Relationships between IGF-1 and IGFBP-1 and adiposity in obese African-American and Latino adolescents

The purpose of this study was to examine interrelationships between insulin-like growth factor 1 (IGF-1), IGF binding proteins (IGFBPs), and adiposity in 49 African-American and 77 Latino obese adolescents (15.3 ± 0.1 and 15.4 ± 0.2 years; BMI: 33.0 ± 0.7 and 35.0 ± 1.0 kg/m(2), respectively). Immunoradiometric assays were used to measure IGF-1, IGFBP-1, and IGFBP-3. Total fat and soft lean tissue were measured by dual-energy X-ray absorptiometry and visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue (SAAT), and hepatic fat fraction (HFF) were measured by magnetic resonance imaging. IGF-1 levels were 23.1% higher and IGFBP-1 were 40.4% higher in African Americans compared to Latinos after adjustment for total lean and total fat mass. IGF-1 and IGFBP-1 were inversely correlated with BMI, total fat mass, VAT, and HFF (r = -0.20 to -0.33, P < 0.05) while IGFBP-1 was inversely correlated with SAAT (r = -0.22, P < 0.05). These relationships did not differ by ethnicity, however, the relationship between IGF-1 and SAAT, as well as IGFBP-1 and HFF, differed by ethnicity. Predicted mean IGF-1 levels were 30.7% higher for African Americans at the 75th compared to 25th percentile of SAAT and only 11.7% higher for Latinos. Predicted mean IGFBP-1 levels were 158% higher for African Americans at the 25th compared to the 75th percentile of HFF while IGFBP-1 levels were 1.7% higher for Latinos at the 75th compared to the 25th percentile. These results demonstrate that the relationship between IGF-1 and SAAT as well as IGFBP-1 and HFF are different in African-American and Latino adolescents and may contribute to the higher IGF-1 levels in African-Americans.     

Relationships between serum IGF-1, IGFBP-2, interleukin-1beta and interleukin-6 in inflammatory bowel disease

AIMS: To study the relationships between serum IGF-1, IGFBP-3 and IGFBP-2 and interleukin (IL)-1beta and IL-6 in inflammatory bowel disease (IBD). METHODS: Thirty-seven patients (18 males, 19 females, aged 8.8-26.1 years) with IBD (Crohn's disease, CD, n = 17, and ulcerative colitis, UC, n = 20) were studied. Patients were in relapse or remission according to established criteria. Serum IGF-1, IGFBP-3, IGFBP-2, IL-1beta and IL-6 levels were determined in patients and 15 healthy controls (aged 8.2-19.0 years). RESULTS: IGF-1 levels were lower in patients with CD in relapse compared with controls (p < 0.05). IGFBP-2 levels were higher in CD in relapse compared with other groups (all p < 0.05). In CD and UC patients (n = 37), IGF-1 levels were inversely correlated with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). IGFBP-2 levels correlated positively with ESR and IL-1beta. IL-6 levels correlated positively with ESR and CRP. IL-1beta levels were elevated in CD in relapse compared to controls (p < 0.05) and were higher in UC in relapse than in other groups (all p < 0.05). In combined CD/UC patients in relapse (n = 20), IL-1beta levels were higher (p < 0.05) in patients with recto-sigmoiditis (n = 5) than in other patients. CONCLUSIONS: IGF-1, IGFBP-2 levels were related to IL levels, disease activity and anatomical distribution, consistent with active inflammation modifying the IGF-IGFBP system, possibly relevant to disturbance of growth.     

Screening for vascular complications in children and adolescents with type 1 diabetes mellitus

Type 1 diabetes mellitus poses a significant health burden, particularly as a result of its microvascular complications. Clinically evident diabetes-related microvascular complications are extremely rare in childhood and adolescence. However, early functional and structural abnormalities may be present a few years after the onset of the disease. Therefore, regular screening for diabetic microvascular disease, particularly retinopathy and nephropathy, are of foremost importance in paediatric diabetes care. Early detection of diabetic microangiopathy and timely treatment of early signs of these complications have a pivotal role in prevention of blindness and end-stage renal failure in children and adolescents with diabetes.     

Association between serum free IGF-I and IGFBP-3 levels in type-I diabetes patients affected with associated autoimmune diseases or diabetic complications

BACKGROUND: Patients with type 1 diabetes (T1DM) present lower serum free IGF and IGFBP-3 values than healthy people. T1DM patients often present with associated autoimmune diseases such as thyroiditis or coeliac disease, and over time they frequently develop proliferative retinopathy, neuropathy or nephropathy in different combinations. OBJECTIVE: The aim of this study was to evaluate the effect of two associated autoimmune diseases or three diabetic complications on the serum free IGF-I or IGFBP-3 levels in T1DM patients, who also have a family history of T1DM. Design. 246 T1DM patients were enrolled, and then subdivided into groups according to diabetic complications or associated autoimmune diseases. Demographic and clinical data were recorded. Serum free IGF-I and IGFBP-3 levels were determined by IRMA. RESULTS: IGF-I and IGFBP-3 generally present correlated serum values as confirmed in this study. Those patients with autoimmune thyroiditis and coeliac disease presented with significantly lower serum values of IGFBP-3, whereas free IGF-I was significantly lower in patients with the different diabetic complications. Retinopathy presented a slightly significant reduction in serum free IGF-I, while neuropathy and nephropathy showed a more pronounced fall. The number of complications was related to progressively decreasing free IGF-I levels. T1DM family history was associated with lower serum free IGF-I concentrations. These findings were confirmed after correction for age, glycosylated haemoglobin levels, insulin treatment protocol, body mass index, serum creatinine and sex. CONCLUSION: Despite a direct correlation between serum free IGF-I and IGFBP-3, the correlation between the two molecules in patients with associated autoimmune diseases was lost, possibly due to different mechanisms of metabolic regulation.     

Inverse correlation between serum free IGF-I and IGFBP-3 levels and blood pressure in patients affected with type 1 diabetes

BACKGROUND: Even though the gene encoding for IGF-I is considered of most importance amongst blood pressure-regulating genes in mouse models, little and discordant data are available in literature for what concerns a possible relationship between blood pressure and serum free IGF-I values in humans. In addition, no information is available on type 1 diabetes patients. AIM: Our aim is to analyze the relationship between systolic and diastolic blood pressure and serum free IGF-I and IGFBP-3 levels in subjects suffering from type 1 diabetes. RESULTS: A highly significant inverse correlation was observed between serum free IGF-I levels and both systolic and diastolic blood pressure in subjects affected with type 1 diabetes. Similar but less significant relationships were observed for IGFBP-3, whose levels were also significantly and directly correlated with those of free IGF-I. The correlation between systolic and diastolic blood pressures with free IGF-I and between systolic blood pressure and IGFBP-3 levels were confirmed after adjusting for age, gender, age at diagnosis, disease duration, familial history, HBA1c, and amount of insulin administered by multivariate logistic regression analysis. A decrease in free IGF-I and IGFBP-3 levels, along with increases in blood pressure, significantly influenced the presence of diabetic complications, confirming how these molecules may be considered as severity markers for patients with type 1 diabetes as well as risk factors for altered pressure control linked diseases.     

Microvascular abnormalities in capillaroscopy correlate with higher serum IL-18 and sE-selectin levels in patients with type 1 diabetes complicated by microangiopathy

