Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice.
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.
Park
Cheol Whee
CW
Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, #62 Yoido-Dong, Youngdungpo-Ku, Seoul, Korea 150-713.
Kim
Hyeong Wook
HW
Ko
Seung Hyun
SH
Lim
Ji Hee
JH
Ryu
Gyeong Ryul
GR
Chung
Hyun Wha
HW
Han
Sang Woo
SW
Shin
Seog Jun
SJ
Bang
Byung Kee
BK
Breyer
Matthew D
MD
Chang
Yoon Sik
YS
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*
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