Low Serum Insulin-like Growth Factor I Levels Research Articles

Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance.

Obesity is a risk factor for Alzheimer’s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aβ clearance and is increased in the serum of overweight mice. Overweight mice showed increased Aβ accumulation by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. We also found that Aβ accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver Aβ accumulation—ameliorated by IGF-I administration, and unchanged brain Aβ levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the Aβ precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ load probably because its brain entrance is reduced.

Current concepts of the diagnosis of adult growth hormone deficiency

In adults, growth hormone (GH) deficiency is associated with increased visceral adiposity, decreased lean body mass, bone mineral density and exercise capacity, dyslipidemia, insulin resistance, increased cardiometabolic and fracture risk, and impaired quality of life. The aim of the present article is to review the diagnosis of GH deficiency in adults. To avoid overdiagnosis of GH deficiency, it is critical to evaluate only patients at risk for pituitary dysfunction, including those who have had sellar masses, pituitary surgery, radiation therapy, traumatic brain injury, subarachnoid hemorrhage or childhood onset GH deficiency. Evaluation for GH deficiency should be undertaken after testing and replacement of other pituitary hormone deficits. Since GH secretion is pulsatile, measuring serum GH levels randomly is not helpful in establishing the diagnosis of GH deficiency. Serum insulin-like growth factor I (IGF-I) levels lack substantial diurnal variation but also lack sufficient sensitivity and specificity in the diagnosis of GH deficiency in adults. However, adults with multiple (≥3) additional pituitary hormone deficiencies, risk factors for hypopituitarism and low serum IGF-I levels are very likely to be GH deficient. In most cases, the diagnosis of GH deficiency requires stimulation testing. These tests involve the administration of a pharmacologic agent that normally stimulates GH release from pituitary somatotrophs, including insulin, glucagon, growth hormone releasing hormone-arginine or macimorelin, followed by sampling of serum specimens at regular intervals for GH assay. Patients with a peak GH level that is below a predetermined cutpoint are classified as GH deficient. A systematic approach to the diagnosis of GH deficiency is essential in order to accurately identify adults who may benefit from GH replacement.

A Concerted Action Of Estradiol And Insulin Like Growth Factor I Underlies Sex Differences In Mood Regulation By Exercise

Mood homeostasis present sexually dimorphic traits which may explain sex differences in the incidence of mood disorders. We explored whether diverse behavioral-setting components of mood may be differentially regulated in males and females by exercise, a known modulator of mood. We found that exercise decreases anxiety only in males. Conversely, exercise enhanced resilience to stress and physical arousal, two other important components of mood, only in females. Because exercise increases brain input of circulating insulin-like growth factor I (IGF-I), a potent modulator of mood, we explored whether sex-specific actions of exercise on mood homeostasis relate to changes in brain IGF-I input. We found that exercise increased hippocampal IGF-I levels only in cycling females. Underlying mechanism involved activation of estrogen (E2) receptors in brain vessels that led to increased uptake of serum IGF-I as E2 was found to stimulate IGF-I uptake in brain endothelial cells. Indeed, modulatory effects of exercise on mood were absent in female mice with low serum IGF-I levels or after either ovariectomy or administration of an E2 receptor antagonist. These results suggest that sex-specific brain IGF-I responses to physiological stimuli such as exercise contribute to dimorphic mood homeostasis that may explain sex differences in affective disorders.

Decreased serum insulin-like growth factor-I level is associated with the increased mortality in type 2 diabetes mellitus.

Mortality is increased in type 2 diabetes mellitus (T2DM). Although previous studies showed that decreased serum insulin-like growth factor-I (IGF-I) levels are associated with diabetic complications, little is known about the association between serum IGF-I level and the mortality in patients with T2DM. This is a historical cohort study with end-point of all-cause mortality in 234 men and 191 women with T2DM. Standard deviation of serum IGF-I [IGF-I (SD)] was calculated by adjusting for age and gender. Of 234 male and 191 female, 46 and 25 patients died, respectively, for the follow-up period of almost 7 years. Unadjusted survival analyses showed that lower IGF-I was associated with higher mortality in men and women (p<0.001 and p=0.004, respectively). In Cox regression analyses adjusted for age, duration of diabetes, body mass index, HbA1c, and serum creatinine, serum IGF-I was inversely associated with the mortality [men, hazard ratio (HR)=0.40, 95% confidence interval (CI)=0.25-0.64 per SD increase, p<0.001; women, HR=0.28, 95%CI 0.08-0.96, p=0.043]. When IGF-I was replaced to IGF-I (SD), the relationships are still significant. After additional adjustments for serum albumin, systolic blood pressure, ALT, LDL-cholesterol, smoking, and past history of cardiovascular disease, the association between serum IGF-I and the mortality in men remained significant (HR=0.31, 95%CI 0.15-0.65, p=0.002), but not in women. The present study showed that lower serum IGF-I levels were associated with the increased all-cause mortality in patients with T2DM, suggesting that serum IGF-I could be clinically useful for assessing the risk of mortality in the population.

The relationship between serum insulin-like growth factor I levels and ischemic stroke risk.

ObjectiveThe aim of the study was to assess the relationship between insulin-like growth factor I (IGF-I) serum levels and acute ischemic stroke (AIS) in a Chinese population.MethodsAll consecutive patients with first-ever AIS from August 1, 2011 to July 31, 2013 were recruited to participate in the study. The control group comprised 200 subjects matched for age, gender, and conventional vascular risk factors. IGF-I serum levels were determined by chemiluminescence immunoassay. The National Institutes of Health Stroke Scale (NIHSS) score was assessed on admission blinded to serum IGF-I levels.ResultsThe median serum IGF-1 levels were significantly (P = 0.011) lower in AIS patients (129; IQR, 109–153 ng/mL) compared with control cases (140; IQR, 125–159 ng/mL). We found that an increased risk of AIS was associated with IGF-I levels ≤135 ng/mL (unadjusted OR: 4.17; 95% CI: 2.52–6.89; P = 0.000). This relationship was confirmed in the dose-response model. In multivariate analysis, there was still an increased risk of AIS associated with IGF-I levels ≤135 ng/mL (OR: 2.16; 95% CI:1.33–3.52; P = 0.002) after adjusting for possible confounders.ConclusionLower IGF-I levels are significantly related to risk of stroke, independent from other traditional and emerging risk factors, suggesting that they may play a role in the pathogenesis of AIS. Thus, strokes were more likely to occur in patients with low serum IGF-I levels in the Chinese population; further, post-ischemic IGF-I therapy may be beneficial for stroke.

Serum Insulin-like Growth Factor-I Level Is an Independent Predictor of Recurrence and Survival in Early Hepatocellular Carcinoma: A Prospective Cohort Study

Insulin-like growth factor-I (IGF-I) reflects hepatic synthetic function and plays an important role in the development and progression of various cancers. In this study, we investigated whether pretreatment serum IGF-I levels predict time-to-recurrence (TTR) and overall survival (OS) in patients with early-stage hepatocellular carcinoma after curative treatment. Consecutive patients with hepatocellular carcinoma who had undergone surgical resection, radiofrequency ablation, or percutaneous ethanol injection as curative treatments of early hepatocellular carcinoma were included from two prospective cohorts and the training set (n = 101) and the validation set (n = 91) were established. Serum samples were collected before treatment and the levels of IGF-I and IGF-binding protein-3 (IGFBP-3) were analyzed with regard to their associations with recurrence and survival. In the training set, patients with low IGF-I levels showed significantly shorter TTR [median, 14.6 months; 95% confidence interval (CI), 1.8-27.5] than patients with high IGF-I levels (median, 50.8 months; 95% CI, 36.9-64.7; P < 0.001) during a median follow-up period of 52.4 months. In the multivariate analysis, low levels of IGF-I were an independent predictor of recurrence (HR, 2.49; 95% CI, 1.52-4.08; P < 0.001). Furthermore, together with high-serum α-fetoprotein and multiple tumors, low levels of IGF-I remained an independent predictor of poorer survival (HR, 8.00; 95% CI, 1.94-33.01; P = 0.004). Applied to the independent validation set, low-serum IGF-I levels maintained their prognostic value for shorter TTR and OS. Low-baseline IGF-I levels independently correlated with shorter TTR and poorer survival in patients with early-stage hepatocellular carcinoma after curative treatment.

