Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs.

Rebrin, Kerstin; Steil, Garry M.; Mittelman, Steven D.; Bergman, Richard N.

doi:10.1172/jci118846

Cited by 270 publications

(205 citation statements)

References 57 publications

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“…It is possible that rosiglitazone has direct effects on the liver, since thiazolidinediones have been shown to modify GR-mediated effects in cell culture (42). However, it is widely supposed that effects on hepatic metabolism are mediated by factors released from adipose tissue that are altered by thiazolidinediones, such as resistin (43), free fatty acids (44) or glucocorticoids (45). Which of these might influence GR expression in liver has not been tested, but this is an important question for further study.…”

Section: Discussionmentioning

confidence: 99%

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Cleasby

Livingstone²,

Nyirenda³

et al. 2003

European Journal of Endocrinology

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Objective: Glucocorticoids may contribute to the association between retarded growth in utero and insulin resistance in adulthood. Administration of dexamethasone (dex) to pregnant rats results in low birth weight offspring, which develop glucose intolerance, hyperinsulinaemia and hypercorticosteronaemia. This may be explained by tissue-specific differences in expression of glucocorticoid receptors (GR) in adult offspring: GR is increased in visceral fat and liver, and decreased in hippocampus and soleus muscle. However, cause and effect between altered GR expression, hypercorticosteronaemia, and hyperinsulinaemia remains to be established. Design and methods: Rats were treated with dex (100 mg/kg per day) or saline during the third week of pregnancy. In 5-8-month-old male offspring, GR expression in insulin target tissues was quantified by RNase protection assay in rats that were adrenalectomised (ADX group), sham operated (SHAM group), or adrenalectomised with supra-physiological corticosterone replacement (CORT group) (n ¼ 7 -8 per group), and in rats treated orally with vehicle, metformin (43 mg/kg per day) or rosiglitazone (1 mg/kg per day), after 3 weeks. Results: Manipulation of corticosterone concentration did not affect GR mRNA in skeletal muscle or adipose. In liver, sham-operated animals showed lower GR mRNA, but there was no difference between adrenalectomised and hypercorticosteronaemic animals (SHAM 0:11^0:01 ratio to b-actin, vs ADX 0:22^0:02; CORT 0:23^0:02; (values expressed as means^S.E.M.), P , 0:001). Rosiglitazone reduced GR mRNA by ,30% in liver of dex-and saline-treated offspring ðP , 0:05Þ; but had no effect on GR in adipose and skeletal muscle. Metformin abolished the 38% up-regulation of liver GR mRNA induced by antenatal dex and also reduced GR mRNA preferentially in muscle of dex-treated animals (0:14^0:01 vs 0:10^0:01; P ¼ 0:03). Conclusions: We conclude that neither hypercorticosteronaemia nor hyperinsulinaemia are sufficient to cause the changes in GR expression in dex-programmed rats, implying that these changes may be primary in determining the programmed insulin resistant phenotype. Normalisation of GR expression by metformin may be important in the mode of action of this anti-diabetic agent and may be especially useful to reverse-programmed up-regulation of GR.

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Section: Discussionmentioning

confidence: 99%

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Cleasby

Livingstone²,

Nyirenda³

et al. 2003

European Journal of Endocrinology

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“…Thus, artificial elevation of circulating FFA levels impairs the ability of insulin to stimulate overall body glucose disposal and also interferes with insulin's ability to inhibit hepatic glucose production (6,19,20). Although there is significant literature on this subject, the precise mechanisms of the lipotoxic effect on insulin action are not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Thiazolidinedione Treatment Prevents Free Fatty Acid–Induced Insulin Resistance in Male Wistar Rats

Hevener

Reichart²,

Olefsky³

2001

Diabetes

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“…Chronic effects of insulin are primarily mediated by direct mechanisms via hepatic insulin receptor (Insr)/phosphatidylinositol 3-kinase/forkhead box O1 (FoxO1) signaling to suppress the expression of gluconeogenic enzymes (4). Acute effects of insulin on HGP are mediated by both direct and indirect mechanisms (5)(6)(7)(8)(9). Multiple mechanisms have been proposed to account for insulin's indirect effects on HGP, including glucagon (10,11), gluconeogenic substrates released from muscle (12) and fat (13), and hypothalamic signals (9,14).…”

mentioning

confidence: 99%

Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice

et al. 2007

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OBJECTIVE-Adiponectin increases insulin sensitivity and contributes to insulin's indirect effects on hepatic glucose production.RESEARCH DESIGN AND METHODS-To examine adiponectin's contribution to insulin action, we analyzed adiponectin levels and activation of AMP-activated protein kinase (AMPK) in insulin receptor transgenic/knockout mice (L1), a genetic model of resistance to insulin's indirect effects on hepatic glucose production.RESULTS-In euglycemic, insulin-resistant L1 mice, we detected hyperadiponectinemia with normal levels of adiponectin receptor-1 and -2. Moreover, adiponectin administration is unable to lower glucose levels or induce activation of AMPK, consistent with a state of adiponectin resistance. In a subset of hyperglycemic L1 mice, we observed decreased mRNA expression of AdipoR2 in liver and muscle, as well as decreased peroxisome proliferator-activated receptor (PPAR)␣ target gene expression in liver, raising the possibility that deterioration of adiponectin/AdipoR2 signaling via PPAR␣ activation contributes to the progression from compensated insulin resistance to diabetes. In contrast, we failed to detect changes in other markers of the systemic or local inflammatory response.CONCLUSIONS-These data provide evidence for a mechanism of adiponectin resistance and corroborate the notion that adiponectin potentiates hepatic insulin sensitivity. Diabetes

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Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs.

Cited by 270 publications

References 57 publications

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Thiazolidinedione Treatment Prevents Free Fatty Acid–Induced Insulin Resistance in Male Wistar Rats

Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice

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