Microvascular abnormalities are one of the most important causes of persistent diabetic complications. The aim of this study was to compare microvascular changes examined by nailfold capillaroscopy with serum concentrations of soluble E-selectin (sE-selectin) and IL-18 in type 1 diabetic patients with and without microangiopathy. Serum levels of sE-selectin and IL-18 were determined by an enzyme-linked immunosorbent assay in 106 patients with type 1 diabetes and in 40 healthy controls. All diabetic patients were evaluated by extensive clinical, laboratory and capillaroscopic studies. Morphological changes were observed by nailfold capillaroscopy in 86 out of 106 (81%) diabetic patients. Severe capillaroscopic changes were seen in 32 out of 54 (59%) patients with microangiopathy, but in only seven out of 52 (13%) patients without microangiopathy. Higher serum levels of sE-selectin (p < 0.001) and IL-18 (p < 0.05) were demonstrated in diabetic patients compared to controls. Significant differences of sE-selectin (p , 0.001) and IL-18 (p < 0.01) serum concentrations were observed between diabetic patients with microangiopathy and controls. Moreover, comparison between patients with and without microangiopathic complications showed a significantly higher capillaroscopic score and sE-selectin serum concentration in the group with microangiopathy (p < 0.001). Furthermore, diabetic patients with severe microvascular changes in capillaroscopy showed significantly higher IL-18 (p < 0.001) and sE-selectin (p < 0.05) serum levels than subgroups without changes or with mild abnormalities. Our findings suggest that abnormalities in nailfold capillaroscopy may reflect the extent of microvascular involvement and are associated with higher sE-selectin and IL-18 serum levels, as well as with microangiopathic complications in diabetic patients.     

Influence of glutathione S-transferase polymorphisms on type-2 diabetes mellitus risk

Glutathione S-transferase (GST) protects cells against oxidative stress. We evaluated the effect of genetic polymorphisms of the GST gene family on the risk of developing type-2 diabetes mellitus and on glycemic control. We also investigated the effects of smoking combined with these polymorphisms on type-2 diabetes mellitus risk. We enrolled 100 type-2 diabetes mellitus patients and 100 healthy controls matched for age, gender and origin, from the Sinai area of Egypt. Fasting serum glucose, HbA(1c) and lipid profiles were determined. Two polymorphisms were identified by multiplex PCR within the GST genes: GSTM1 and GSTT1. The proportion of the GSTT1- and GSTM1-null genotypes was significantly greater in diabetic patients when compared to controls. Patients carrying both null polymorphisms had a 3.17-fold increased risk of having type-2 diabetes mellitus compared to those with normal genotypes of these two genes (P = 0.009). Additionally, patients with the GSTT1-null genotype had higher levels of triglycerides and very low-density lipoprotein cholesterol compared to those with the GSTT1-present genotype. On the other hand, patients with the GSTM1- null genotype had significantly higher levels of HbA(1c) and significantly higher diastolic blood pressure compared to those with the GSTM1- present genotype. The interaction between these genotypes and smoking status was not significant. These results give evidence that the GSTT1- and GSTM1-null genotypes, alone or combined, are associated with increased risk of type-2 diabetes mellitus, regardless of smoking status. Only the GSTM1-null genotype had an effect on glycemic control.     

4周有氧运动与饮食控制对肥胖女青少年血清IGF-1和IGF-1结合蛋白-3水平的影响

目的：研究4周中等强度有氧运动结合饮食控制对肥胖女青年、少年血清总胰岛素样生长因子1（IGF-1）、IGF-1结合蛋白3（IGFBP-3）水平和IGF-1活性的影响及其在体脂减少和糖脂代谢改善中的作用。方法：招募9名18~19岁肥胖女青年和30名14~16岁肥胖女少年,进行全封闭的4周中等强度有氧运动结合饮食控制干预。运动项目有游泳、跑步、健身操等,每周运动6 d,每天运动4 h,每运动30 min,休息5 min。运动强度从第1周的低强度（运动后即刻心率约100~120次/分）递增至第2~4周的中强度（运动后即刻心率约120~140次/分）。根据基础代谢率给予每日1 400或1 600 kcal的总能量。另招募正常体重女青年和女少年各9名作为对照组。检测肥胖女青年、少年在4周干预前、后和对照组女青年、少年的体重、身体质量指数（BMI）、腰围、空腹血糖、胰岛素和血脂水平以及血清总IGF-1和IGFBP-3的水平和IGF-1活性。结果：①与对照组相比,肥胖女青年、少年的血清总IGF-1和IGFBP-3水平均降低且肥胖女少年的IGF-1活性降低;②4周中等强度有氧运动结合饮食控制在显著降低肥胖女青年、少年的体脂、腰围和改善糖脂代谢的同时,降低血清IGFBP-3水平、增加IGF-1活性,但血清总IGF-1水平没有显著改变。且相关性分析显示IGF-1活性增加可能与肥胖女青年的腰围减少有关,但血清IGFBP-3水平的降低和IGF-1活性的增加与糖脂代谢的改善没有显著相关性。结论：4周中等强度有氧运动结合饮食控制降低肥胖女青年、少年的血清IGFBP-3水平、增加IGF-1活性;且IGF-1活性的增加可能与运动结合饮食控制降低肥胖女青年的腰围有关。     

