Calcium and cholecalciferol supplementation provides no added benefit to nutritional counseling to improve bone mineral density in survivors of childhood acute lymphoblastic leukemia (ALL).

BACKGROUND: We sought to improve lumbar spine bone mineral density (LS-BMD) in long-term survivors of childhood acute lymphoblastic leukemia (ALL) using calcium and cholecalciferol supplementation. PROCEDURE: This double-blind, placebo-controlled trial randomized 275 participants (median age, 17 [9-36.1] years) with age- and gender-specific LS-BMD Z-scores <0 to receive nutritional counseling with supplementation of 1,000 mg/day calcium and 800 International Unit cholecalciferol or placebo for 2 years. The primary outcome was change in LS-BMD assessed by quantitative computerized tomography (QCT) at 24 months. Linear regression models were employed to identify the baseline risk factors for low LS-BMD and to compare LS-BMD outcomes. RESULTS: Pre-randomization LS-BMD below the mean was associated with male gender (P = 0.0024), White race (P = 0.0003), lower body mass index (P < 0.0001), and cumulative glucocorticoid doses of ≥ 5,000 mg (P = 0.0012). One hundred eighty-eight (68%) participants completed the study; 77% adhered to the intervention. Mean LS-BMD change did not differ between survivors randomized to supplements (0.33 ± 0.57) or placebo (0.28 ± 0.56). Participants aged 9-13 years and those 22-35 years had the greatest mean increases in LS-BMD (0.50 ± 0.66 and 0.37 ± 0.23, respectively). Vitamin D insufficiency (serum 25[OH]D <30 ng/ml) found in 296 (75%), was not associated with LS-BMD outcomes (P = 0.78). CONCLUSION: Cholecalciferol and calcium supplementation provides no added benefit to nutritional counseling for improving LS-BMD among adolescent and young adult survivors of ALL (93% of whom had LS-BMD Z-scores above the mean at study entry).

Endocannabinoid crosstalk between placenta and maternal fat in a baboon model (Papio spp.) of obesity.

INTRODUCTION: Maternal obesity (MO) remains a serious obstetric problem with acute and chronic morbidities for both mothers and offspring. The mechanisms underlying these adverse consequences of MO remain unknown. Endocannabinoids (ECB) are neuromodulatory lipids released from adipocytes and other tissues. Metabolic crosstalk between placenta and adipocytes may mediate sequelae of MO. The goal of this study was to elucidate placental and systemic ECB in MO. MATERIAL AND METHODS: Placentas, sera, and subcutaneous fat were collected at Cesarean sections performed near term (0.9 G) in four non-obese (nOB) and four obese (OB) baboons (Papio spp.). Concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled to tandem mass spectrometry. AEA and 2-AG pathways were characterized in placentas by Q-RT-PCR, Western blot and immunohistochemistry. RESULTS: Placental 2-AG levels were lower and maternal fat AEA levels were higher in OB (1254.1 ± 401.3 nmol/kg and 17.3 ± 4 nmol/kg) vs. nOB (3124.2 ± 557.3 nmol/kg and 3.1 ± 0.6 nmol/kg) animals. Concentrations of 2-AG correlated positively between maternal fat and placenta (r = 0.82, p = 0.013), but correlated negatively with maternal leptin concentrations (r = -0.72, p = 0.04 and r = -0.83, p = 0.01, respectively). CONCLUSION: This is the first study to demonstrate differential ECB pathway regulation in maternal fat and placenta in MO. Differential regulation and function exist for AEA and 2-AG as the major ECB pathways in placenta.

Abruptio placentae in the baboon (Papio spp.).

INTRODUCTION: Placental abruption is a serious condition that increases perinatal morbidity and mortality. Clinical prevention and treatment options are limited, especially in human preterm deliveries. Knowledge of the mechanisms that keep the placenta in place during pregnancy is critical for developing strategies for the prevention of abruption. Failure of physiological transformation of spiral arteries has been described as a major contributing factor of the placental abruption development. Baboons (Papio spp.) share striking similarities with humans in regard to placental structure, utero-placental blood flow, and fetal development; however, the mode of trophoblast invasion is shallow in baboons. This fact prompted the hypothesis that the incidence of placental abruption will be increased in baboons compared to humans. MATERIAL AND METHODS: Baboon placentas were collected between 2002 and 2008. Two independent veterinary pathologists evaluated the slides. A certified physician pathologist performed additional histology. RESULTS: Placental abruption was diagnosed in 22 baboons among 2423 live births during the study period (0.9% prevalence). The most common clinical presentations were fetal demise and vaginal bleeding. The most common pathological findings were intraplacental hemorrhages with or without hematoma formation (86.4%). Other findings consisted of neutrophil infiltration (50%), decidual necrosis (22.7%), decidual vascular congestion and inflammation, villous congestion and retroplacental hemorrhage/hematoma (each 18.2%). These pathologic findings were the same for term and preterm deliveries. CONCLUSION: This is the first systematic study of placental abruption in non-human primates, analyzing a large colony of baboons. Despite differences in trophoblast invasion, the clinical features observed in placental abruption affecting baboons resembled those reported in humans. The cluster of placental pathological findings in baboons also agreed with clinical reports, but the prevalence of these findings differed between baboons and humans. We discuss a mechanism of anti-abruption forces that offset shallow trophoblast invasion observed in baboons.

The morphometry of materno-fetal oxygen exchange barrier in a baboon model of obesity.

INTRODUCTION: More than one-fourth of U.S. women are overweight; more than one-third are obese. Maternal obesity has been linked to an increased incidence of stillbirths, fetal macrosomia, fetal intrauterine growth restriction and pre-eclampsia. The placenta plays a key role in the nutrients and oxygen supply to the fetus. The data about structural changes in the placental villous membrane (VM), a major component of the feto-maternal nutrient and oxygen exchange barrier, during obesity are sparse and inconsistent. Our objective was to evaluate the morphometric changes in the placental exchange barrier in a baboon model of obesity. MATERIALS AND METHODS: The previously described baboon model of maternal obesity was studied. We compared 4 obese to 4 non-obese baboons. Placental stereology with the use of transmission electron microscopy was performed to estimate VM oxygen diffusing capacities and morphometry. RESULTS: The specific placental oxygen diffusing capacities per unit of fetal weight were similar in baboons and humans. Maternal leptin concentrations correlated negatively with placental basement membrane thickness (r = -0.78, p < 0.05), while fetal leptin levels correlated negatively with endothelial thickness of fetal capillaries (r = -0.78, p < 0.05). The total and specific villous membrane oxygen diffusing capacities were not different between the two groups. CONCLUSION: To the best of our knowledge this is the first report of placental oxygen diffusing capacities and placental ultrastructural changes in a baboon model of obesity. Previously reported placental inflammation in maternal obesity is not associated with changes in the VM diffusing capacities and ultrastructure.

The IGF axis in baboon pregnancy: placental and systemic responses to feeding 70% global ad libitum diet.

Information on the influence of poor maternal nutrition on the regulation of responses to pregnancy, placental and fetal growth and development is critical to a better understanding of pregnancy physiology and pathophysiology. We determined normal changes and effects of controlled and monitored moderate nutrient restriction (NR) (global nutrient intake reduced to 70% of food consumed by mothers feeding ad libitum from 0.16 to 0.5 of gestation) in the baboon, on important hematological, biochemical, and hormonal indices of fetal growth and placental function. Serum IGF-I:IGFBP-3 ratio was lower in pregnant than control non-pregnant baboons feeding ad libitum. Serum concentrations of total and free IGF-I were decreased in NR mothers compared with controls (p<0.05). The decrease in fetal IGF-I did not reach significance (p=0.057). Serum IGF-I: IGFBP-3 ratio was decreased by NR in both mothers and fetuses. Maternal serum IGF-II was unchanged by NR. Placental IGF-I mRNA and protein abundance were similarly reduced whereas IGF-II mRNA increased in placental tissue of NR compared to control mothers. Systemic (maternal) and local (placental) IGFBP-1 and IGFBP-3 mRNA and protein abundance were unchanged by NR. Type 1 IGF receptor protein in the syncytiotrophoblast increased in NR. Type 2 IGF receptor protein was present in the stem villi core, and decreased after NR. We conclude that moderate NR in this important non-human primate model significantly disrupts the maternal and placental IGF-IGFBP axis and influences placental expression of this key system at the gene and protein level. Changes observed appear to be directed toward preserving placental growth.

Insulin-like growth factor binding protein-3 mediates serum starvation- and doxorubicin-induced apoptosis in H9c2 cardiac cells.

Insulin-like growth factor binding protein 3 (IGFBP-3) modulates the activity of IGF-I, which exerts antiapoptotic action upon the myocardiocyte. IGFBP-3 also exerts IGF-independent actions to inhibit cell growth and induce apoptosis, mediating the effects of several antiproliferative agents. We hypothesized that IGFBP-3 mediates cardiomyocyte apoptosis. IGFBP-3 expression was studied in H9c2 rat cardiac cells cultured in serum-deprived medium in the absence or presence of 1 microM doxorubicin during a 72 h time-span. To a greater degree than serum withdrawal, doxorubicin induced IGFBP-3 up-regulation that was time-dependent. IGFBP-3 mRNA levels positively correlated with the degree of apoptosis. Exogenous IGFBP-3 decreased cell viability and induced apoptosis in serum-starved cells exposed to doxorubicin. IGFBP-3 antisense oligonucleotides markedly decreased apoptosis induced by either serum withdrawal or doxorubicin. Binding studies revealed specific high-affinity sites for IGFBP-3 in H9c2 cardiomyocytes, with binding characteristics typical of receptor-ligand interactions. These findings indicate that IGFBP-3 could play proapoptotic action at the myocardial level and suggest a novel role for this protein in cardiovascular dysfunction.