Insulin-like growth factors and risk of kidney cancer in men.

Background:Insulin-like growth factor-I (IGF-I) has been shown to increase kidney growth, glomerular filtration rate, and renal function.Methods:In the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study of 29 133 Finnish male smokers aged 50–69 years, serum concentrations of IGF were measured in samples collected in 1985–1988. A total of 100 men with kidney cancer diagnosed ⩾5 years after blood collection through 1997 were compared with a subcohort of 400 men; logistic regression models were used to estimate the risk of developing kidney cancer.Results:Men with IGF-I levels >113 ng ml−1 were 59% less likely to develop kidney cancer than men with levels ⩽113 ng ml−1 (odds ratio=0.41; 95% confidence interval=0.23–0.75). The IGF binding protein-3 (IGFBP-3) levels did not alter the association. No association was observed between IGFBP-3, or molar ratio of IGF-I/IGFBP-3, and kidney cancer.Conclusions:Low serum IGF-I levels in this cohort of older middle-aged male smokers are associated with increased kidney cancer risk, independent of IGFBP-3.

Abstract 4830: Insulin-like growth factors and kidney cancer risk in men

Abstract Context: Causes of kidney cancer are not fully understood. Incidence is highest in those ages 50 to 70, and almost twice as high in men as in women. Smokers are twice as likely as non-smokers to develop renal cell carcinoma and about four times as likely to develop cancer of the renal pelvis. Insulin-like growth factor-I (IGF-I) has been shown to increase kidney microvascular growth and glomerular filtration rate, and its administration increases renal function in animal models of chronic renal failure, and has been proposed as a possible therapeutic agent (Hirschberg et al, 1998). However, the possible roles of IGF in the development of kidney cancer have not been well-studied. Objective: To examine the relation of serum levels of IGF-I and insulin-like growth factor binding protein 3 (IGFBP-3) to kidney cancer risk. Methods: We conducted a case-cohort study nested within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of 29,133 Finnish male smokers who were 50-69 years of age and not diagnosed with cancer at study entry. Serum concentrations of IGF-I, IGFBP-3 were measured in blood samples collected in 1985 to 1988. One hundred men were identified who had a diagnosis of kidney cancer &amp;gt;5 years after blood collection through the end of 1997. Self-reported information on lifestyle and medical history was collected and weight and height were measured at baseline. Multivariable logistic regression models were used to estimate the relative risk of kidney cancer associated with IGF levels. Results: A history of hypertension (known to be increased in those who are older, overweight, or heavier smokers) was more common among cases than among noncases. Men with IGF-I levels &amp;gt;108 ng/mL were 63% less likely to develop kidney cancer than men with IGF-I levels ≤108 ng/mL (OR=0.37; 95% CI=0.20-0.69). IGFBP-3 levels did not alter the association between IGF-I and kidney cancer risk. Further, no association was observed between IGFBP-3 levels and the development of kidney cancer. Conclusions: Low serum IGF-I levels in this cohort of older middle-aged male smokers are associated with increased kidney cancer risk, independent of IGFBP-3, age, anthropometry, lifestyle and medical history. Further research is needed to confirm the findings and examine the association in women and non-smokers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4830.

Serum insulin-like growth factor I and ischemic brain injury

Serum insulin-like growth factor I (IGF-I), which is mostly produced by the liver, has recently been shown to have the unexpected ability to modulate normal brain function as well as brain response to injury. Moreover, serum IGF-I levels are modified in many brain diseases, including stroke. However, whether these modifications are related to the disease process remains uncertain. We now examined a potential relationship between serum IGF-I and ischemic brain injury after middle cerebral artery occlusion (MCAo) and reperfusion in mice with either high or low serum IGF-I levels prior to insult. Surprisingly, we found that chronic high serum IGF-I correlates with increased brain infarct size following MCAo, while low levels correlate with reduced lesion size. Immunocytochemistry and immunoblot analyses revealed that levels of phosphorylated (i.e., activated) MAPK, known to be associated with the severity of ischemic brain injury, were increased in IGF-I treated mice. No overall effect of IGF-I treatment on IGF family mRNA expression in the brain was observed. Altogether, these results indicate that serum IGF-I levels negatively correlate with stroke outcome. Therefore, lowering serum IGF-I levels in aging mammals, including humans, may be beneficial against the increased risk of stroke associated to old age.

Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects

Increasing evidence indicates that circulating insulin-like growth factor I (IGF-I) acts as a peripheral neuroactive signal participating not only in protection against injury but also in normal brain function. Epidemiological studies in humans as well as recent evidence in experimental animals suggest that blood-borne IGF-I may be involved in cognitive performance. In agreement with observations in humans, we found that mice with low-serum IGF-I levels due to liver-specific targeted disruption of the IGF-I gene presented cognitive deficits, as evidenced by impaired performance in a hippocampal-dependent spatial-recognition task. Mice with serum IGF-I deficiency also have disrupted long-term potentiation (LTP) in the hippocampus, but not in cortex. Impaired hippocampal LTP was associated with a reduction in the density of glutamatergic boutons that led to an imbalance in the glutamatergic/GABAergic synapse ratio in this brain area. Behavioral and synaptic deficits were ameliorated in serum IGF-I-deficient mice by prolonged systemic administration of IGF-I that normalized the density of glutamatergic boutons in the hippocampus. Altogether these results indicate that liver-derived circulating IGF-I affects crucial aspects of mature brain function; that is, learning and synaptic plasticity, through its trophic effects on central glutamatergic synapses. Declining levels of serum IGF-I during aging may therefore contribute to age-associated cognitive loss.

Effects of arginine treatment on nutrition, growth and urea cycle function in seven Japanese boys with late-onset ornithine transcarbamylase deficiency

The aim of this study was to investigate the effects of arginine on nutrition, growth and urea cycle function in boys with late-onset ornithine transcarbamylase deficiency (OTCD). Seven Japanese boys with late-onset OTCD enrolled in this study resumed arginine treatment after the cessation of this therapy for a few years. Clinical presentations such as vomiting and unconsciousness, plasma amino acids and urinary orotate excretion were followed chronologically to evaluate urea cycle function and protein synthesis with and without this therapy. In addition to height and body weight, blood levels of proteins, lipids, growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein -3 (IGFBP-3) were monitored. The frequency of hyperammonemic attacks and urinary orotate excretion decreased significantly following the resumption of arginine treatment. Despite showing no marked change in body weight, height increased gradually. Extremely low plasma arginine increased to normal levels, while plasma glutamine and alanine levels decreased considerably. Except for a slight increase in high-density lipoprotein cholesterol level, blood levels of markers for nutrition did not change. In contrast, low serum IGF-I and IGFBP-3 levels increased to age-matched control levels, and normal urinary GH secretion became greater than the level observed in the controls. Arginine treatment is able to reduces attacks of hyperammonemia in boys with late-onset OTCD and to increase their growth.

Identification of a Distal STAT5-binding DNA Region That May Mediate Growth Hormone Regulation of Insulin-like Growth Factor-I Gene Expression

Growth hormone (GH) regulates insulin-like growth factor-I (IGF-I) gene expression through signal transducer and activator of transcription 5b (STAT5b) and STAT5a. The objective of this study was to identify the cis-regulatory DNA region involved in this process. By cotransfection analyses of shotgun DNA fragments of a bacterial artificial chromosome sequence containing the entire human IGF-I gene and a large 5'-flanking region, a approximately 700-bp DNA region approximately 75 kb 5' to the IGF-I gene was found to have the ability to enhance gene expression from both heterologous and homologous promoters in the presence of constitutively active STAT5a or STAT5b. This 700-bp DNA region contains two closely located consensus STAT5-binding sites, and its sequence appears to be evolutionarily conserved. Electrophoretic mobility shift assays verified the ability of the two putative STAT5-binding sites to bind to STAT5a and STAT5b. Cotransfection analyses confirmed that both STAT5-binding sites were necessary for the 700-bp DNA region to mediate STAT5a or STAT5b activation of gene transcription. Chromatin immunoprecipitation assays demonstrated that the chromosomal region containing these two STAT5-binding sites was bound by constitutively active STAT5b protein in HepG2 cells and that the binding was accompanied by increased expression of IGF-I mRNA. In reconstituted GH-responsive cells, this 700-bp DNA region was able to mediate GH-induced STAT5a or STAT5b activation of gene expression. These results together suggest that this STAT5-binding site-containing distal 5'-flanking region of IGF-I gene may be an enhancer mediating GH-induced STAT5 activation of IGF-I gene transcription.

