title: Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice.
abstract: Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone and is a new clinically available class of agents for improving of insulin resistance in both animals and humans with type 2 diabetes. These studies aimed to determine whether long-term treatment with a long-acting GLP-1 analog, exendin-4, delayed the progression of diabetes. Male db/db mice and db/m mice at 8 wk of age were treated with exendin-4 for 8 wk, whereas the control db/db mice received only vehicle. Urinary albumin excretion was significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in db/db mice that were treated with 0.5 nmol/kg exendin-4 and control db/db mice (P < 0.005). Intraperitoneal glucose tolerance test was improved in db/db mice that were treated with 1 nmol/kg exendin-4 compared with other groups (P < 0.05). Despite this, fasting blood glucose, glycated hemoglobin, and creatinine concentrations were not significantly different among db/db mice. Renal histology studies further demonstrated that glomerular hypertrophy, mesangial matrix expansion, TGF-beta1 expression, and type IV collagen accumulation and associated glomerular lipid accumulation were significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4. Furthermore, there were fewer infiltrating inflammatory cells and apoptotic cells in the glomeruli of db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in the other groups accompanied by an increase in the renal immunoreactivity of peroxisome proliferator-activated receptor alpha and GLP-1 receptor-positive cells and a decrease in 24-h urinary 8-hydroxy-deoxyguanosine levels (P < 0.01, respectively) along with decreases in lipid content. Taken together, exendin-4 treatment seems to ameliorate diabetic nephropathy together with improvement of the metabolic anomalies. These results suggest that exendin-4 could provide a therapeutic role in diabetic nephropathy that results from type 2 diabetes.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, #62 Yoido-Dong, Youngdungpo-Ku, Seoul, Korea 150-713.
authors.forename: Cheol Whee
authors.initials: CW
authors.lastname: Park
authors.forename: Hyeong Wook
authors.initials: HW
authors.lastname: Kim
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Ko
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Lim
authors.forename: Gyeong Ryul
authors.initials: GR
authors.lastname: Ryu
authors.forename: Hyun Wha
authors.initials: HW
authors.lastname: Chung
authors.forename: Sang Woo
authors.initials: SW
authors.lastname: Han
authors.forename: Seog Jun
authors.initials: SJ
authors.lastname: Shin
authors.forename: Byung Kee
authors.initials: BK
authors.lastname: Bang
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
authors.forename: Yoon Sik
authors.initials: YS
authors.lastname: Chang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D053148:Caspase 3 / Q000032:analysis; D003404:Creatinine / Q000097:blood; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin / Q000032:analysis; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007668:Kidney / Q000473:pathology; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000032:analysis; D010455:Peptides / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000032:analysis; D013599:Systole; D053773:Transforming Growth Factor beta1 / Q000032:analysis; D014688:Venoms / Q000627:therapeutic use*
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D001786:Blood Glucose; D053148:Caspase 3; D003404:Creatinine; D003849:Deoxyguanosine; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D047493:PPAR alpha; D010455:Peptides; D018027:Receptors, Glucagon; D053773:Transforming Growth Factor beta1; D014688:Venoms; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse