Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism

Qi, Dake; Rodrigues, Brian

doi:10.1152/ajpendo.00453.2006

Cited by 133 publications

(87 citation statements)

References 209 publications

(224 reference statements)

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“…Thus, a reduction in intrahepatic cortisol levels via 11␤-HSD1 inhibition would be expected to decrease hepatic glycogenolysis. In addition to its glucoregulatory effects on the liver, cortisol can also regulate whole body substrate metabolism in part by sensitizing adipose tissue to the action of lipolytic hormones (47,60). Whereas epinephrine infusion caused an initial increase in circulating glycerol and NEFA levels in both groups, lipolysis was reduced by 11␤-HSD1 inhibition, which was in line with studies in adrenalectomized rats in which epinephrine-stimulated NEFA and glycerol release were impaired (22).…”

Section: Discussionsupporting

confidence: 83%

Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

Winnick

Ramnanan

Saraswathi

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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The aim of this study was to determine the effect of prolonged 11␤-hydroxysteroid dehydrogenase-1 (11␤-HSD1) inhibition on basal and hormone-stimulated glucose metabolism in fasted conscious dogs. For 7 days prior to study, either an 11␤-HSD1 inhibitor (HSD1-I; n ϭ 6) or placebo (PBO; n ϭ 6) was administered. After the basal period, a 4-h metabolic challenge followed, where glucagon (3ϫ-basal), epinephrine (5ϫ-basal), and insulin (2ϫ-basal) concentrations were increased. Hepatic glucose fluxes did not differ between groups during the basal period. In response to the metabolic challenge, hepatic glucose production was stimulated in PBO, resulting in hyperglycemia such that exogenous glucose was required in HSD-I (P Ͻ 0.05) to match the glycemia between groups. Net hepatic glucose output and endogenous glucose production were decreased by 11␤-HSD1 inhibition (P Ͻ 0.05) due to a reduction in net hepatic glycogenolysis (P Ͻ 0.05), with no effect on gluconeogenic flux compared with PBO. In addition, glucose utilization (P Ͻ 0.05) and the suppression of lipolysis were increased (P Ͻ 0.05) in HSD-I compared with PBO. These data suggest that inhibition of 11␤-HSD1 may be of therapeutic value in the treatment of diseases characterized by insulin resistance and excessive hepatic glucose production.11␤-hydroxysteroid dehydrogenase-1; cortisol; hepatic glucose production; glycogenolysis; gluconeogenesis CORTISOL IS A STEROID HORMONE with many physiological effects, including the regulation of carbohydrate, protein, and fat metabolism. At pathological concentrations, cortisol produces metabolic abnormalities similar to the metabolic syndrome, including obesity, insulin resistance, fasting hyperglycemia, hypertension, and dyslipidemia (2,42,56,58). In vivo cortisol action can be modified by 11␤-hydroxysteroid dehydrogenase-1 (11␤-HSD1), an enzyme that converts intracellular cortisone into active cortisol without necessarily modifying plasma cortisol concentrations (4, 6, 59). Liver (55, 57) and adipose (30, 33) 11␤-HSD1 activity has been shown to be elevated in obese humans with type 2 diabetes mellitus and the metabolic syndrome, and an intracellular Cushings-like state may contribute to these abnormalities (28, 32). In mice, hepatic 11␤-HSD1 overexpression can increase hepatic lipid flux, thereby causing dyslipidemia and insulin resistance (46), whereas overexpression in adipose tissue causes obesity, impaired glucose tolerance, and hypertension (35, 36). Conversely, when the enzyme is knocked out or acutely inhibited, mouse models of diabetes are protected against the manifestations of the metabolic syndrome (1, 31, 43). Together, these data demonstrate an overarching ability of dysregulated cortisol metabolism to generate a phenotype similar to that of type 2 diabetes and illustrate the potential therapeutic value of 11␤-HSD1 inhibition in the treatment of insulin resistance.Cortisol has potent effects on the glucoregulatory actions of hormones that regulate hepatic glucose production (HGP). For example, cortisol has been...