Age, body mass index, current smoking history, and serum insulin-like growth factor-I levels associated with bone mineral density in middle-aged Korean men.

Osteoporosis is a growing health problem in women and in men. This cross-sectional study examined the association of anthropometric, lifestyle, and hormonal factors with bone mineral density (BMD) in 152 healthy Korean middle-aged men. Smoking habits and alcohol consumption were assessed by interview. Serum testosterone and insulin-like growth factor-I (IGF-I) levels were measured by radioimmunoassay, and serum growth hormone (GH) levels were measured by immunoradiometric assay. GH stimulation tests were performed after the ingestion of 500 mg of L-dopa. BMD was measured at the lumbar spine and at the femoral neck by dual-energy X-ray absorptiometry. Of the middle-aged men, 3.9% were osteoporotic and 28.3% were osteopenic at the lumbar spine site, and 5.9% were osteoporotic and 45.4% were osteopenic at the femoral neck site. Lumbar spine BMD correlated significantly with body mass index (BMI), and femoral neck BMD correlated significantly with age, BMI, and serum IGF-I levels. The lowest quartile group for serum IGF-I levels showed the lowest femoral neck BMD. Osteoporotic men by lumbar spine BMD showed significant differences from the normal BMD group in terms of BMI and smoking habits. Also, osteoporotic men by femoral neck BMD were significantly different for mean age, BMI, and serum IGF-I levels compared with the normal BMD group. On multiple regression analysis, BMI was found to be the only independent predictor of lumbar spine BMD, whereas both BMI and serum IGF-I levels were found to be the independent predictors of femoral neck BMD. Overall, 28.3%-45.4% of middle-aged Korean men were osteopenic. We suggest that higher age, a lower BMI, current smoking history, and lower serum IGF-I levels are risk factors for lower BMD in middle-aged Korean men; however, serum testosterone levels and GH secretory capacity were not found to be correlated with BMD.

Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study.

Several experimental investigations have emphasized the favorable effects of insulin-like growth factor I (IGF-I) on left ventricular remodeling, partly through its antiapoptotic effects. Cross-sectional clinical studies have reported that low serum IGF-I levels in patients with heart failure correlate with cachexia and severity of ventricular dysfunction. It is unclear whether low serum IGF-I is a risk factor for heart failure. To prospectively study the association between serum IGF-I level and the incidence of congestive heart failure. Community-based, prospective cohort study. Framingham, Massachusetts. 717 elderly individuals (mean age, 78.4 years; 67% women) who did not have myocardial infarction and congestive heart failure at baseline. Incidence of a first episode of congestive heart failure on follow-up. During follow-up (mean, 5.2 years), 56 participants (35 women) developed congestive heart failure. In multivariable Cox regression models adjusting for established risk factors at baseline, there was a 27% decrease in risk for heart failure for every 1 standard deviation increment in log IGF-I. Individuals with serum IGF-I level at or above the median value (140 microg/L) had half the risk for heart failure (hazard ratio, 0.49 [95% CI, 0.26 to 0.92]) of those with serum IGF-I levels below the median. These comparisons were maintained in analyses adjusting for the occurrence of a myocardial infarction on follow-up. In our prospective, community-based investigation, serum IGF-I level was inversely related to the risk for congestive heart failure in elderly people without a previous myocardial infarction. Additional investigations are warranted to confirm these findings.

