Insulin Binding Protein Research Articles

Effect of 10-hours Time Restricted Diet on Breast Cancer Risk in Pre and Postmenopausal Women with Overweight or Obesity: TRED Pilot Study

ObjectivesThis study examined the effect of 10-h time restricted diet on breast cancer risk, assessing changes in body weight, insulin, IGF-1, and IGF binding protein 1, 2, and 3 among pre and postmenopausal women with overweight and obesity.MethodsWomen with overweight or obesity (n = 25) were enrolled into a time-restricted diet for 6 months. Participants were instructed to eat only from 10am until 8pm and to record consumption on the TRED smartphone app. At weeks 1, 2, 12, and 24, participants were asked to complete food diaries. During the other weeks, participants simply recorded the category of food consumed (meal or snack). Compliance was calculated as percentage of days when food consumption was reported.Results25 women with a BMI between 25 and 40 (32.3 ± 4.2) and age between 18–65 years old (46.5 ± 11.0) were enrolled. Average weight loss was 0.8 ± 4.6 kg (−0.6%). Fat percentage, muscle mass remained unchanged. Insulin and IGFBP 2 significantly increased from baseline to post intervention and to follow up. However, the change is not clinically significant. IGF-1 and IGFBP1 significantly decreased from baseline to follow up. Average adherence to the diet protocol was high: 78% of participants recorded dietary intake on at least 77% of intervention days.ConclusionsThe TRED 10-hour eating window did not lead to weight loss, body fat loss, or decreasing waist circumference among pre and postmenopausal women with overweight or obesity. However, the intervention significantly improved some biomarkers of breast cancer risk (IGF-1, IGFBP 2 and IGFBP 3).Funding SourcesThis study was supported by NIH/NCI training grant T32 CA193193.

Endocrinology: Non-insulin-producing cells secrete insulin under nutrient shortage

A new study reveals that Drosophila insulin-like peptides (Dilps) accumulate in adipokinetic hormone (AKH)-producing cells in a manner dependent on the insulin-binding protein ImpL2. Under nutrient limitation, AKH and Dilps are released from these cells, maintaining the local tissue-specific activation of insulin signaling in steroidogenic organs and impacting the timing of pupariation.

The steroid hormone ecdysone regulates growth rate in response to oxygen availability

In almost all animals, physiologically low oxygen (hypoxia) during development slows growth and reduces adult body size. The developmental mechanisms that determine growth under hypoxic conditions are, however, poorly understood. Here we show that the growth and body size response to moderate hypoxia (10% O2) in Drosophila melanogaster is systemically regulated via the steroid hormone ecdysone. Hypoxia increases level of circulating ecdysone and inhibition of ecdysone synthesis ameliorates the negative effect of low oxygen on growth. We also show that the effect of ecdysone on growth under hypoxia is through suppression of the insulin/IGF-signaling pathway, via increased expression of the insulin-binding protein Imp-L2. These data indicate that growth suppression in hypoxic Drosophila larvae is accomplished by a systemic endocrine mechanism that overlaps with the mechanism that slows growth at low nutrition. This suggests the existence of growth-regulatory mechanisms that respond to general environmental perturbation rather than individual environmental factors.

Wearables, Respiratory Rehabilitation, Acute Myocardial Infarction and Frailty, and High-Intensity Respiratory Muscle Training

Wearables, Respiratory Rehabilitation, Acute Myocardial Infarction and Frailty, and High-Intensity Respiratory Muscle Training

Secretagogin Regulates Insulin Signaling by Direct Insulin Binding.

SummarySecretagogin (SCGN) is a β-cell enriched, secretory/cytosolic Ca2+-binding protein with unknown secretory regulation and functions. Recent findings suggest that SCGN deficiency correlates with compromised insulin response and diabetes. However, the (patho)physiological SCGN-insulin nexus remains unexplored. We here report that SCGN is an insulin-interacting protein. The protein-protein interaction between SCGN and insulin regulates insulin stability and increases insulin potency in vitro and in vivo. Mutagenesis studies suggest an indispensable role for N-terminal domain of SCGN in modulating insulin stability and function. SCGN supplementation in diabetogenic-diet-fed mice preserves physiological insulin responsiveness while relieving obesity and cardiovascular risk. SCGN-insulin interaction mediated alleviation of hyperinsulinemia by increased insulin internalization, which translates to reduced body fat and hepatic lipid accumulation, emerges as a plausible mechanism for the preservation of insulin responsiveness. These findings establish SCGN as a functional insulin-binding protein (InsBP) with therapeutic potential against diabetes.

Increased Akt signaling in the fat body of Anopheles stephensi extends lifespan and increases lifetime fecundity through modulation of insulin-like peptides

Insulin-like peptides (ILPs) and the insulin/insulin-like growth factor 1 signaling (IIS) cascade regulate numerous physiological functions, including lifespan, reproduction, immunity, and metabolism, in diverse eukaryotes. We previously demonstrated that in female Anopheles stephensi and Aedes aegypti mosquitoes, activation of the IIS cascade in the fat body led to a significant increase in lifespan. In this work, we elucidated two putative mechanisms in A. stephensi behind the observed lifespan extension and assessed whether this lifespan extension confers an overall fitness advantage to the mosquito. Specifically, we demonstrated that increased Akt signaling in the mosquito fat body following a blood meal significantly suppressed the expression of ILP2 in the head. Moreover, overexpression of active Akt in the fat body altered the expression of a putative insulin binding protein ortholog, Imaginal morphogenesis protein-Late 2 (Imp-L2), in response to transgene expression. Combined, these two factors may act to reduce overall levels of circulating ILP2 or other ILPs in the mosquito, in turn conferring increased survival. We also examined the impact increased fat body IIS had on lifetime fecundity and demonstrated that transgenic female mosquito populations had higher lifetime fecundity relative to non-transgenic sibling controls. These studies provide new insights into the complex hormonal and molecular mechanisms regulating the interplay between IIS, aging, and reproduction in this important vector of human malaria parasites.

Effects of dietary chromium propionate on growth performance, metabolism, and immune biomarkers in heat-stressed finishing pigs1.

Study objectives were to determine the effects of chromium (Cr) propionate (Cr propionate 0.04%; 0.5 g/kg of feed to deliver 200 parts per billion Cr/d; KemTRACE Cr, Kemin Industries, Inc., Des Moines, IA) on growth performance, metabolism, and health biomarkers in heat-stressed and nutrient-restricted pigs. Crossbred barrows (n = 96; 105 ± 1 kg BW) were enlisted in an experiment conducted in two replicates, blocked by initial BW, and randomly assigned to one of six dietary-environmental treatments: (i) thermoneutral (TN) and fed ad libitum a control diet (TNCtl), (ii) TN and fed ad libitum a Cr supplemented diet (TNCr), (iii) TN and pair-fed a control diet (PFCtl), (iv) TN and pair-fed a Cr supplemented diet (PFCr), (v) heat stress (HS) and ad libitum fed a control diet (HSCtl), or (vi) HS and ad libitum fed a Cr supplemented diet (HSCr). The study consisted of three experimental periods (P). During P0 (5 d), all pigs were housed in TN conditions (21.3 ± 0.1 °C, 56.8 ± 0.3% relative humidity [RH]) and fed the control diet ad libitum. During P1 (5 d), pigs were fed their respective dietary treatments ad libitum and kept in TN conditions. During P2 (35 d), HSCtl and HSCr-treated pigs were fed ad libitum and exposed to progressive cyclical HS conditions (27 to 31 °C, 50 ± 0.3% RH), while TNCtl, TNCr, PFCtl, and PFCr pigs remained in TN conditions and were fed ad libitum or pair-fed to their respective HSCtl and HSCr counterparts to eliminate the confounding effects of dissimilar feed intake. Overall, HS pigs had increased (P < 0.01) rectal temperature, skin temperature, and respiration rate (0.3 °C, 3.8 °C, and 32 breaths per minute, respectively) relative to TN pigs. Overall, HS decreased ADFI and ADG (20 and 21%, respectively; P < 0.01) compared with TN controls. Final BW tended to be increased in HSCr (2.7 kg, P = 0.06) compared with HSCtl pigs. Similarly, ADG tended to be increased during P2 in HSCr relative to HSCtl-treatment (0.77 vs. 0.72 kg/d; P = 0.10). There were no effects of Cr on most production parameters, but ADFI tended to be increased in Cr relative to Ctl-fed pigs (3.19 vs. 3.09 kg/d; P = 0.08). No effects of Cr supplementation were detected on circulating glucose, insulin, NEFA, cholesterol, triglycerides, or lipopolysaccharide binding protein. However, blood neutrophils were increased in HSCr (37%; P < 0.01) relative to HSCtl pigs. In summary, these results suggest Cr supplementation may benefit growth performance during HS.

