title: Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats.
abstract: Accumulating evidences have showed that gatifloxacin causes dysglycemia in both diabetic and non-diabetic patients. Our preliminary study demonstrated that gatifloxacin stimulated glucagon-like peptide 1 (GLP-1) secretion from intestinal cells. The aim of the study was to investigate the association between gatifloxacin-stimulated GLP-1 release and dysglycemia in both normal and streptozotocin-induced diabetic rats and explore the possible mechanisms. Oral administration of gatifloxacin (100 mg/kg/day and 200 mg/kg/day) for 3 and 12 days led to marked elevation of GLP-1 levels, accompanied by significant decrease in insulin levels and increase in plasma glucose. Similar results were found in normal rats treated with 3-day gatifloxacin. Gatifloxacin-stimulated GLP-1 release was further confirmed in NCI-H716 cells, which was abolished by diazoxide, a K(ATP) channel opener. QT-PCR analysis showed that gatifloxacin also upregulated expression of proglucagon and prohormone convertase 3 mRNA. To clarify the contradiction on elevated GLP-1 without insulinotropic effect, effects of GLP-1 and gatifloxacin on insulin release were investigated using INS-1 cells. We found that short exposure (2h) to GLP-1 stimulated insulin secretion and biosynthesis, whereas long exposure (24 h and 48 h) to high level of GLP-1 inhibited insulin secretion and biosynthesis. Moreover, we also confirmed gatifloxacin acutely stimulated insulin secretion while chronically inhibited insulin biosynthesis. All the results gave an inference that gatifloxacin stimulated over-secretion of GLP-1, in turn, high levels of GLP-1 and gatifloxacin synergistically impaired insulin release, worsening hyperglycemia.
authors.affiliation: Department of Pharmaceutics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China. chrisyu1255@yahoo.com.cn
authors.forename: Yunli
authors.initials: Y
authors.lastname: Yu
authors.forename: Xinting
authors.initials: X
authors.lastname: Wang
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Yao
authors.forename: Mengyue
authors.initials: M
authors.lastname: Hu
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D024841:Fluoroquinolones / Q000633:toxicity*; D000077734:Gatifloxacin; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000378:metabolism*; D006943:Hyperglycemia / Q000139:chemically induced* / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D052336:Proglucagon / Q000235:genetics / Q000378:metabolism; D045664:Proprotein Convertase 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D024841:Fluoroquinolones; D007328:Insulin; D012333:RNA, Messenger; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D045664:Proprotein Convertase 1; D000077734:Gatifloxacin