Persistent short stature, other potential outcomes, and the effect of growth hormone treatment in children who are born small for gestational age.

Persistent short stature, other potential outcomes, and the effect of growth hormone treatment in children who are born small for gestational age.

Insulin-like growth factor I, insulin-like growth factor binding protein 3, and urologic measures of benign prostatic hyperplasia.

Laboratory studies suggest that insulin-like growth factor I (IGF-I) promotes prostatic growth. The authors evaluated the association between benign prostatic hyperplasia and IGF-I and its binding protein IGFBP-3 in community-dwelling men to determine whether this laboratory finding is manifest at the population level. Participants (n = 471) were Olmsted County, Minnesota, Caucasian males aged 40-79 years in 1990. Urologic measures were assessed from the International Prostate Symptom Score, peak urinary flow rates, prostate volume, and serum prostate-specific antigen (PSA), and serum IGF-I and IGFBP-3 levels were measured. After adjustment for age, the relative odds (odds ratios) of an abnormal urologic measure in men with high versus low serum IGF-I levels were 0.98 (95% confidence interval (CI): 0.66, 1.45) for a symptom score of >7, 1.14 (95% CI: 0.72, 1.80) for a peak urinary flow rate of <12 ml/second, 1.11 (95% CI: 0.72, 1.72) for a prostate volume of >30 ml, and 0.71 (95% CI: 0.46, 1.09) for a PSA level of >1.4 ng/ml. A low IGFBP-3 level was associated with an enlarged prostate (odds ratio = 1.72, 95% CI: 1.05, 2.82), after simultaneous adjustment for IGF-I and age, but not with other urologic measures. These data do not provide evidence for an association between benign prostatic hyperplasia and serum IGF-I.

Is the somatotropic axis related to sympathetic nerve activity in healthy ageing men?

The mechanisms underlying the age-related increase in blood pressure and sympathetic nerve activity remain largely unknown. The decline in growth hormone (GH) secretion and insulin-like growth factor-I (IGF-I) with age has been related to several cardiovascular risk factors. Low serum IGF-I levels in severe adult GH deficiency is associated with markedly increased sympathetic nerve activity. This study evaluates whether a relationship between serum IGF-I and sympathetic nerve traffic exists in healthy aging men. Sympathetic nerve activity to the muscle vascular bed (MSA) was recorded in 56 healthy normotensive males, and related to age (range 21-71 years), body mass index (BMI, range 18.4-32.2), serum IGF-I and plasma nitrate levels. Blood pressure, BMI and MSA increased with age, whereas IGF-I and plasma nitrate decreased. In a forward stepwise multiple regression analysis, age explained 40% of the variability in MSA and excluded other variables. Omitting age, IGF-I became the strongest independent predictor, explaining 23% of the variability in MSA. MSA was an independent predictor of diastolic blood pressure, but its influence (10%) was less than that of BMI (28%). BMI was not related to MSA or IGF-I. Decreased serum IGF-I levels are coupled to increased MSA during ageing, an effect independent from the impact of increased body weight. Although MSA is a weak predictor of rising blood pressure with age, it constitutes one possible pathway for the somatotropic axis to affect cardiovascular function in ageing.

Effect of protein intake on plasma and erythrocyte free amino acids and serum IGF-I and IGFBP-1 levels in rats.