Staphylococcus aureus blocks insulin function.

The bacterial pathogen Staphylococcus aureus secretes a high-affinity insulin-binding protein that mediates insulin resistance, a major driver of obesity and type 2 diabetes, in a mouse model of infection.

The extracellular domain of Staphylococcus aureus LtaS binds insulin and induces insulin resistance during infection

Insulin resistance is a risk factor for obesity and diabetes and predisposes individuals to Staphylococcus aureus colonization; however, the contribution of S. aureus to insulin resistance remains unclear. Here, we show that S. aureus infection causes impaired glucose tolerance via secretion of an insulin-binding protein extracellular domain of LtaS, eLtaS, which blocks insulin-mediated glucose uptake. Notably, eLtaS transgenic mice (eLtaS trans ) exhibited a metabolic syndrome similar to that observed in patients, including increased food and water consumption, impaired glucose tolerance and decreased hepatic glycogen synthesis. Furthermore, transgenic mice showed significant metabolic differences compared to their wild-type counterparts, particularly for the early insulin resistance marker α-hydroxybutyrate. We subsequently developed a full human monoclonal antibody against eLtaS that blocked the interaction between eLtaS and insulin, which effectively restored glucose tolerance in eLtaS trans and S. aureus-challenged mice. Thus, our results reveal a mechanism for S. aureus-induced insulin resistance.

Molecular Analysis of the SRD5A1 and SRD5A2 Genes in Patients with Benign Prostatic Hyperplasia with Regard to Metabolic Parameters and Selected Hormone Levels.

Introduction: The etiology of benign prostatic hyperplasia (BPH) has not so far been fully explicated. However, it is assumed that changes in the levels of hormones associated with aging can contribute to the development of prostatic hyperplasia. Dihydrotestosterone combines with the androgen receptor (AR) proteins of the prostate gland. Enzyme activity is based on two isoenzymes: type 1 and type 2. 5α-reductase type 1 is encoded by the SRD5A1 gene, and type 2 is encoded by the SRD5A2 gene. The aim of our study was to determine the frequency of the SRD5A1 (rs6884552, rs3797177) and SRD5A2 (rs523349, rs12470143) genes’ polymorphisms, and to assess the relationships between the genotypes of the tested mutations, and the levels of biochemical and hormonal parameters in patients with BPH. Material and Methods: The study involved 299 men with benign prostatic hyperplasia. We determined the serum levels of particular biochemical parameters—fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides (TG)—by the spectrophotometric method, using ready reagent kits. The ELISA method was used to determine the levels of the following hormonal parameters and proteins: total testosterone (TT), free testosterone (FT), insulin (I), luteinizing hormone (LH), and sex hormone binding protein (SHBG). Metabolic syndrome was diagnosed. Genotyping was performed by real-time PCR. Results: We analyzed the relationships between the incidence of particular diseases and the genotypes of the SRD5A1 and SRD5A2 polymorphisms among patients with BPH. The BPH patients with the CC genotype of the SRD5A2 rs523349 and rs12470143 polymorphisms were considerably less frequently diagnosed with metabolic syndrome (MetS) (p = 0.022 and p = 0.023 respectively). Our analysis revealed that homozygotes with the CC of the SDR5A2 rs12470143 polymorphism had visibly higher HDL levels than those with the TT and CT genotypes (p = 0.001). Additionally, we found that the patients with the CC genotype of the SDR5A2 rs12470143 polymorphism had considerably higher FT levels (p = 0.001) than the heterozygotes with the CT and the homozygotes with the TT of the genetic variant analyzed in our study. Furthermore, the patients with at least one G allele of the SRD5A2 rs523349 polymorphism had significantly lower SGBG levels (p = 0.022) compared with the homozygotes with the CC genotype. The presence of at least one A allele (AA + AG genotypes) of the SRD5A1 rs3797177 polymorphism entailed notably lower serum insulin levels than those observed in homozygotes with the GG genotype (p = 0.033). Conclusions: The study described in this article shows that selected SRD5A1 and SRD5A2 polymorphisms can alter the levels of metabolic and hormonal parameters in patients with BPH. Special attention should be paid to the SDR5A2 rs12470143 polymorphism, which is associated with a change in lipid profile, as well as with the inheritance and incidence rate of MetS among these patients. An analysis of the frequency of this polymorphism among BPH patients could be useful in estimating the risk of getting ill, and planning therapies of concomitant diseases for BPH patients.

