title: Acute exposure of beta-cells to troglitazone decreases insulin hypersecretion via activating AMPK.
abstract: BACKGROUND
  It has been recognized that insulin hypersecretion can lead to the development of insulin resistance and type 2 diabetes mellitus. There is substantial evidence demonstrating that thiazolidinediones are able to delay and prevent the progression of pancreatic β-cell dysfunction. However, the mechanism underlying the protective effect of thiazolidinediones on β-cell function remains elusive.
  
  
  METHODS
  We synchronously detected the effects of troglitazone on insulin secretion and AMP-activated protein kinase (AMPK) activity under various conditions in isolated rat islets and MIN6 cells.
  
  
  RESULTS
  Long-term exposure to high glucose stimulated insulin hypersecretion and inhibited AMPK activity in rat islets. Troglitazone-suppressed insulin hypersecretion was closely related to the activation of AMPK. This action was most prominent at the moderate concentration of glucose. Glucose-stimulated insulin secretion was decreased by long-term troglitazone treatment, but significantly increased after the drug withdrawal. Compound C, an AMPK inhibitor, reversed troglitazone-suppressed insulin secretion in MIN6 cells and rat islets. Knockdown of AMPKα2 showed a similar result. In MIN6 cells, troglitazone blocked high glucose-closed ATP-sensitive K(+) (KATP) channel and decreased membrane potential, along with increased voltage-dependent potassium channel currents. Troglitazone suppressed intracellular Ca(2+) response to high glucose, which was abolished by treatment with compound C.
  
  
  CONCLUSIONS
  Our results suggest that troglitazone provides β-cell "a rest" through activating AMPK and inhibiting insulin hypersecretion, and thus restores its response to glucose.
  
  
  CONCLUSIONS
  These data support that AMPK activation may be an important mechanism for thiazolidinediones preserving β-cell function.
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Ruyuan
authors.initials: R
authors.lastname: Deng
authors.forename: Aifang
authors.initials: A
authors.lastname: Nie
authors.forename: Fangfang
authors.initials: F
authors.lastname: Jian
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Hongju
authors.initials: H
authors.lastname: Tang
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Shao
authors.forename: Fengying
authors.initials: F
authors.lastname: Li
authors.forename: Libin
authors.initials: L
authors.lastname: Zhou
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004594:Electrophysiology; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D007328:Insulin; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D000077288:Troglitazone; D005947:Glucose; D002118:Calcium
keywords: ACC; AMP-activated protein kinase; AMPK; ATP-sensitive K(+) channel; Beta-cell; GSIS; IFG; IGT; Insulin hyperscretion; K(ATP); Kv; PPARγ; TZD; Troglitazone; acetyl-CoA carboxylase; glucose-stimulated insulin secretion; impaired fasting glucose; impaired glucose tolerance; peroxisome proliferator-activated receptor γ; shRNA; short hairpin RNA; thiazolidinediones; voltage-dependent potassium channel