[The protection of islet β-cells in db/db mice by combination pioglitazone and glucagon like peptide-1 treatment].

OBJECTIVES: To evaluate the effect of combination of liraglutide, a glucagon-like peptide-1 analogue and pioglitazone, an insulin sensitizer, on diabetic db/db mice.

METHODS: Thirty-five 8-week old male db/db mice were divided into control group (n = 8), pioglitazone group (n = 9), liraglutide group (n = 9) and combined therapeutic group (n = 9), which was given normal saline 0.1 ml, 2/d, pioglitazone 24 mg×kg(-1)×d(-1) (feed contained 0.02% pioglitazone) + normal saline 0.1 ml, 2/d, liraglutide 300 mg/kg, 2/d, and pioglitazone 20 mg×kg(-1)×d(-1) (feed contained 0.02% pioglitazone) + liraglutide 300 mg/kg, 2/d, respectively. Liraglutide were given at 8:00 and 16:00 via subcutaneous injection after having been diluted with sterilized normal saline. Effect on glucose, lipid metabolism and islet β-cell preservation were assessed after 4 weeks. Oneway ANOVA was adopted for statistical analysis.

RESULTS: Combination therapy displayed promising anti-hyperglycemic [glycosylated hemoglobin A1c: (4.5 ± 0.6)% vs. (7.3 ± 0.4)%, P < 0.001]. Glucose tolerance were improved assessed by area under curve (AUC) of glucose by intraperitoneal glucose tolerance test (IPGTT) [(1814 ± 91) mmol×min×L(-1) vs. (4042 ± 183) mmol×min×L(-1), P < 0.001]; insulin release response to glucose were also preserved as AUC of insulin by IPGTT was higher [(1639 ± 372) µg×min×L(-1) vs.(834 ± 201) µg×min×L(-1)]. Combination therapy also reduced circulated free fatty acids and TG [(202.0 ± 20.4) µmol/L vs. (272.5 ± 21.7) µmol/L, (0.81 ± 0.28) mmol/L vs. (1.35 ± 0.21) mmol/L], and increased plasma adiponectin [(16.7 ± 2.0) mg/L vs. (10.2 ± 1.8) mg/L]. All P value < 0.05. Islet immunohistochemistry showed that combination therapy significantly increased insulin positive area were [(59.5 ± 1.5)% vs. (22.4 ± 1.5)%] and ratio of Brdu positive β-cells was three folds than vehicle-treated mice [(2.4 ± 0.5)% vs. (0.8 ± 0.3)%], both greater than each single treatment. Combined therapy significantly improved islet β cell/α cell distribution, which led to islet recovery.

CONCLUSIONS: Combined therapy improves glucose and lipid metabolism, preserves islet β-cell function and stimulates β-cell proliferation, greater than either liraglutide or pioglitazone treatment alone.