2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP) induces gene expression changes in JAK/STAT and MAPK pathways related to inflammation, diabetes and cancer.

Background2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), a heterocyclic aromatic amine (HCA) formed in meat that is cooked at high temperatures and then ingested, can potentially be retained in human adipose tissues.MethodsTo determine if PhIP is bioactive in the adipocyte, we exposed a human adipocyte cell line,HepG2 and Caco-2 cells to low dose PhIP. Uptake and retention of PhIP was determined and cytotoxicity was assessed by the TUNEL assay. Relative expression of PhIP-activating genes (CYP1A1, CYP1A2, SULT1A1 and UGT1A1) was determined by RT-PCR and global expression changes were also examined.ResultsThe percent retention of 0.1 μCi [14C]-PhIP over a 24 h period was significantly higher in the adipocyte than the HepG2 (p = 0.0001) and Caco-2 (p = 0.0007) cell lines. Cytotoxicity rates were 14.4 and 2.6 % higher compared to controls in Caco-2 and HepG2 cells (p < 0.001 and 0.054, respectively); no significant differences were detected in adipocyte cells (p = 0.18). Caco-2 and HepG2 cells, respectively, had significantly higher basal expression of CYP1A1 (p = 0.001, p = 0.003), SULT1A1 (p = 0.04, p < 0.001) and UGT1A1 (p < 0.001, p = 0.01) compared to the adipocyte. Exposure to 5nM PhIP did not significantly induce expression of these genes in any of the cell lines. Global gene expression analysis of mature adipocytes exposed to 5nM PhIP for 72 h resulted in statistically significant changes in 8 genes (ANGPTL2, CD14, CIDEA, EGR1, FOS, IGFBP5, PALM and PSAT1). Gene-gene interaction and pathway analysis indicates that PhIP modulates genes controlled by the STAT3 transcriptional factor and initiates leptin signaling via the JAK/STAT and MAPK pathway cascades. Early growth response 1 (EGR1) and prostaglandin synthase 2 (COX-2) were down-regulated via c-Fos, while insulin binding protein 5 (IBP5) was up regulated. Expression of transcription factors (ANGPTL2, HP, LEP, SAA1, SAA2), genes related to inflammation (SAA1, LEP), diabetes (IGFBP5) and cancer risk (SAA2) were also elevated upon exposure to 5 nM PhIP..ConclusionsPhIP mediates gene expression changes within the adipocyte, and the pathways most affected are related to cancer and other chronic diseases. Further studies are needed on the relationship between dietary carcinogens such as PhIP with cancer, obesity and diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-016-0111-0) contains supplementary material, which is available to authorized users.

An insulin-binding protein from the venom of a solitary wasp Eumenes pomiformis binds to apolipophorin III in lepidopteran hemolymph

EpIBP, an insulin-like peptide-binding protein, is a major protein component of the venom of a solitary hunting wasp, Eumenes pomiformis. To evaluate the bioactivity, bacteria-expressed EpIBP was injected into Spodoptera exigua larvae, resulting in a higher survival rate and reduced loss of body weight under starvation conditions than control larvae. EpIBP was found to interact with apolipophorin III (apoLp III), implying that EpIBP might function by altering the apoLp III-mediated metabolism of prey.

Amblyomma americanum tick saliva insulin-like growth factor binding protein-related protein 1 binds insulin but not insulin-like growth factors.

Silencing Amblyomma americanum insulin-like growth factor binding protein-related protein 1 (AamIGFBP-rP1) mRNA prevented ticks from feeding to repletion. In this study, we used recombinant (r)AamIGFBP-rP1 in a series of assays to obtain further insight into the role(s) of this protein in tick feeding regulation. Our results suggest that AamIGFBP-1 is an antigenic protein that is apparently exclusively expressed in salivary glands. We found that both males and females secrete AamIGFBP-rP1 into the host during feeding and confirmed that female ticks secrete this protein from within 24-48 h after attachment. Our data suggest that native AamIGFBP-rP1 is a functional insulin binding protein in that both yeast- and insect cell-expressed rAamIGFBP-rP1 bound insulin, but not insulin-like growth factors. When subjected to anti-blood clotting and platelet aggregation assays, rAamIGFBP-rP1 did not have any effect. Unlike human IGFBP-rP1, which is controlled by trypsinization, rAamIGFBP-rP1 is resistant to digestion, suggesting that the tick protein may not be under mammalian host control at the tick feeding site. The majority of tick-borne pathogens are transmitted 48 h after the tick has attached. Thus, the demonstrated antigenicity and secretion into the host within 24-48 h of the tick starting to feed makes AamIGFBP-rP1 an attractive target for antitick vaccine development.