Amino acid (AA) levels in plasma and erythrocytes (RBC) were determined in rats (n = 29) fed diets with 6, 21, and 35% protein, and their association with insulin-like growth factor I (IGF-I), insulin, or IGF-binding protein (IGFBP)-1 levels was studied. Free AA in plasma and RBC were determined by reversed-phase high-pressure liquid chromotography, and IGF-I, IGFBP-1, and insulin plasma levels were determined by RIA. Rats fed the low-protein (6%) diet were growth-retarded and had lower serum IGF-I levels and higher serum IGFBP-1 levels than the other two groups (P < 0.0001). In rats fed the low-protein diet, most of the nonessential AA (NEAA) in both plasma and RBC increased, whereas the essential AA (EAA), with the exception of threonine, decreased. When the groups were combined, both RBC and plasma EAA-to-NEAA ratios were positively correlated to IGF-I (r = 0.76 and 0.80, respectively; P < 0.0001) and inversely correlated to IGFBP-1 levels (r = -0.67, P < 0.001 and r = -0.78, P < 0.0001, respectively). A significant inverse correlation was found between RBC glutamate and IGF-I (r = -0.85, P < 0.0001, n = 25) and insulin (r = -0.72, P < 0.001, n = 21), and a positive correlation was found for IGFBP-1 (r = 0.78, P < 0.0001, n = 24). In multiple regression analysis, only IGF-I remained as an independent variable. Threonine was the only EAA with a significant inverse correlation to insulin (r = -0.66, P < 0.001). We hypothesize that AA metabolism is associated to changes in IGF-I, insulin, and IGFBP-1 levels in rats on different protein intakes.

Bone mineral density, serum insulin-like growth factor I, and bone turnover markers in viral cirrhosis.

Previous studies suggest that low bone mass is a complication of alcoholic liver disease. Nevertheless, little is known about bone mass and bone metabolism in viral cirrhosis. To evaluate the prevalence and magnitude of hepatic osteopenia in these patients, bone remodeling status, and its relationship with the severity of liver disease and serum levels of insulin-like growth factor I (IGF-I), we studied 32 consecutive patients with viral cirrhosis and no history of alcohol intake. Bone mineral density (BMD) was measured by dual x-ray absorptiometry in the lumbar spine (LS) and femoral neck (FN), and the values were expressed as the z score. Bone metabolism markers and hormone profiles were measured. Patients with viral cirrhosis showed reduced BMD in all sites (LS: -1.27 +/- 1.06, P < .001; FN: -0.48 +/- 0.96; P < .01). Of the 32 patients, 53% met the diagnostic criteria for osteoporosis. In patients, urine deoxypyridinoline (D-Pyr) as a marker of bone resorption and serum bone alkaline phosphatase (b-AP) as a marker of bone formation were significantly higher than in control subjects (P < .001 and P < .01, respectively). Serum IGF-I was lower than in control subjects (P < .001), and significant differences were also found between patients with and without osteoporosis (P < .05). BMD in LS correlated with severity of the disease, with serum levels of IGF-I, and with urine D-Pyr. Our findings show that viral cirrhosis is a major cause of osteoporosis in men, and that low serum IGF-I levels seem to play a role in the bone mass loss in these patients. The biochemical markers of bone remodeling suggest high-turnover osteoporosis in patients with viral cirrhosis.

High-affinity growth hormone binding protein, insulin-like growth factor I and insulin-like growth factor binding protein 3 in adults with growth hormone deficiency.

The high-affinity growth hormone binding protein (GHBP) circulates in human blood and represents the extracellular domain of the growth hormone (GH) receptor. The effects of GH deficiency on GHBP in adults are not clear. The aim of this study was to evaluate serum GHBP levels in adults with GH deficiency and to assess whether GHBP measurement may contribute to the diagnosis of adult GH deficiency, based on a two-step model. We measured insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP-3) and GHBP levels in serum samples of 36 patients with adult-onset GH deficiency. The GHBP levels were measured by FPLC size-exclusion chromatography; IGF-I and IGFBP-3 levels were measured by RIA. Serum GHBP levels were elevated above the upper limit of the 95% confidence interval in 26 patients, whereas IGF-I and IGFBP-3 levels were low in 10 patients and in 16 patients, respectively. The combination of low serum IGF-I and low IGFBP-3 levels was found in 10 patients. In nine patients, serum IGF-I levels were low, with elevated GHBP levels. Low serum IGF-I, low IGFBP-3 and elevated GHBP levels were found in five patients. Only four out of 36 patients had serum IGF-I, IGFBP-3 and GHBP levels that were within the 95% confidence interval of the control values. We conclude that adults with acquired GH deficiency have elevated GHBP levels in comparison to healthy subjects. We suggest that measurement of GHBP levels might contribute to the diagnosis of adult GH deficiency, though further research is required to study the additional value of GHBP measurements.