Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice

Silha, Josef V.; Gui, Yaoting; Murphy, Liam

doi:10.1152/ajpendo.00014.2002

Cited by 89 publications

(79 citation statements)

References 33 publications

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“…In obesity, AT Timp1 significantly increases (38,39), and mice injected with TIMP1 develop insulin resistance and systemic fatty acid overload (38). IGFBP3-treated adipocytes exhibit insulin resistance (36), and mice overexpressing Igfbp3 exhibit decreased glucose uptake in AT and muscle (37). Mice lacking Spp1 (osteopontin) are less likely to develop obesity and insulin resistance and exhibit less AT macrophage infiltration (34,35).…”

Section: Discussionmentioning

confidence: 99%

Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

Elks

Zhao

Grant

et al. 2016

Journal of Biological Chemistry

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Oncostatin M (OSM) is a multifunctional gp130 cytokine.Although OSM is produced in adipose tissue, it is not produced by adipocytes. OSM expression is significantly induced in adipose tissue from obese mice and humans. The OSM-specific receptor, OSM receptor ␤ (OSMR), is expressed in adipocytes, but its function remains largely unknown. To better understand the effects of OSM in adipose tissue, we knocked down Osmr expression in adipocytes in vitro using siRNA. Adipose tissue (AT) 3 plays an important role in the maintenance of systemic metabolic homeostasis. Adipokine production is a critical AT function and is highly regulated in several physiological and pathological conditions, including AT expansion, insulin resistance, obesity, and type 2 diabetes. Obesity is closely associated with a chronic, low grade inflammatory state characterized by macrophage infiltration of AT and subsequent proinflammatory adipokine expression (1, 2). Adipokine modulation has been shown to be a key contributor to the insulin resistance often observed in obesity.Cytokines in the interleukin-6 (IL-6)/gp130 family include IL-6, IL-11, leukemia inhibitory factor, cardiotrophin-1, ciliary neurotrophic factor, and oncostatin M (OSM) (3). The gp130 cytokines regulate several physiological and biological processes (4), and some of these cytokines, namely IL-6 and ciliary neurotrophic factor, have profound effects on metabolism and as such have been previous targets for obesity treatment (5-8). Although originally identified for its ability to inhibit tumorigenesis (9), OSM modulates a host of other biological processes that are cell type-dependent (10). Elevated OSM levels have been observed in a variety of inflammatory diseases in humans, including rheumatoid arthritis and atherosclerosis (11,12). OSM also has important roles in hepatic insulin resistance and steatosis (13), inflammation (14), and cardiomyocyte remodeling (15) and has several well characterized actions in the liver (16 -18). Unlike other gp130 cytokines, OSM has its own specific receptor subunit (OSM receptor ␤; hereafter referred to as OSMR) that heterodimerizes with gp130 to create the functional OSM receptor complex, and this complex is responsible for the majority of OSM effects (19).Adipocytes and AT are highly responsive to OSM (20), and Osmr is highly expressed in AT compared with other tissues (21, 22). Significant induction of both Osm and Osmr expres-* This work was supported in part by National Institutes of Health Grant R01DK052968 (to J. M. S.) and National Institutes of Health Nutrition Obesity Research Centers Grant P30DK072476 entitled "Nutritional Programming: Environmental and Molecular Interactions." The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Section: Discussionmentioning

confidence: 99%

Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

Elks

Zhao

Grant

et al. 2016

Journal of Biological Chemistry

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“…It has previously been shown that transgenic mice that over-express human IGFBP-3 cDNA exhibit fasting hyperglycemia, impaired glucose toleranc, and insulin resistance, without an apparent change in total IGF-I levels, and this was not clearly explained by disturbances in growth hormone secretion or adiposity (16).…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor Binding Protein-3 Induces Insulin Resistance in Adipocytes In Vitro and in Rats In Vivo

et al. 2007

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Insulin-like growth factor binding protein (IGFBP)-3 binds to IGF and modulates their actions and also possesses intrinsic activities. We investigated its effects on insulin action and found that when IGFBP-3 was added to fully differentiated 3T3-L1 adipocytes in culture, insulin-stimulated glucose transport was significantly inhibited to 60% of control in a time-and dose-dependent manner. Tumor necrosis factor (TNF)-␣ treatment also inhibited glucose transport to the same degree as IGFBP-3 and, in addition, increased IGFBP-3 levels 3-fold. Co-treatment with TNF-␣ and IGFBP-3 antisense partially prevented the inhibitory effect of TNF-␣ on glucose transport, indicating a role for IGFBP-3 in cytokine-induced insulin resistance. Insulin-stimulated phosphorylation of the insulin receptor was markedly decreased by IGFBP-3 treatment. IGFBP-3 treatment suppressed adiponectin expression in 3T3-L1 adipocytes. Infusion of IGFBP-3 to Sprague-Dawley rats for 3 h decreased peripheral glucose uptake by 15% compared with controls as well as inhibiting glycogen synthesis. Systemic administration of IGFBP-3 to rats for 7 d resulted in a dramatic 40% decrease in peripheral glucose utilization and glycogen synthesis. These in vitro and in vivo findings demonstrate that IGFBP-3 has potent insulin-antagonizing capability and suggest a role for IGFBP-3 in cytokine-induced insulin resistance and other mechanisms involved in the development of type-2 diabetes. (Pediatr Res 61: 159-164, 2007)

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“…Because IGFBP-3 is induced by hypoxia (16,26), it may be involved in angiogenesis (33) and glucose metabolism (48). These possibilities warrant further investigation in esophageal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I

Takaoka¹,

Smith²,

Mashiba³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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IGF and EGF regulate various physiological and pathological processes. IGF binding protein (IGFBP)-3 regulates cell proliferation in IGF-dependent and -independent fashions. Recently, we identified IGFBP-3 as a novel EGF receptor (EGFR) downstream target molecule in primary and immortalized human esophageal epithelial cells, suggesting an interplay between the EGF and IGF signaling pathways. However, the regulatory mechanisms for IGFBP-3 expression and its functional role in esophageal cell proliferation remain to be elucidated. Herein, we report that IGFBP-3 mRNA and protein were induced upon growth factor deprivation in primary and immortalized human esophageal cells through mechanisms requiring p53-independent de novo mRNA transcription and protein synthesis. This occurred in the face of the activated phosphatidylinositol 3-OH-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. Secreted IGFBP-3 neutralized IGFs and prevented IGF-I receptor (IGF-IR) activation. In contrast, EGF suppressed IGFBP-3 mRNA and protein expression through activation of MAPK in an EGFR-tyrosine kinase-dependent manner to restore the cellular response to IGF-I. When stably overexpressed, wild-type IGFBP-3 but not I56G/L80G/L81G (GGG) mutant IGFBP-3, which has a reduced affinity to IGFs, prevented IGF-I from activating IGF-IR and Akt as well as stimulating cell proliferation. However, unlike other cell types where IGFBP-3 exerts antiproliferative effects, neither wild-type nor GGG mutant IGFBP-3 alone affected cell proliferation or EGFR activity. These results indicate that IGF signaling is subject to negative regulation through IGFBP-3 and positive regulation by EGF, the latter of which suppresses IGFBP-3. This provides a platform for understanding the novel cross talk between EGF- and IGF-mediated pathways.

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Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice

Cited by 89 publications

References 33 publications

Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

Insulin-Like Growth Factor Binding Protein-3 Induces Insulin Resistance in Adipocytes In Vitro and in Rats In Vivo

EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I

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