Effect of endogenous galanin on glucose transporter 4 expression in cardiac muscle of type 2 diabetic rats

Although galanin has been shown to increase glucose transporter 4 (GLUT4) expression in skeletal muscle and adipocytes of rats, there is no literature available about the effect of galanin on GLUT4 expression in cardiac muscle of type 2 diabetic rats. In this study, we investigated the relationship between intracerebroventricular administration of M35, a galanin receptor antagonist, and GLUT4 expression in cardiac muscle of type 2 diabetic rats. The rats tested were divided into four groups: rats from healthy and type 2 diabetic drug groups were injected with 2μM M35 for three weeks, while both control groups with 2μl vehicle control. The euglycemic-hyperinsulinemic clamp test was conducted for an index of glucose infusion rates. The cardiac muscle was processed for determination of GLUT4 expression levels. The present study showed that the plasma insulin and retinol binding protein 4 (RBP4) levels were higher in both drug groups than controls respectively. Moreover, the results showed the inhibitive effect of central M35 treatment on glucose infusion rates in the euglycemic-hyperinsulinemic clamp test and GLUT4 expression levels in the cardiac muscle. These results demonstrate that endogenous galanin, acting through its central receptor, has an important attribute to increase GLUT4 expression, leading to enhance insulin sensitivity and glucose uptake in cardiac muscle of type 2 diabetic rats. Galanin and its fragment can play a significant role in regulation of glucose metabolic homeostasis in cardiac muscle and galanin is an important hormone relative to diabetic heart.

Plasma non-esterified fatty acid levels in children and their relationship with sex steroids

ObjectivePuberty is associated with decreased insulin sensitivity. Sexual hormones have been related with the onset of insulin resistance, but their relationship with non-esterified fatty acids (NEFA) remains unexplored. The aim of this study was to evaluate circulating NEFA levels in population-based samples of prepubertal children and adolescents and to analyze the association of NEFA with obesity, insulin resistance, and sexual hormones in adolescents. ExperimentalThe studied population included 854 randomly selected 6–8-year-old children and 822 children aged 12–16years. NEFA levels were determined using a commercial kit. Testosterone and estradiol levels were determined by RIA, and insulin and sex hormone binding protein by IRMA. HOMA was calculated as an indicator of insulin resistance. ResultsNEFA levels were lower in adolescents than in 6–8-year-old children, and decreased progressively with age between 12-year-olds and 16-year-olds. No significant differences in NEFA levels were observed between obese and non-obese adolescents. NEFA were not correlated with insulin or HOMA in 12–16-year-old girls, and appear negatively correlated with these variables in boys. Insulin and HOMA were negatively correlated with SHBG levels in both sexes adjusting by age but NEFA levels were not. ConclusionsNEFA levels decrease with age in adolescents and are not significantly increased in obese children, supporting the fact that the decreased insulin sensitivity at this age is not affecting NEFA metabolism. Although SHBG is related to insulin and HOMA independently of age in both sexes, SHBG levels are not associated with NEFA.

Local requirement of the Drosophila insulin binding protein imp-L2 in coordinating developmental progression with nutritional conditions

In Drosophila, growth takes place during the larval stages until the formation of the pupa. Starvation delays pupariation to allow prolonged feeding, ensuring that the animal reaches an appropriate size to form a fertile adult. Pupariation is induced by a peak of the steroid hormone ecdysone produced by the prothoracic gland (PG) after larvae have reached a certain body mass. Local downregulation of the insulin/insulin-like growth factor signaling (IIS) activity in the PG interferes with ecdysone production, indicating that IIS activity in the PG couples the nutritional state to development. However, the underlying mechanism is not well understood. In this study we show that the secreted Imaginal morphogenesis protein-Late 2 (Imp-L2), a growth inhibitor in Drosophila, is involved in this process. Imp-L2 inhibits the activity of the Drosophila insulin-like peptides by direct binding and is expressed by specific cells in the brain, the ring gland, the gut and the fat body. We demonstrate that Imp-L2 is required to regulate and adapt developmental timing to nutritional conditions by regulating IIS activity in the PG. Increasing Imp-L2 expression at its endogenous sites using an Imp-L2-Gal4 driver delays pupariation, while Imp-L2 mutants exhibit a slight acceleration of development. These effects are strongly enhanced by starvation and are accompanied by massive alterations of ecdysone production resulting most likely from increased Imp-L2 production by neurons directly contacting the PG and not from elevated Imp-L2 levels in the hemolymph. Taken together our results suggest that Imp-L2-expressing neurons sense the nutritional state of Drosophila larvae and coordinate dietary information and ecdysone production to adjust developmental timing under starvation conditions.

