Vascular Insulin-Like Growth Factor-I Resistance and Diet-Induced Obesity

Imrie, Helen; Abbas, Afroze; Viswambharan, Hema; Rajwani, Adil; Cubbon, Richard M; Gage, Matthew; Kahn, Morton C.; Ezzat, Vivienne; Duncan, Edward; Grant, Peter J.; Ajjan, Ramzi; Wheatcroft, Stephen; Kearney, Mark T.

doi:10.1210/en.2008-1641

Cited by 46 publications

(56 citation statements)

References 46 publications

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“…In contrast to Magel2-null mice, these mutant mice suffer from severe postnatal growth retardation and low fat mass. Similar to calorie restricted lean mice (68,69), MBII-85/SNORD116 mice exhibit reduced serum Igf-I. GH release was not reported in this strain.…”

Section: Magel2 and The Gh Axismentioning

confidence: 65%

Impaired Hypothalamic Regulation of Endocrine Function and Delayed Counterregulatory Response to Hypoglycemia in Magel2-Null Mice

Tennese

Wevrick

2011

Endocrinology

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Hypothalamic dysfunction may underlie endocrine abnormalities in Prader-Willi syndrome (PWS), a genetic disorder that features GH deficiency, obesity, and infertility. One of the genes typically inactivated in PWS, MAGEL2, is highly expressed in the hypothalamus. Mice deficient for Magel2 are obese with increased fat mass and decreased lean mass and have blunted circadian rhythm. Here, we demonstrate that Magel2-null mice have abnormalities of hypothalamic endocrine axes that recapitulate phenotypes in PWS. Magel2-null mice had elevated basal corticosterone levels, and although male Magel2-null mice had an intact corticosterone response to restraint and to insulin-induced hypoglycemia, female Magel2-null mice failed to respond to hypoglycemia with increased corticosterone. After insulin-induced hypoglycemia, Magel2-null mice of both sexes became more profoundly hypoglycemic, and female mice were slower to recover euglycemia, suggesting an impaired hypothalamic counterregulatory response. GH insufficiency can produce abnormal body composition, such as that seen in PWS and in Magel2-null mice. Male Magel2-null mice had Igf-I levels similar to control littermates. Female Magel2-null mice had low Igf-I levels and reduced GH release in response to stimulation with ghrelin. Female Magel2-null mice did respond to GHRH, suggesting that their GH deficiency has a hypothalamic rather than pituitary origin. Female Magel2-null mice also had higher serum adiponectin than expected, considering their increased fat mass, and thyroid (T 4 ) levels were low. Together, these findings strongly suggest that loss of MAGEL2 contributes to endocrine dysfunction of hypothalamic origin in individuals with PWS. (Endocrinology 152: 967-978, 2011) P rader-Willi syndrome (PWS) is a complex genetic disorder, whose clinical features suggest abnormalities of the hypothalamic-pituitary axis. These include GH deficiency with short stature, increased fat mass and reduced lean mass, hypogonadotropic hypogonadism, childhood-onset hyperphagia and obesity, and sleep disorders. Structural abnormalities of the brain documented in PWS include frequent ventriculomegaly and cortical abnormalities. Pituitary abnormalities are common, but structural abnormalities of the hypothalamus are not typically found (1-3). Children with PWS typically have decreased spontaneous GH secretion and low peak GH response in stimulation tests (4, 5), accompanied by reduced serum IGF-I and low IGF-binding protein 3 (6 -8). GH deficiency contributes to abnormal body composition consisting of increased body fat mass and reduced lean mass, and treatment with GH partially normalizes body composition and short stature (9 -11). In contrast, obesity in the general population is often associated with a relative GH deficiency but normal or high levels of IGF-I, suggesting defective feedback mechanisms in GH pathways that can resolve on weight loss.In normal adults, serum leptin levels increase with increasing adiposity, but levels of adiponectin, particularly in its multimeric high mole...

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Section: Magel2 and The Gh Axismentioning

confidence: 65%

Impaired Hypothalamic Regulation of Endocrine Function and Delayed Counterregulatory Response to Hypoglycemia in Magel2-Null Mice

Tennese

Wevrick

2011

Endocrinology

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“…IGF-1 resistance has been observed in dysmetabolic states 1,20,46-48 such as chronic renal failure, associated with increased compensatory serum IGF-1 aiming at overcoming IGF-1 signaling defects. 49 Chronic renal failure is a prototypical state of reduced IGF-1 sensitivity, 50-52 developing with progressing renal disease and increased binding proteins, and accounting for growth defects or lost responsiveness to the administration of IGF-1, 53 otherwise able to increase glomerular filtration rate, effectively delaying the beginning of hemodialysis. Resistance training improved IGF-1 sensitivity, thus confirming the state of IGF-1 resistance as causal for the described cross-sectional association between higher IGF-1 levels and chronic renal failure.…”

