Effect of Sitagliptin and Exendin-4 on metabolic homeostasis in rats with dietary-induced insulin resistance

MASSA ML; FRANCINI F; MAIZTEGUI B; MADRID V; RASCHIA A; FLORES L; DEL ZOTTO H; BORELLI MI; GAGLIARDINO JJ

New Orleans USA

Congreso; 69th Scientific Sessions American Diabetes Association; 2009

American Diabetes Association

We studied the effect of sitagliptin (S) and exendin-4 (E) on fructose-induced increase of serum triglyceride and insulin levels, insulin resistance (IR) and liver enzymes, and impairment of glucose tolerance. Normal male Wistar rats received a standard commercial diet and water without (control, C) or with 10% F for 3 weeks. Simultaneously, C and F received E (0.35 nmol/kg/day; CE and FE) or S (115mg/rat/day; CS and FS). Fifteen h fasted animals were bled at 0, 30 and 120 min after an oral glucose (1g/kg) load to measure glucose, triglyceride and insulin concentrations, and HOMA-R. Animals were sacrificed removing the liver to determine glucokinase (GK) and glucose-6-phosphate dehydrogenase (G6PDH) activity. No significant differences in food consumption were recorded among groups. Body weight of F rats increased significantly as compared to C but it was significantly lower in FE and FS. Comparable blood glucose levels were measured in all groups, but F had significantly higher triglyceride and insulin levels, which decreased to almost control values in FE and FS. HOMA-R was significantly higher in F (4.9± vs. 2.0±0.4) becoming close to C values after E and S treatment. The glucose area under the curve (AUC) was significantly higher in F, returning to near control levels in FE (2480±401) and FS (3183±230). FS had higher hepatic GK (6.8±0.2 vs 3.8±0.3 mU/mg protein, p<0.001) and G6PDH (0.17±0.01 vs 0.06±0.01 mU/mg protein, p<0.001) activity. These high values returned almost to control levels in FE and FS rats. Our results show a new therapeutic profile of E and S effects: they decrease IR and improve lipid and glucose metabolism as well as liver enzyme levels.   Glucose (mg/dl) Triglyceride (mg/dl) Insulin (ng/ml) HOMA-R OGT (AUC) C 80.8±2.3 42.4±0.7 0.33±0.08 2.00±0.4 3660±395 CE 75.3±1.7 42.5±5.8 0.25±0.06 1.18±0.2 2915±499 CS 80.1±2.9 56.2±8.8 0.31±0.06 1.39±0.3 3034±627 F 89±4 101.7±10.8* 0.98±0.19* 4.97±1.2* 5595±259 FE 75.5±3.2 64.7±7.7* 0.7±0.17 3.52±1.0 2480±401 FS 84.3±4.8 60.2±4.5* 0.35±0.09* 1.58±0.4* 3183±230 Results are means ± S.E.M; n= 20 rats each group. *P< 0.05 compared with its corresponding control. Results are means ± S.E.M; n= 20 rats each group. *P< 0.05 compared with its corresponding control.