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Interactive influences of peroxisome proliferator-activated receptor alpha activation and glucocorticoids on pancreatic beta cell compensation in insulin resistance induced by dietary saturated fat in the rat.

Abstract：

AIMS/HYPOTHESIS:We sought to elucidate whether excess glucocorticoids and increased dietary lipids act synergistically to impair glucose tolerance and, if so, whether activation of peroxisome proliferator-activated receptor alpha (PPARalpha) has an adverse or beneficial effect on glucose tolerance. METHODS:Dexamethasone (100 microg kg(-1) body weight day(-1); 5 days) was administered to insulin-resistant rats fed a high-saturated-fat (HF) diet for 4 weeks. The PPARalpha agonist WY14643 was administered (50 mg kg(-1) body weight intraperitoneally) 24 h before sampling. Glucose-stimulated insulin secretion (GSIS) was assessed in vivo after an acute glucose bolus injection, and in vitro using step-up and step-down islet perifusions. RESULTS:Although neither PPARalpha activation nor dexamethasone alone affected fasting glycaemia in the HF group, dexamethasone in combination with PPARalpha activation elicited marked postabsorptive hyperglycaemia. Dexamethasone treatment of HF rats had little effect on GSIS after an acute glucose challenge in vivo, but induced glucose intolerance. PPARalpha activation augmented GSIS in dexamethasone-treated HF rats in vivo, restoring glucose tolerance. Contrasting with data obtained in vivo, greatly enhanced peak rates of GSIS were observed ex vivo in perifusions of islets from dexamethasone-treated HF rats compared with those from untreated HF rats, an effect attenuated by antecedent PPARalpha activation. CONCLUSIONS/INTERPRETATION:The study demonstrates that glucocorticoid excess precipitates the development of glucose intolerance in rats maintained on a high-saturated-fat diet. It does this by interrupting the negative feedback loop between insulin sensitivity and secretion in vivo, such that further enhancement of compensatory insulin secretion is not possible. PPARalpha activation restores the coupling between insulin secretion and action.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Holness MJ,Smith ND,Greenwood GK,Sugden MC

doi

10.1007/s00125-005-1894-0

subject

Has Abstract

pub_date

2005-10-01 00:00:00

pages

2062-8

issue

eissn

0012-186X

issn

1432-0428

journal_volume

pub_type

杂志文章

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Interactive influences of peroxisome proliferator-activated receptor alpha activation and glucocorticoids on pancreatic beta cell compensation in insulin resistance induced by dietary saturated fat in the rat.