the work.
STATISTICAL ANALYSIS:
Results are presented as mean standard deviation (mean SD). Statistical analysis was performed using one-way analysis of variance (ANOVA) to detect significant differences between the group means. Probability (P) values of 0.05 were considered as statistically significant.
RESULTS:
-Effect of treatment with sitagliptin (10 mg/kg/day) p.o for 6 weeks from experimental induction of diabetes mellitus by a single (i.p) injection of 65 mg/kg body weight STZ, 15 minutes (min) after (i.p) administration of 110 mg/kg body weight of nicotinamide.
Data in table (1) show that untreated diabetic group resulted in significant increase (p100%) compared to control group with significant reduction(p100% 86±2.8b
*1.1%
**↓71.3%
Serum urea
Mg/dl
28.82±1.2 83±3.4a
*>100% 30±1.3b
*4.1%
**↓63.9%
Serum creatinine
Mg/ dl
0.72±0.01 2.1±0.12a
*>100% 0.8±0.06b
*11.1%
**↓61.9%
24h UAE mg/24h 1.52±0.23 4.7±0.45a
*>100% 1.6±0.01b
*5.3%
↓**65.9%
Renal blood flow
Ml/Min 11.2±0.6 2.8±0.16a
*↓75% 10.6±0.4b
*5.4%
**↑73.6%
a: Significant difference versus control at p |
