New mechanisms of glucocorticoid-induced insulin resistance: Make no bones about it

The Journal of clinical investigation (Impact Factor: 13.22). 10/2012; 122(11). DOI: 10.1172/JCI66180
Source: PubMed


Glucocorticoids are a powerful tool used to treat a range of human illnesses, including autoimmune diseases and cancer, and to prevent rejection following organ transplantation. While lifesaving for many, they come with a steep price, often leading to obesity, insulin resistance, diabetes, and osteoporosis. In this issue of the JCI, Brennan-Speranza and colleagues provide evidence that the osteoblast-derived peptide osteocalcin is one of the drivers of the metabolic derangements associated with glucocorticoid therapy. This novel mechanism could open up new avenues for the treatment of these disorders.

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Available from: Heather Ferris, Jun 11, 2014
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    • "Res. (2015), [3] "
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    ABSTRACT: Elevated cortisol levels and dysregulated insulin-like growth factor binding protein-1 (IGFBP-1; a marker of hepatic insulin sensitivity) are both related to insulin resistance and glucose abnormalities. It is unknown whether improvement in these parameters is related to improved glucose metabolism during treatment with sitagliptin. To determine whether improved insulin sensitivity and beta-cell function during treatment with sitagliptin is related to lower cortisol levels and/or improved regulation of IGFBP-1 in patients with recent acute coronary syndrome (ACS) and newly discovered glucose abnormalities. Samples were taken from The BEta-cell function in Glucose abnormalities and Acute Myocardial Infarction (BEGAMI) trial, a double-blinded, placebo-controlled randomized clinical trial on the efficacy and safety of sitagliptin for patients with ACS and newly discovered glucose abnormalities. Cardiology departments (cardiac ICU and outpatient clinic) in two hospitals in Stockholm, Sweden. Subjects hospitalized (or recently hospitalized) for ACS, in whom an oral glucose tolerance test revealed previously unknown glucose abnormalities. Subjects were randomized to sitagliptin 100mg once daily (n=34) or placebo (n=37) for twelve weeks. Oral glucose tolerance test (OGTT) and randomization occurred after stabilization median 7days after ACS. Fasting serum cortisol and IGFBP-1 were analyzed before OGTT, around 8a.m., and after at 10a.m. The latter time point was chosen as the spread in cortisol levels around is small then, allowing improved chances to detect differences between groups. Glucose tolerance and insulin sensitivity improved in both groups, while HbA1c and indices of β-cell function improved only in the sitagliptin group as reported previously. Both groups displayed decreased cortisol levels around 10a.m. (from 338±21 to 278±14nmol/L, p=0.038, in the sitagliptin group; from 343±17 to 302±15nmol/L, p=0.017, in the placebo group), and improved correlation between fasting log-IGFBP-1 and insulin. These findings suggest that a stress-related elevation in cortisol may have negative impact on glucose tolerance in patients with recent ACS. However, improved glycemic control with sitagliptin does not appear to be related to changes in cortisol levels or hepatic insulin sensitivity as assessed by IGFBP-1. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jul 2015 · Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society
    • "Decreased levels of IRS Decreased secretion of insulin PI-103 [48] [49] [50] " Not measured PI3K/AKT/mTOR inhibitor Decreased levels of IRS Decreased secretion of insulin IC87114 [48] [49] [50] – – p110d-selective inhibitor mTOR inhibition Everolimus [8] [54] [55] [100] " ; mTORC1 inihibitor Altered activation of AKT and IRS "
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    ABSTRACT: Epidemiological and experimental evidence strongly suggests an association between type 2 diabetes mellitus and cancer. Insulin resistance, causing hyperinsulinaemia and eventually hyperglycaemia, appears to increase cancer incidence and disease progression. In addition, insulin resistance seems to reduce the efficacy of cancer therapy. Treatment with cancer therapeutics such as glucocorticoids, chemotherapy, hormonal therapies and targeted drugs can actually induce insulin resistance. The question arises whether cancer-therapy induced insulin resistance impairs anticancer treatment efficacy and disease outcome. Here, we review current literature regarding the incidence of cancer-therapy induced insulin resistance and describe the systemic and extra- and intracellular changes that occur in insulin signalling pathways and glucose metabolism. Subsequently, clinical and preclinical evidence for consequences of insulin resistance in terms of cancer progression and survival is presented. Finally, potential interventions including diabetes medication and limiting energy availability through diets and exercise are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Feb 2015 · Cancer Treatment Reviews
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    • "An impairment in glucose homeostasis was identified as one potential side effect in many patients administered GCs. Increments in insulin resistance in insulin-targeted organs, including the liver, adipose tissues, and skeletal muscle, as well as the up-regulation of gluconeogenesis in the liver are mainly involved in GC-induced hyperglycemia (Ferris and Kahn, 2012). Osteoblasts were also recently identified as novel targets that play a role in GC-induced hyperglycemia (Brennan-Speranza et al., 2012). "
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    ABSTRACT: Glucocorticoids are widely used as anti-inflammatory or immunosuppressive drugs, but often induce hyperglycemia as a side effect. Glucagon-like peptide-1 (GLP-1) is secreted from intestinal L cells and plays crucial roles in maintaining glucose homeostasis. However, the direct effects of glucocorticoids on the GLP-1 production pathway in L cells remain unclear. We investigated the effects of glucocorticoids on GLP-1 production in vitro and in vivo. In L cell lines, glucocorticoids decreased GLP-1 release and expression of the precursor, proglucagon, at protein and mRNA levels, which were inhibited by mifepristone. The administration of dexamethasone or budesonide to mice significantly decreased the mRNA expression of proglucagon in the ileum and partially decreased glucose-stimulated GLP-1 secretion. Compound A, a dissociated glucocorticoid receptor modulator, did not affect the expression of proglucagon in vitro. These results suggested that glucocorticoids directly reduced GLP-1 production at the transcriptional level in L cells through a glucocorticoid receptor dimerization-dependent mechanism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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