Angiotensin converting enzyme (ACE) activity levels in insulin-independent diabetes mellitus and effect of ACE levels on diabetic patients with nephropathy

Involvement of complications is considered to be one of the major factors in the prognosis of diabetes mellitus (DM). Recent studies indicate that most diabetic complications such as nephropathy and hypertension are vascular-originated. Renin-angiotensin involvement, especially changes in ACE activity level, is considered to be a key factor since ACE converts angiotensin I to angiotensin II which is a potent vasoconstrictor and plays a vital role in the regulation of blood pressure. Our present study focused on ACE activity levels along with blood glucose and HbA(1c) levels in diabetic patients with (n=18) or without (n=25) nephropathy as compared to control subjects (n=25). Blood glucose levels were significantly higher in both diabetic groups compared to controls (p<0.001). On the other hand, compared to controls, blood HbA(1c) levels were slightly higher in DM patients without complications whereas they were significantly increased in nephropatic DM patients (p<0.001). There was a very strong increase (p<0.001) at the level of ACE activity in both of the diabetic groups (with nephropathy: 47.11+/-3.70 U l(-1); without complications: 43.72+/-2.93 U l(-1); controls: 25.15+/-2.30 U l(-1)). ACE activity levels were also significantly higher in diabetic patients with nephropathy than in type II DM patients without complication (p<0.01). Our results demonstrate that ACE activity levels are increased in diabetic patients. Additional significant increase in ACE activity levels in diabetic patients with complications such as nephropathy supports the hypothesis that ACE activity has an essential role in the development of complications in diabetes.     

Normal tissue plasminogen activator and plasminogen activator inhibitor activity in plasma from patients with type 1 diabetes mellitus.

The fibrinolytic system was investigated in 38 patients (21 males and 17 females) affected by type 1 diabetes mellitus (18 free from complications, 10 with retinopathy, and 10 with autonomic neuropathy) and in 8 healthy controls. Two separate fibrinolysis-stimulating tests were done: standardized venous occlusion and 1-desamino-8-D-arginine vasopressin infusion. Plasma tissue plasminogen activator antigen and activity and plasma plasminogen activator inhibitor activity were measured. All the patients were in good metabolic control (mean HbA1c 7.4%, range 6.1-8.0%). No significant differences were observed either between the diabetic patients and the control subjects, nor among the subgroups of diabetic patients. The fibrinolytic system is probably not involved in type 1 diabetes mellitus.     

Microvascular permeability is increased in both types of diabetes and correlates differentially with serum levels of insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF).

Vascular endothelial growth factor (VEGF) and insulin-like growth factor-I (IGF-I) both play a pivotal role in diabetic microangiopathy. This study assessed the relationship between capillary permeability as a marker of endothelial dysfunction and serum VEGF and IGF-I levels in normotensive diabetics. Subjects were 10 Type 1 (6/4, male/female, age: 30 [mean] +/- 5 [SD] years, HbA1c: 7.5 +/- 1.1 %), 13 Type 2 diabetics (9/4, m/f; 63 +/- 7 years, 8.3 +/- 1.8 %), and 24 age- and sex-matched control subjects. We determined nailfold capillary permeability by intravital fluorescence videomicroscopy after intravenous injection of sodium-fluorescein. Serum VEGF, free and total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and insulin levels were measured by specific immunoassays. Capillary permeability was increased in both types of diabetes patients compared to age- and sex-matched controls. In Type 1 diabetics, fluorescence light intensities increased over time, reaching significance 30 minutes after dye injection. Type 2 diabetics already revealed an early onset of elevated fluorescence light intensities after one minute. Capillary permeability showed a significant positive correlation with VEGF levels in Type 1 diabetics, (r = 0.76, p < 0.05; 20 min after dye injection) but with free IGF-I levels in type 2 diabetics (r = 0.65, p < 0.05; 5 min after dye injection). IGFBP-3 correlated negatively with capillary permeability in both diabetes types, whereas IGFBP-1 levels correlated positively in Type 2 patients. In conclusion, capillary permeability is increased in both types of diabetes mellitus. However, VEGF and IGF-I may differentially affect microvascular permeability depending on the diabetes type.     

