Normal growth and development in the absence of hepatic insulin-like growth factor I

Yakar, Shoshana; Liu, Jun Li; Stannard, Bethel; Butler, Andrew A.; Accili, Domenici; Sauer, Brian; LeRoith, Derek

doi:10.1073/pnas.96.13.7324

Cited by 1,301 publications

(1,022 citation statements)

References 40 publications

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“…Its is known that normal hepatocytes express few IGF-I receptors, and that growth of normal liver is not affected by circulating IGF-I [11,48,49]. In agreement with this, we have not detected the expression of IGF-I receptors in total liver homogenates of CO, CI nor healthy control rats treated with IGF-I, when analysed by Western blotting (data not shown).…”

Section: Discussionsupporting

confidence: 88%

Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I

Mirpuri

Garcı́a-Trevijano

Castilla‐Cortázar

et al. 2002

The International Journal of Biochemistry & Cell Biology

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We have previously shown that the administration of low doses of insulin-like growth factor-I (IGF-I) to CCl 4 -cirrhotic rats improves liver function and reduces fibrosis. To better understand the mechanisms behind the hepatoprotective effects of IGF-I, and to identify those genes whose expression is affected in cirrhosis and after IGF-1 treatment, we have performed differential display of mRNA analysis by means of polymerase chain reaction (PCR) in livers from control and CCl 4 -cirrhotic rats treated or not with IGF-I. We have identified 16 genes that were up-or down-regulated in the cirrhotic liver. IGF-I treatment partially normalized the expression of eight of these genes, including serine proteinase inhibitors such as serpin-2 and alpha-1-antichymotripsin, alpha-1-acid glycoprotein, and alpha-2u-globulin. Additionally, we show that IGF-I enhanced the regenerative activity in the cirrhotic liver, as determined by the increased expression of the proliferating cell nuclear antigen (PCNA). Finally, IGF-I treatment partially restored the expression of growth hormone receptor (GHR) and the levels of global genomic DNA methylation, which are reduced in human and experimental cirrhosis. Taken together, our observations confirm the hepatoprotective effects of IGF-I, and suggest that this action can be exerted in part through the normalization of liver gene expression, growth hormone (GH) responsiveness and global genomic DNA methylation.

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Section: Discussionsupporting

confidence: 88%

Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I

Mirpuri

Garcı́a-Trevijano

Castilla‐Cortázar

et al. 2002

The International Journal of Biochemistry & Cell Biology

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“…Thus, the changes seen in body composition could be due to the action of growth hormone or to the autocrine or paracrine actions of IGF-1. The importance of the autocrine or paracrine production of IGF-1 has been well documented in the liver insulin-like growth factor-1-deficient mouse model [20]. Another possibility is that the level of free, but not total IGF-1 could have been altered, since we only measured and reported total IGF-1 in this study.…”

Section: Discussionmentioning

confidence: 87%

Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes

et al. 2009

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Aims/hypothesis Growth hormone has been used experimentally in two studies to treat individuals with type 2 diabetes, with both reporting beneficial effects on glucose metabolism. However, concerns over potential diabetogenic actions of growth hormone complicate its anticipated use to treat type 2 diabetes. Thus, an animal model of type 2 diabetes could help evaluate the effects of growth hormone for treating this condition. Methods Male C57BL/6J mice were placed on a high-fat diet to induce obesity and type 2 diabetes. Starting at 16 weeks of age, mice were treated once daily for 6 weeks with one of four different doses of growth hormone. Body weight, body composition, fasting blood glucose, insulin, glucose tolerance, liver triacylglycerol, tissue weights and blood chemistries were determined. Results Body composition measurements revealed a dosedependent decrease in fat and an increase in lean mass. Analysis of fat loss by depot revealed that subcutaneous and mesenteric fat was the most sensitive to growth hormone treatment. In addition, growth hormone treatment resulted in improvement in glucose metabolism, with the highest dose normalising glucose, glucose tolerance and liver triacylglycerol. In contrast, insulin levels were not altered by the treatment, nor did organ weights change. However, fasting plasma leptin and resistin were significantly decreased after growth hormone treatment. Conclusions/interpretation Growth hormone therapy improves glucose metabolism in this mouse model of obesity and type 2 diabetes, providing a means to explore the molecular mechanism(s) of this treatment.

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“…(1)(2)(3)(4) Mouse models with liver-specific IGF-1 inactivation demonstrate that a major part (75% to 80%) of serum IGF-1 is liver-derived. (5,6) However, IGF-1 is also expressed locally in bone. (2,3) Thus there are two main sources of IGF-1 with a possible impact on the skeleton.…”

Section: Introductionmentioning

confidence: 99%

Older men with low serum IGF-1 have an increased risk of incident fractures: The MrOS Sweden study

Ohlsson

Mellström

Carlzon

et al. 2010

Journal of Bone and Mineral Research

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Osteoporosis-related fractures constitute a major health concern not only in women but also in men. Insulin-like growth factor 1 (IGF-1) is a key determinant of bone mass, but the association between serum IGF-1 and incident fractures in men remains unclear. To determine the predictive value of serum IGF-1 for fracture risk in men, older men (n ¼ 2902, mean age of 75 years) participating in the prospective, population-based Osteoporotic Fractures in Men (MrOS) Sweden study were followed for a mean of 3.3 years. Serum IGF-1 was measured at baseline by radioimmunoassay. Fractures occurring after the baseline visit were validated. In age-adjusted hazards regression analyses, serum IGF-1 associated inversely with risk of all fractures [hazard ratio (HR) per SD decrease ¼ 1.23, 95% confidence interval (CI) 1.07-1.41], hip fractures (HR per SD decrease ¼ 1.45, 95% CI 1.07-1.97), and clinical vertebral fractures (HR per SD decrease ¼ 1.40, 95% CI 1.10-1-78). The predictive role of serum IGF-1 for fracture risk was unaffected by adjustment for height, weight, prevalent fractures, falls, and major prevalent diseases. Further adjustment for bone mineral density (BMD) resulted in an attenuated but still significant association between serum IGF-1 and fracture risk. Serum IGF-1 below but not above the median was inversely related to fracture incidence. The population-attributable risk proportion was 7.5% for all fractures and 22.9% for hip fractures. Taken together, older men with low serum IGF-1 have an increased fracture risk, especially for the two most important fracture types, hip and vertebral fractures. The association between serum IGF-1 and fracture risk is partly mediated via BMD. ß

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Normal growth and development in the absence of hepatic insulin-like growth factor I

Cited by 1,301 publications

References 40 publications

Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I

Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I

Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes

Older men with low serum IGF-1 have an increased risk of incident fractures: The MrOS Sweden study

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