Effect of Sitagliptin and Exendin-4 on Metabolic Homeostasis in Rats with Dietary-Induced Insulin Resistance

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

New Orleans, Estados Unidos

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. F-induced changes    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±SEM; n= 20 rats each group.*P< 0.05 compared with its corresponding control. 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