缺氧复氧对滑膜细胞IGF-IGFBP-3 以及线粒体的影响

目的:探讨氧波动环境对原代成纤维样滑膜细胞(fibroblast-like synoviocyte, FLS)胰岛素样生长因子-1(insulin growth factor-1,IGF-1)、胰岛素样生长因子结合蛋白-3(insulin-like growth factor binding protein-3, IGFBP-3)及线粒体的影响。方法:分离并鉴定正常人滑膜细胞,再对滑膜细胞进行分组:对照组、缺氧/再充氧(hypoxia/reoxygenation,H/R)干预组。采用实时定量PCR检测滑膜细胞中IGF-1、IGFBP-3的m RNA水平;Western blot检测滑膜细胞中IGF-1、IGFBP-3的蛋白水平;流式细胞仪检测线粒体膜电位(Mitochondrial membrane potential, MMP)以及线粒体通透性转换孔(Mitochondrial Permeability Transition Pore, MPTP)的变化。结果:与对照组比较,H/R干预组的相对IGF-1和IGFBP-3的m RNA水平和蛋白表达水平显著升高(P0.05),膜电位水平降低(P0.05),线粒体通透性转换孔开放。结论:氧波动环境可促进IGF-1和IGFBP-3的表达及细胞线粒体损伤,其可能是骨关节炎(OA)发病的重要机制之一。     

The relationship between the IGF-I system and its binding proteins and microvascular reactivity in Type 1 diabetes mellitus

The system of IGF-I and its binding proteins may be involved in the pathogenesis of vascular damage in Type 1 diabetes. The aim of this study was to analyze the relationship between this system and the microvascular reactivity in Type 1 diabetes as measured by laser-Doppler flowmetry. Twenty-two Type 1 diabetic patients (13 women and 9 men) with microangiopathy and fifteen healthy subjects (8 women and 7 men) were examined clinically, underwent laser-Doppler flowmetry and intima-media thickness measurements. Fasting serum levels of IGF-I, free IGF-I, IGFBPs and lipids were examined. The microvascular reactivity was impaired in Type 1 diabetic patients. Maximal perfusion during post-occlusive reactive hyperemia (PORHmax) and during thermal hyperemia (THmax) was significantly decreased in Type 1 diabetes (p<0.01). Percentage perfusion increase in both tests (PORH and TH) was lower in Type 1 diabetes mellitus (p<0.01) and the reaction after heating was slower in diabetic patients (THmax) (p<0.01). We did not find any significant dependence of microvascular reactivity on the parameters of IGF-I or its binding proteins. We conclude that the microvascular reactivity is impaired in Type 1 diabetes mellitus, but this impairment is not clearly dependent on the activity of the IGF-I system. It is probably only a complementary pathogenic factor.     

