Acute exposure of beta-cells to troglitazone decreases insulin hypersecretion via activating AMPK.
Biochim Biophys Acta
; 1840(1): 577-85, 2014 Jan.
Article
em En
| MEDLINE
| ID: mdl-24144566
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 ß-cell dysfunction. However, the mechanism underlying the protective effect of thiazolidinediones on ß-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.CONCLUSION:
Our results suggest that troglitazone provides ß-cell "a rest" through activating AMPK and inhibiting insulin hypersecretion, and thus restores its response to glucose. GENERALSIGNIFICANCE:
These data support that AMPK activation may be an important mechanism for thiazolidinediones preserving ß-cell function.Palavras-chave
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
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Quinases
/
Cálcio
/
Cromanos
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Tiazolidinedionas
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Células Secretoras de Insulina
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Hipoglicemiantes
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Insulina
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article