title: [The protection of islet β-cells in db/db mice by combination pioglitazone and glucagon like peptide-1 treatment].
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China.
authors.forename: Lu-lu
authors.initials: LL
authors.lastname: Song
authors.forename: Jian-zhong
authors.initials: JZ
authors.lastname: Xiao
authors.forename: Wen-ying
authors.initials: WY
authors.lastname: Yang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Bin-bin
authors.initials: BB
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Pan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D007328:Insulin; D045162:Thiazolidinediones; D052216:Glucagon-Like Peptide 1; D000077205:Pioglitazone