Synthesis and characterization of biotinylated forms of insulin-like growth factor-1: topographical evaluation of the IGF-1/IGFBP-2 AND IGFBP-3 interface

Activation of the insulin-like growth factor-1 (IGF)-1 receptor signaling pathways by IGF-1 and IGF-2 results in mitogenic and anabolic effects. The bioavailability of the IGFs is regulated by six soluble binding proteins, the insulin-like growth factor binding proteins (IGFBPs), which bind with approximately 0.1 nM affinity to the IGFs and often serve as endogenous antagonists of IGF action. To identify key domains of IGF-1 involved in the interaction with IGFBP-2 and IGFBP-3, we employed IGF-1 selectively biotinylated on residues Gly 1, Lys 27, Lys 65, and Lys 68. All monobiotinylated species of IGF-1 exhibited high affinity ( approximately 0.1-0.2 nM) for IGFBP-2 and IGFBP-3 in solid-phase-binding assays. However, different labeling intensities were observed in ligand blot analysis of IGFBP-2 and IGFBP-3. The N(epsilon)(Lys65/68)(biotin)-IGF-1 (N(epsilon)(Lys65/68b)-IGF-1) probe exhibited the highest signal intensity, while N(alpha)(Gly1b)-IGF-1 and N(epsilon)(Lys27b)-IGF-1 demonstrated significantly lower signals. When taken together, these results suggest that, once bound to IGFBP-2 or IGFBP-3, the biotin moieties of N(alpha)(Gly1b)-IGF-1 and N(epsilon)(Lys27b)-IGF-1 are inaccessible to NeutrAvidin-peroxidase, the secondary binding component. Ligand blots using IGF-1 derivatized with a long chain form of the N-hydroxysuccinimide biotin (NHS-biotin) to yield N(alpha)(Gly1)(LC-biotin)-IGF-1 and N(epsilon)(Lys27)(LC-biotin)-IGF-1 demonstrated increased signal intensity compared with their NHS-biotin counterparts. In BIAcore analysis, IGFBP-2 and IGFBP-3 bound only to the N(epsilon)(Lys65/68b)-IGF-1-coated flowcell of a biosensor chip, confirming the inaccessibility of Gly 1 and Lys 27 when IGF-1 is bound to IGFBP-2 and IGFBP-3. These data confirm the involvement of the IGFBP-binding domain on IGF-1 in binding to IGFBP-2 and IGFBP-3 and support involvement of the IGF-1R-binding domain in IGFBP binding.     

Mutual regulation between IGF-1R and IGFBP-3 in human corneal epithelial cells

The insulin-like growth factor type 1 receptor (IGF-1R) is part of the receptor tyrosine kinase superfamily. The activation of IGF-1R regulates several key signaling pathways responsible for maintaining cellular homeostasis, including survival, growth, and proliferation. In addition to mediating signal transduction at the plasma membrane, in serum-based models, IGF-1R undergoes SUMOylation by SUMO 1 and translocates to the nucleus in response to IGF-1. In corneal epithelial cells grown in serum-free culture, however, IGF-1R has been shown to accumulate in the nucleus independent of IGF-1. In this study, we report that the insulin-like growth factor binding protein-3 (IGFBP-3) mediates nuclear translocation of IGF-1R in response to growth factor withdrawal. This occurs via SUMOylation by SUMO 2/3. Further, IGF-1R and IGFBP-3 undergo reciprocal regulation independent of PI3k/Akt signaling. Thus, under healthy growth conditions, IGFBP-3 functions as a gatekeeper to arrest the cell cycle in G0/G1, but does not alter mitochondrial respiration in cultured cells. When stressed, IGFBP-3 functions as a caretaker to maintain levels of IGF-1R in the nucleus. These results demonstrate mutual regulation between IGF-1R and IGFBP-3 to maintain cell survival under stress. This is the first study to show a direct relationship between IGF-1R and IGFBP-3 in the maintenance of corneal epithelial homeostasis.     

Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans

Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species. Calorie restriction (CR) decreases serum IGF-1 concentration by ~40%, protects against cancer and slows aging in rodents. However, the long-term effects of CR with adequate nutrition on circulating IGF-1 levels in humans are unknown. Here we report data from two long-term CR studies (1 and 6 years) showing that severe CR without malnutrition did not change IGF-1 and IGF-1 : IGFBP-3 ratio levels in humans. In contrast, total and free IGF-1 concentrations were significantly lower in moderately protein-restricted individuals. Reducing protein intake from an average of 1.67 g kg(-1) of body weight per day to 0.95 g kg(-1) of body weight per day for 3 weeks in six volunteers practicing CR resulted in a reduction in serum IGF-1 from 194 ng mL(-1) to 152 ng mL(-1). These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans. In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.     