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Section: Discussionsupporting

confidence: 83%

Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

Winnick

Ramnanan

Saraswathi

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Although glucocorticoids could produce insulin resistance in mammal and avian (Qi & Rodrigues 2007;Yuan et al 2008) and the dexamethasone-induced muscle size decreases were not affected by insulin in this study, the appropriate exogenous insulin could partly reverse the dexamethasone-induced ultrastructural muscle damage. The discriminatory effects of dexamethasone and the discriminatory interactions of insulin-dexamethasone on the ultrastructure of skeletal muscle and cardiac muscle in chicks suggested that the interactive complexity of endogenous or exogenous glucocorticoids and insulin.…”

Section: Discussionmentioning

confidence: 55%

“…However, excessive insulin is hazardous to health by causing hypoglycemia. Moreover, in some cases, glucocorticoids produced whole body insulin resistance in mammal and avian (Qi & Rodrigues 2007;Yuan et al 2008). The functional complexity of glucocorticoids and insulin means the diversity of their interaction.…”

Section: Introductionmentioning

confidence: 99%

Effect of insulin on dexamethasone-induced ultrastructural changes in skeletal and cardiac muscle

Qin

Yang

et al. 2012

Biologia

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Glucocorticoids help animals respond to stressors but excessive glucocorticoids cause muscle atrophy, while insulin can promote anabolism and growth. In order to compare the glucocorticoids-induced ultrastructural changes between skeletal muscle and cardiac muscle, and investigate the preventive effects of insulin on the changes, eighteen male chicks with similar initial weight were randomly divided into three groups. The two test groups were respectively treated with high-dose dexamethasone alone or together with low-dose insulin by intraperitoneal injection, and the control group was treated with an equal volume of saline solution. The experiment lasted for ten days, and then the body weight, muscle size and ultrastructure in skeletal and cardiac muscles of twelve chicks were qualitatively or quantitatively analyzed. The results showed that high-dose dexamethasone induced obvious skeletal and cardiac muscle atrophy. The differences of ultrastructural changes between skeletal muscle and cardiac muscle (such as for the former or the latter, the intermyofibrillar-and-interfilamentary spaces reducing or enlarging, the mitochondria swelling seriously or enlarging lightly, the myofibril filaments compacting or loosing) suggested that dexamethasone induced skeletal and cardiac muscle atrophy by different mechanisms. Low-dose insulin did not affect the dexamethasone-induced decreases of body weight and skeletal muscle size, but alleviated lightly the dexamethasone-induced ultrastructural changes in skeletal muscle. Different from skeletal muscle, low-dose insulin almost resisted the dexamethasone-induced ultrastructural changes in cardiac muscle.

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“…As glucocorticoids and mineralocorticoids have similar affinity for MR, it is possible that MR blockade decreases clearance of cortisol, leading to impaired insulin action in numerous tissues such as skeletal muscle, adipose, hepatic and cardiovascular tissues, 43 whole-body insulin resistance and impaired glucose homeostasis. Glucocorticoids in turn are known to cause insulin resistance through numerous mechanisms, including increased fatty acids oxidation, 43 decreased insulin-mediated glucose uptake in skeletal muscle, 44 decreased serine phosphorylation of Akt/protein kinase B (PKB), 45 impaired insulin receptor tyrosine phosphorylation and insulin receptor substrate 1 (IRS-1) expression, 46 as well as increased hepatic glucose output. 47 The findings of augmented Ang II and cortisol during MR block might explain not only the deleterious effects on insulin sensitivity, but also the lack of benefit in terms of endothelial function observed in these studies.…”

Section: Raas Inhibition In the Clinical Settingmentioning

confidence: 99%

Role of aldosterone and angiotensin II in insulin resistance: an update

Lastra-Lastra

Sowers

Restrepo-Erazo

et al. 2009

Clinical Endocrinology

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SummaryThe role of the Renin-Angiotensin-Aldosterone system (RAAS) on the development of insulin resistance and cardiovascular disease is an area of growing interest. Most of the deleterious actions of the RAAS on insulin sensitivity appear to be mediated through activation of the Angiotensin II (Ang II) Receptor type 1 (AT 1 R) and increased production of mineralocorticoids. The underlying mechanisms leading to impaired insulin sensitivity remain to be fully elucidated, but involve increased production of reactive oxygen species and oxidative stress. Both experimental and clinical studies also implicate aldosterone in the development of insulin resistance, hypertension, endothelial dysfunction, cardiovascular tissue fibrosis, remodelling, inflammation and oxidative stress. There is abundant evidence linking aldosterone, through non-genomic actions, to defective intracellular insulin signalling, impaired glucose homeostasis and systemic insulin resistance not only in skeletal muscle and liver but also in cardiovascular tissue. Blockade of the different components of the RAAS, in particular Ang II and AT 1 R, results in attenuation of insulin resistance, glucose homeostasis, as well as decreased cardiovascular disease morbidity and mortality. These beneficial effects go beyond to those expected with isolated control of hypertension. This review focuses on the role of Ang II and aldosterone in the pathogenesis of insulin resistance, as well as in clinical relevance of RAAS blockade in the prevention and treatment of the metabolic syndrome and cardiovascular disease.

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Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism

Cited by 133 publications

References 209 publications

Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

Effect of insulin on dexamethasone-induced ultrastructural changes in skeletal and cardiac muscle

Role of aldosterone and angiotensin II in insulin resistance: an update

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