Severe Hyperemesis Gravidarum Is Associated With Reduced Insulin Sensitivity in the Offspring in Childhood

Hyperemesis gravidarum alters maternal (and possibly fetal) nutrition throughout pregnancy, but there are no data on long-term effects on offspring metabolism. Thus, we aimed to assess whether severe hyperemesis gravidarum (SHG) affects glucose homeostasis and body composition in the offspring in childhood. Healthy prepubertal children (aged 4-11 years) born at term were studied: offspring of mothers who were admitted to hospital with SHG (n = 36) and offspring of mothers from control pregnancies (n = 42). Primary outcome was insulin sensitivity measured using iv glucose tolerance tests and Bergman's minimal model. Other assessments included lipid and hormonal profiles and body composition using whole-body dual-energy x-ray absorptiometry. Insulin sensitivity in SHG children was 20% lower than in controls (8.49 vs 10.60 × 10(-4)·min(-1)·(mU/L); P = .014). SHG children also had higher fasting insulin (6.88 vs 5.04 mIU/L; P = .024) and lower IGF binding protein 1 (11.8 vs 19.0 ng/mL; P = .004) concentrations than controls. Baseline cortisol concentrations were 22% higher in SHG offspring (256 vs 210 nmol/L; P = .021). Children in both groups were anthropometrically similar. Children born to mothers who experienced SHG have lower insulin sensitivity, which may increase their long-term risk of developing diabetes mellitus. Follow-up of SHG offspring is essential to determine later risk of metabolic disease.

183 Isolation and partial characterization of a general hormone transporting blood protein complex

Using immobilized insulin, human blood serum insulin-binding proteins were isolated at physiological pH values and zinc concentrations. By means of enzyme-linked immunoassay, albumin (26.7 ± 1.75%), α-fetoprotein (2 ± 0.61%), transferin (10 ± 0.73%), retinol-binding protein (4 ± 0.75%), and immunoglobulin G (20.3 ± 0.95%) were identified in isolated protein complex from human blood serum. Gel filtration of isolated proteins on Sephadex G-75 has demonstrated formation of a supramolecular complex under pH 7.2 and zinc concentration of 1 mg/mL (Garipova et al., 2010). The possible existence of such complex is supported by the presence of lipocalin glycoproteins such as retinol-binding protein and transferrin in obtained proteins; lipocalins form the protein family, which is capable to form intermolecular complexes to ensure the delivery of hormones to target cells through their own cell receptors (Flower, 1996). It has been shown that the isolated protein complex, along with insulin, transports other hydrophilic hormones. By means of ELISA, protein hormones such as luteinizing (1 mU/mg), thyreotropic (0.03 mM/mg) hormones, and prolactin (0.5 mU/mg) were identified. In addition, the complex has included hydrophobic hormones: thyroxin (11.0 ± 0.5 nmol/mg), triiodothyronine (1.3 ± 0.06 nmol/mg), and testosterone (7.0 ± 0.03 nmol/mg). Based on these data, we have proposed an existence in human blood of a general transporting complex that is common for both hydrophobic and hydrophilic hormones. The core of this complex is formed by transporting proteins, including those relating to lipokalins. This complex transfers thyroxin, triiodothyronine, testosterone, thyroid-stimulating hormone, prolactin, and luteinizing hormone, as well as triglycerides and cholesterol to the tissues. The composition of insulin-binding protein complex was significantly changed in the insulin-dependent diabetes mellitus patient’s blood. Albumin and α-fetoprotein, which are present in a normal complex, are revealed only in trace amounts in samples isolated from the diabetic blood and are replaced by α1-acid glycoprotein, and possibly other unidentified proteins. Disturbance of hormone-transporting complex protein composition in the diabetic blood may be a reason of insulin delivery disruption. Perhaps, for the same reason, delivery to target cells of not only insulin, but also other members of the hormone-transporting complex, is disrupted in the diabetic blood.