Association between Circulating Levels of IGF-1 and IGFBP-3 and Lung Cancer Risk: A Meta-Analysis

Background

The insulin-like growth factor (IGF) system was documented to play a predominant role in neoplasia. As lung cancer is one of the most malignant cancers, we conducted a meta-analysis in order to investigate the strength of association between circulating IGF-1 and IGFBP-3 levels and lung cancer.

Methodology/Principal Findings

A systematic literature search was conducted to identify all prospective case-control studies and case-control studies on circulating IGFs and IGFBPs levels. Six nested case-control studies (1 043 case subjects and 11 472 control participants) and eight case-control studies (401 case subjects and 343 control participants) were included in this meta-analysis. Pooled measure was calculated as the inverse variance-weighted mean of the natural logarithm of multivariate adjusted OR with 95% CIs for highest vs. lowest levels to assess the association of circulating IGF-1 and IGFBP-3 concentrations and lung cancer. Standard mean difference (SMD) was also calculated to indicate the difference of the circulating IGF-1 and IGFBP-3 concentrations between the lung cancer case group and the control group. Of the nested case-control studies, ORs for the highest vs. lowest levels of IGF-1 and IGFBP-3 were 1.047 (95% CI: [0.802,1.367], P = 0.736) and 0.960 (95%CI: [0.591,1.559], P = 0.868) respectively; and SMDs were −0.079 (95%CI:[ −0.169, 0.011], P = 0.086) and −0.097 (95%CI:[ −0.264,0.071], P = 0.258) for IGF-1 and IGFBP-3 respectively. As to the case-control studies, SMDs were 0.568 (95%CI:[ −0.035, 1.171], P = 0.065) and −0.780 (95%CI:[ −1.358, −0.201], P = 0.008) for IGF-1 and IGFBP-3 respectively.

Conclusions/Significance

Inverse association was shown between IGFBP-3 and lung cancer in the case-control studies,and the circulating level of IGFBP-3 underwent a decline during tumorogenesis and development of lung cancer, which suggested IGFBP-3 a promising candidate for the biomarker of lung cancer.     

IGFBP-3, a marker of cellular senescence, is overexpressed in human papillomavirus-immortalized cervical cells and enhances IGF-1-induced mitogenesis

Human ectocervical cells, following retroviral transduction with the human papillomavirus type 16 E6/E7 oncogenes, are altered in their array of transcribed cellular genes, including increased mRNA for the insulin-like growth factor binding protein 3 (IGFBP-3). IGFBP-3 expression is associated with cellular senescence, and its addition to many cell types inhibits growth or induces apoptosis. By immunoblotting and enzyme-linked immunosorbent assay methods, we demonstrate that late-passage, immortalized E6/E7-transduced cells secrete high levels of IGFBP-3 (25 ng/ml), which represent a 500-fold increase compared to levels in early-passage, nonimmortalized transduced cells (<0.05 ng/ml). Concomitantly, these late-passage cervical cells exhibit an increase in sensitivity to IGF-1, including enhanced phosphorylation of the IGF receptor (IGF-R) and insulin receptor substrate as well as increased DNA synthesis (5-fold) and cell proliferation (3.7-fold). However, there was no change in the level of IGF-R in these cells (surface or total), and the cells did not synthesize IGF-1, indicating that these arms of the IGF pathway were independently regulated and not responsible for the augmented signaling. Consistent with a causal relationship between IGFBP-3 expression and enhanced IGF-1 responses, we found that early-passage cells could be converted to the late-passage, IGF-1-responsive phenotype by preincubation with IGFBP-3. Thus, in contrast to findings with some cell types, IGFBP-3 expression in cervical cells is associated with augmented IGF-1 signaling and cell proliferation and correlates with the timing of cellular immortalization.     