Section: Discussionmentioning

confidence: 99%

Revisiting the Relationship Between Blood Pressure and Insulin-Like Growth Factor-1

et al. 2014

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Abstract-Conflicting evidence exists on the relationship between blood pressure (BP) and insulin-like growth factor-1 (IGF-1). We reviewed available articles and pooled extrapolated regression coefficients for the association between BP and total IGF-1 as reported in the literature and included additional data from 912 individuals from the general population. We identified 20 studies including 11 704 subjects. We also measured total IGF-1, insulin-like binding protein-3, and BP in 912 black and white men and women from South Africa (aged 20-70 years). When plotting positive and negative weighed regression coefficients (29 data points) against IGF-1, we found a significant positive relationship (r=0.31; P<0.001; n=11 704) intercepting the 0 point at 191 ng/mL IGF-1, suggesting an inverse BP/IGF-1 relationship in low IGF-1 conditions, and a positive relationship in overtly high IGF-1 conditions. In conclusion, our findings suggest that the relationship between BP and IGF-1 is dependent on, or related to, IGF-1 concentrations, as an expression of direct or reverse causality. Low IGF-1 bioavailability (associated with aging and vascular deterioration), resistance to IGF-1, and the complex interplay between IGF-1 and other vasoactive hormones could mask the vasoprotective functions of IGF-1 in cross-sectional studies or could modify their functions in prospective studies.

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“…Several studies have shown that IGF1 has potential beneficial effects on vasculopathy and glucose metabolism in cardiovascular tissue, [32][33][34] whereas IGF1 reportedly induces vascular remodeling. 35,36 Expression of IGF1R is much higher than that of IR, and increased IGF1R forms hybrid receptors in VSMCs.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Induces Vascular Insulin Resistance by Increasing Insulin-Like Growth Factor-1 Receptor and Hybrid Receptor

Sherajee

Fujita

Rafiq

et al. 2012

ATVB

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Objective-We previously showed that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs).Because insulin-like growth factor-1 receptor (IGF1R) affects insulin signaling, we hypothesized that aldosterone induces vascular insulin resistance and remodeling via upregulation of IGF1R and its hybrid insulin/insulin-like growth factor-1 receptor. Methods and Results-Hybrid receptor expression was measured by immunoprecipitation. Hypertrophy of VSMCs was evaluated by 3 H-labeled leucine incorporation. Aldosterone (10 nmol/L) significantly increased protein and mRNA expression of IGF1R and hybrid receptor in VSMCs but did not affect insulin receptor expression. Mineralocorticoid receptor blockade with eplerenone inhibited aldosterone-induced increases in IGF1R and hybrid receptor. Aldosterone augmented insulin (100 nmol/L)-induced extracellular signal-regulated kinase 1/2 phosphorylation. Insulin-induced leucine incorporation and ␣-smooth muscle actin expression were also augmented by aldosterone in VSMCs. These aldosterone-induced changes were significantly attenuated by eplerenone or picropodophyllin, an IGF1R inhibitor. Chronic infusion of aldosterone (0.75 g/hour) increased blood pressure and aggravated glucose metabolism in rats. Expression of hybrid receptor, azan-positive area, and oxidative stress in aorta was increased in aldosterone-infused rats. Spironolactone and tempol prevented these aldosterone-induced changes. Key Words: insulin resistance Ⅲ reactive oxygen species Ⅲ receptors Ⅲ signal transduction Ⅲ aldosterone I nsulin resistance is a major attribute of type 2 diabetes mellitus and metabolic syndrome. 1 Cardiovascular complications are often seen in these patients, and vascular insulin resistance is considered to be involved in proatherogenic changes and subsequent cardiovascular events. 2 There is growing interest in the role of aldosterone and its receptor, mineralocorticoid receptor (MR), in the pathogenesis of insulin resistance. 3 For instance, clinical studies have shown that patients with primary aldosteronism exhibit impaired glucose tolerance. 4 Some possible mechanisms of insulin resistance induced by aldosterone have been considered, such as a low serum potassium concentration, and direct effects of aldosterone on insulin signaling. 5,6 Previously, we have demonstrated that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs) via the downregulation of insulin receptor substrate-1, a key molecule of insulin signaling pathway. 7 Our data also clearly showed that aldosterone attenuates glucose metabolism in VSMCs. However, the precise molecular mechanisms responsible for aldosterone-induced VSMC insulin resistance and proatherogenic changes have not been identified. Conclusion-AldosteroneInsulin induces various actions, such as glucose metabolism and normal cell physiology, by binding to the insulin receptor (IR). 8 The VSMCs express not only IR but also insulin-like growth factor-1 receptor (IGF1R). 8 Compared with IR, IGF1R is more ab...

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Vascular Insulin-Like Growth Factor-I Resistance and Diet-Induced Obesity

Cited by 46 publications

References 46 publications

Impaired Hypothalamic Regulation of Endocrine Function and Delayed Counterregulatory Response to Hypoglycemia in Magel2-Null Mice

Impaired Hypothalamic Regulation of Endocrine Function and Delayed Counterregulatory Response to Hypoglycemia in Magel2-Null Mice

Revisiting the Relationship Between Blood Pressure and Insulin-Like Growth Factor-1

Aldosterone Induces Vascular Insulin Resistance by Increasing Insulin-Like Growth Factor-1 Receptor and Hybrid Receptor

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