Insulin‐like growth factor‐I and the liver

Insulin‐like growth factors (IGFs) play an essential role in growth and development, as well as in the overall cellular regulation and metabolism in the human body. In chronic liver disease, IGF levels are decreased, and the circulating levels correlate to the extent of hepatocellular dysfunction. Patients with cirrhosis are characterised by a variety of metabolic disturbances, including nutritional and metabolic complications such as insulin resistance, malnutrition, osteopenia and hypogonadism, all related to IGF‐I deficiency. The complex process of hepatic fibrogenesis and the systemic consequences in cirrhosis are only partly understood. Disruption of the growth hormone (GH)–IGF‐I axis seems to be closely associated with the development of liver disease, and treatment with recombinant human IGF (rhIGF)‐I has been shown to halt, and even reverse, the fibrotic degeneration. IGF‐I in itself has a strong antifibrotic effect that acts directly through the GH/IGF system and indirectly by the regulation of hepatoprotective and profibrogenic factors. It is most likely that IGF‐I deficiency contributes to the diverse metabolic complications of cirrhosis. At present, liver transplantation remains the only efficient treatment of cirrhosis, and thus new methods of managing the disease are called for. RhIGF‐I supplementation and IGF‐I gene therapy may represent future perspectives of treatment.     

Insulin‐like growth factor‐I restores the reduced somatostatinergic tone controlling growth hormone secretion in cirrhotic rats

Abstract: Background/Aims: An altered growth hormone/insulin‐like growth factor‐I (GH/IGF‐I) axis occurs in advanced liver cirrhosis, characterised by diminished serum levels of IGF‐I and increased concentrations of GH. Under normal conditions, GH release is mediated by somatostatin (SS) inhibition. However, the influence of SS on GH release in cirrhosis is not well known. IGF‐I supplementation has beneficial effects in experimental cirrhosis, and – under physiological conditions – IGF‐I increases SS, inhibiting GH. The aims of this work were to study SS tone in cirrhotic animals and to evaluate whether IGF‐I treatment influences SS tone, controlling GH secretion in cirrhosis. Methods: We studied the influence of SS on GH secretion by assessing GH response to pyridostigmine (PD) in cirrhotic rats treated and untreated with IGF‐I. Liver cirrhosis was induced with CCl₄‐inhalation for 11 weeks in male Wistar rats. The animals were randomly divided into two groups: CI+IGF (n=12), which received IGF‐I treatment for 12 days (2 μg/100 g body wt^?1×d^?1) and CI (n=12), which received saline. Healthy controls (CO, n=12) were studied at the same time. On day 13, animals from each group were subdivided into two groups (n=6) in order to explore the effect of a PD intrajugular bolus (10 μg×100 gbw^?1) on serum GH levels (at 0,10,20,30 and 60 min), which were assessed by RIA. Results: PD bolus did not exert any effect on GH serum levels in the CI group, suggesting a low SS tone in cirrhotic rats. However, PD induced an increase in GH levels into CO and CI+IGF groups. In conclusion, as occurs under normal conditions, the cholinergic system is a significant modulator of GH secretion in experimental liver cirrhosis. Conclusion: Cirrhotic rats have a reduced somatostatinergic tone which can be restored by IGF‐I supplementation, suggesting that somatostatin is the main factor involved in the feed‐back regulation between GH and IGF‐I in cirrhosis.     

The role of insulin‐like growth factor‐I and its binding proteins in glucose homeostasis and type 2 diabetes

This review addresses the possible role of the insulin‐like growth factor (IGF)‐axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF‐I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin‐like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre‐diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross‐sectionally with altered circulating levels of IGF‐I and its binding proteins (IGFBPs). Administration of recombinant human IGF‐I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF‐I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic β‐cell mass and function. There is considerable inter‐individual heterogeneity in endogenous levels of IGF‐I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association. Copyright © 2009 John Wiley & Sons, Ltd.     

Serum insulin‐like growth factor‐I and body composition in community dwelling older people

Objectives The decline in the growth hormone/insulin‐like growth factor‐I (GH/IGF‐I) axis during normal aging might be involved in the changes in body composition associated with increasing age. We conducted a study to investigate serum IGF‐I levels across different age categories and a possible association between serum IGF‐I and measurements of body composition in older people. Design A cross‐sectional analysis of community dwelling older people, which participated in a large longitudinal cohort study (Longitudinal Aging Study Amsterdam). Subjects 1319 subjects, 644 men, mean age 75·6 ± 6·6 years and 675 women, mean age 75·4 ± 6·6 years. Main Outcome Measurements IGF‐I, body mass index (BMI), waist, waist‐hip ratio (WHR), fat mass, lean body mass and total bone mineral density. Results IGF‐I levels were significantly lower in the highest age categories. BMI and biceps skinfold measurements were lower in the lowest IGF‐I quartile in men aged ≥75·5 years. In men with a low total physical activity score (<131 min/day), BMI, WHR and skinfolds were significantly lower in the lowest IGF‐I quartile. In women with a high total physical activity score (>174 min/day), WHR was lower in the lowest IGF‐I quartiles. Conclusion In this large cohort of community dwelling older people, we observed lower serum IGF‐I levels in the higher age categories. A low serum IGF‐I was associated with significantly lower measurements of body composition, such as BMI, skinfolds and WHR. These results do not support previous findings that high IGF‐I levels are favourable for a healthy body composition in community dwelling older people.