Increased circulating IL-8 is associated with reduced IGF-1 and related to poor metabolic control in adolescents with type 1 diabetes mellitus

Background: A dysregulated growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis is well-recognized in children and adolescents with type 1 diabetes mellitus (T1DM). Decreased IGF-1 levels can also be found in chronic inflammatory diseases, while hyperglycemia promotes inflammatory cytokine production. Therefore, inflammatory cytokines may link poor metabolic control with GH/IGF-1 axis changes. This study examined the relationship between serum inflammatory cytokines and IGF-1 in adolescents (age 13–18) with TIDM in chronic poor (n = 17) or favorable (n = 19) glucose control. Poor control (PC) was defined as 3, consistent HbA1C > 9% during the previous 2 years, while favorable control (FC) was consistent levels of HbA1C < 9%. Results: HbA1C (FC: 7.5 ± 0.6%; PC: 10.5 ± 0.9%, p < 0.001) and interleukin (IL)-8 (FC: 3.7 ± 4.0 pg/ml; PC: 7.4 ± 4.3 pg/ml, p = 0.01) were increased and IGF-1 (FC: 536.5 ± 164.3 ng/ml; PC: 408.9 ± 157.1 ng/ml, p = 0.03) was decreased in patients with poor control compared to patients with favorable control. Moreover, IL-8 was inversely correlated with IGF-1 (r = −0.40, p = 0.03) and positively correlated with HbA1C (r = 0.36, p = 0.03). Conclusions: In adolescents with T1DM and chronic, poor glucose control, increased serum IL-8 is associated with reduced IGF-1 suggesting a pro-inflammatory milieu that may contribute to alterations in the GH/IGF-1 axis.     

Protection of blood retinal barrier and systemic vasculature by insulin-like growth factor binding protein-3

Previously, we showed that insulin growth factor (IGF)-1 binding protein-3 (IGFBP-3), independent of IGF-1, reduces pathological angiogenesis in a mouse model of the oxygen-induced retinopathy (OIR). The current study evaluates novel endothelium-dependent functions of IGFBP-3 including blood retinal barrier (BRB) integrity and vasorelaxation. To evaluate vascular barrier function, either plasmid expressing IGFBP-3 under the regulation of an endothelial-specific promoter or a control plasmid was injected into the vitreous humor of mouse pups (P1) and compared to the non-injected eyes of the same pups undergoing standard OIR protocol. Prior to sacrifice, the mice were given an injection of horseradish peroxidase (HRP). IGFBP-3 plasmid-injected eyes displayed near-normal vessel morphology and enhanced vascular barrier function. Further, in vitro IGFBP-3 protects retinal endothelial cells from VEGF-induced loss of junctional integrity by antagonizing the dissociation of the junctional complexes. To assess the vasodilatory effects of IGFBP-3, rat posterior cerebral arteries were examined in vitro. Intraluminal IGFBP-3 decreased both pressure- and serotonin-induced constrictions by stimulating nitric oxide (NO) release that were blocked by L-NAME or scavenger receptor-B1 neutralizing antibody (SRB1-Ab). Both wild-type and IGF-1-nonbinding mutant IGFBP-3 (IGFBP-3NB) stimulated eNOS activity/NO release to a similar extent in human microvascular endothelial cells (HMVECs). NO release was neither associated with an increase in intracellular calcium nor decreased by Ca(2+)/calmodulin-dependent protein kinase II (CamKII) blockade; however, dephosphorylation of eNOS-Thr(495) was observed. Phosphatidylinositol 3-kinase (PI3K) activity and Akt-Ser(473) phosphorylation were both increased by IGFBP-3 and selectively blocked by the SRB1-Ab or PI3K blocker LY294002. In conclusion, IGFBP-3 mediates protective effects on BRB integrity and mediates robust NO release to stimulate vasorelaxation via activation of SRB1. This response is IGF-1- and calcium-independent, but requires PI3K/Akt activation, suggesting that IGFBP-3 has novel protective effects on retinal and systemic vasculature and may be a therapeutic candidate for ocular complications such as diabetic retinopathy.