Abstract P3-01-01: Insulin, Insulin-like Growth Factor-1 and cycling estrogen predict premenopausal mammographic density.

Abstract Background: Mammographic density, a strong biomarker for breast cancer risk, represents epithelial and stromal proliferation. Insulin and insulin-like growth factor (IGF)-1 are suggested to influence cellular proliferation, while estrogen is a key factor in breast cancer development. However, whether the effects of these hormones among premenopausal women are mediated through mammographic density is less known. Material and Methods: Fasting serum insulin, IGF-1, and IGF binding protein (IGFBP)-3 were assessed among 202 healthy premenopausal women (Norwegian Energy Balance and Breast cancer Aspects study-I (EBBA-I). Daily salivary levels of 17β-estradiol throughout an entire menstrual cycle were measured at the reproductive Ecology Laboratory, Harvard University, USA. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms taken at day 7–12 of the menstrual cycle. Uni- and multivariable regression models were used to study the associations between hormones and premenopausal percent mammographic density. Results: Among women with a mean age of 30,7 years, a mean premenopausal percent mammographic density of 29.8 % was observed. Throughout the menstrual cycle when comparing women with a high percent mammographic density (≥28.5%) to women with a low percent mammographic density (&amp;lt;28.5%), we observed insulin, IGF-1 and IGFBP-3 independently and in combination with cycling 17β-estradiol to predict premenopausal percent mammographic density. We observed among women with either serum insulin ≥89 pmol/, IGF-1 ≥24 nmol/l, IGFBP-3 ≥ 100 nmol/l, having a high (≥28.5%) versus a low (&amp;lt;28.5%) percent mammographic density was associated with an increase in overall average 17β-estradiol of 4.0 %, 10.9 % and 14.9%, respectively. Moreover, we observed a higher adjusted Odds Ratio (OR) for having a high percent mammographic density for each standard deviation (SD) increase in overall average 17β -estradiol, insulin, IGF-1 and IGFBP-3: 17β-estradiol, 1.55 (1.06–2.27); insulin, 1.62 (0.76–3.48), IGF-1, 1.90 (1.10–3.27); IGFBP-3, 1.88 (1.05–3.37) (adjusted for age, body mass index-BMI kg/m2)). Conclusion: Our study supports that insulin, IGF-1 and IGFBP-3 independently, and in combination with cycling estrogen, predicts premenopausal mammographic density. These hormones may be important biomarkers in breast cancer control and clinical practice. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-01-01.

Effects of chronic slow release-lanreotide treatment on insulin-like growth factor system and metabolic parameters in acromegalic patients.

Insulin and IGF binding protein (IGFBP)-1 are linked by negative association. Somatostatin (SS) reduces insulin secretion by acting on pancreatic β-cell and also by decreasing GH secretion. SS analogues in acromegaly reduce total IGF-I levels inhibiting GH hypersecretion, but they also reduce free IGF-I bioactivity increasing IGFBP-1 levels by inducing insulin decrease. In 13 acromegalic patients we studied GH, IGF system, insulin, and glucagon levels at baseline and at 7 days, 1 and 6 months under treatment with slow release (SR)-lanreotide (LAN) (60 mg im monthly). The hormonal and metabolic response to arginine (ARG) (0.5 g/kg iv in 30 min) was also studied at each time point. LAN decreased GH, total IGF-I, and IGFBP-3 levels at each time point. Insulin and glucagon levels were reduced, while IGFBP-1 and free IGF-I levels were increased by LAN at day 7 and after 1 month only. LAN did not modify the GH, insulin, glucagon, glucose, and IGFBP-1 responses to ARG. At each time point ARG-induced insulin increase was coupled to increase in glucagon and IGFBP-1 levels. This study shows that acromegalic patients under chronic treatment with LAN display: a) inhibition of GH and total IGF-I levels, not coupled to persistent decrease in free IGF-I levels; b) persistent decrease in IGFBP- 3 but transient decrease and increase in insulin and IGFBP- 1, respectively; c) unchanged hormonal and metabolic response to ARG. Our findings also show that ARG stimulates IGFBP-1 despite marked increase in insulin secretion; this escape from the negative relationship linking insulin and IGFBP- 1 would likely reflect the ARG-induced glucagon increase.