Effect of Sitagliptin and Exendin-4 on beta cells and Glucose Homeostasis in Rats with Fructose-Induced Insulin Resistance

DEL ZOTTO HÉCTOR; BORELLI MARÍA INÉS; MAIZTEGUI BÁRBARA; MADRID VIVIANA; RASCHIA MARÍA AGUSTINA; FLORES LUIS EMILIO; MASSA MARÍA LAURA; FRANCINI FLAVIO; GAGLIARDINO JUAN JOSÉ

New Orleans, Louisiana.

Congreso; American Diabetes Association’s 69th Scientific Sessions; 2009

Asociacion Americana de Diabetes

Fructose (F) administration to normal rats for 3 weeks increases serum triglyceride (T) and insulin (I) levels and insulin resistance (IR), impairing glucose (G) tolerance. We studied the effect of exendin-4 (E) and sitagliptin (S) on these abnormalities and beta-cell mass. 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 rats received E (0.35 nmol/kg/day; CE and FE) or S (115 mg/rat/day; CS and FS). Fifteen-h fasted animals were bled at 0, 30 and 120 min after an oral G load (1g/kg) to measure G, T and I concentrations, and HOMA-IR. Rats were sacrificed and pancreases removed for immunocytochemical studies. F had a significantly larger body weight increase than C (28.2±3 vs. 66.6±3.9 g); this increase was significantly lower (p< 0.05) in FE (13.6±4.1 g) and FS (13.6±2.8 g). While all groups had comparable blood G levels, F had significantly higher T (101.7±10.8 vs. 42.4±0.7mg/dl) and I (0.98±0.19 vs. 0.33±0.0ng/ml) levels, attaining almost C values in FE (0.7±0.17 ng/ml) and FS (0.35±0.09ng/ml). HOMA-IR was significantly higher in F (4.9:0± vs. 2.0±0.4) becoming close to C values after E and S treatment. The area under the G curve was significantly higher in F (5595±259 vs. 3660±395). These values returned to near C levels in FE (2480±401) and FS (3183±230). F increased significantly (p<0.05) islet number (1.9 ±0.4 vs. 1.1±0.0 i/mm2) and beta-cell replication (4.3±0.9 vs. 0.9±.04 %). In C rats, E increased significantly islet number (2.2±0.4 vs. 1.1± i/mm2), beta-cell mass (10.4±1.9 vs. 3.9±0.9 mg) and beta-cell replication rate (4.0±0.9 vs. 0.9±0.4%), lowering the rate of beta-cell apoptosis (0.1±0.0 vs. 0.2±0.0%). In F, E increased beta-cell mass (11.9±3.2 vs. 3.8±0.7 mg) and decreased beta-cell apoptosis (0.1±0.0 vs. 0.3±0.0). S showed a similar trend, attaining significance only in C islet number (1.8±0.2 vs. 1.1±0.01) and F apoptosis rate (0.2±0.01 vs. 0.3±0.02). In conclusion, incretins promote an increase in â-cell mass by increasing replication and decreasing apoptosis. These changes contribute to recover normal G homeostasis in rats with F-induced IR.