Acarbose treatment of postprandial hypoglycemia in children after Nissen fundoplication.

Dumping syndrome and postprandial hypoglycemia have been reported after Nissen fundoplication. The physiopathologic mechanisms are poorly understood and a variety of therapies have failed to control the hypoglycemia in these patients. We report a series of 6 infants with postprandial hypoglycemia after Nissen fundoplication who were treated successfully with acarbose.

Acute insulin responses to leucine in children with the hyperinsulinism/hyperammonemia syndrome.

Mutations of glutamate dehydrogenase cause the hyperinsulinism/hyperammonemia syndrome by desensitizing glutamate dehydrogenase to allosteric inhibition by GTP. Normal allosteric activation of glutamate dehydrogenase by leucine is thus uninhibited, leading us to propose that children with hyperinsulinism/hyperammonemia syndrome will have exaggerated acute insulin responses to leucine in the postabsorptive state. As hyperglycemia increases beta-cell GTP, we also postulated that high glucose concentrations would extinguish abnormal responsiveness to leucine in hyperinsulinism/hyperammonemia syndrome patients. After an overnight fast, seven hyperinsulinism/hyperammonemia syndrome patients (aged 9 months to 29 yr) had acute insulin responses to leucine performed using an iv bolus of L-leucine (15 mg/kg) administered over 1 min and plasma insulin measurements obtained at -10, -5, 0, 1, 3, and 5 min. The acute insulin response to leucine was defined as the mean increase in insulin from baseline at 1 and 3 min after an iv leucine bolus. The hyperinsulinism/hyperammonemia syndrome group had excessively increased insulin responses to leucine (mean +/- SEM, 73 +/- 21 microIU/ml) compared with the control children and adults (n = 17) who had no response to leucine (1.9 +/- 2.7 microU/ml; P < 0.05). Four hyperinsulinism/hyperammonemia syndrome patients then had acute insulin responses to leucine repeated at hyperglycemia (blood glucose, 150-180 mg/dl). High blood glucose suppressed their abnormal baseline acute insulin responses to leucine of 180, 98, 47, and 28 microU/ml to 73, 0, 6, and 19 microU/ml, respectively. This suppression suggests that protein-induced hypoglycemia in hyperinsulinism/hyperammonemia syndrome patients may be prevented by carbohydrate loading before protein consumption.

Hyponatremia and polyuria in children with central diabetes insipidus: challenges in diagnosis and management.

Five patients with well-controlled, long-standing, central diabetes insipidus had acute development of dehydration, hyponatremia, and inappropriate natriuresis in the setting of polyuria resistant to exogenous antidiuretic hormone. Hyponatremia and dehydration worsened with fluid restriction or use of exogenous antidiuretic hormone. We discuss the challenges in diagnosis and management of probable salt wasting in children with central diabetes insipidus.

Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations.

Mutations in the high-affinity sulfonylurea receptor (SUR)-1 cause one of the severe recessively inherited diffuse forms of congenital hyperinsulinism or, when associated with loss of heterozygosity, focal adenomatosis. We hypothesized that SUR1 mutations would render the beta-cell insensitive to sulfonylureas and to glucose. Stimulated insulin responses were compared among eight patients with diffuse hyperinsulinism (two mutations), six carrier parents, and ten normal adults. In the patients with diffuse hyperinsulinism, the acute insulin response to intravenous tolbutamide was absent and did not overlap with the responses seen in either adult group. There was positive, albeit significantly blunted, acute insulin response to intravenous dextrose in the patients with diffuse hyperinsulinism. Graded infusions of glucose, to raise and then lower plasma glucose concentrations over 4 h, caused similar rises in blood glucose but lower peak insulin levels in the hyperinsulinemic patients. Loss of acute insulin response to tolbutamide can identify children with diffuse SUR1 defects. The greater response to glucose than to tolbutamide indicates that ATP-sensitive potassium (KATP) channel-independent pathways are involved in glucose-mediated insulin release in patients with diffuse SUR1 defects. The diminished glucose responsiveness suggests that SUR1 mutations and lack of KATP channel activity may contribute to the late development of diabetes in patients with hyperinsulinism independently of subtotal pancreatectomy.

Somatic growth failure after the Fontan operation.

Our study was designed to characterize the patterns of growth, in the medium term, of children with functionally univentricular hearts managed with a hemi-Fontan procedure in infancy, followed by a modified Fontan operation in early childhood. Failure of growth is common in patients with congenital cardiac malformations, and may be related to congestive heart failure and hypoxia. Repair of simple lesions appears to reverse the retardation in growth. Palliation of the functionally single ventricular physiology with a staged Fontan operation reduces the adverse effects of hypoxemia and prolonged ventricular volume overload. The impact of this approach on somatic growth is unknown. Retrospectively, we reviewed the parameters of growth of all children with functionally univentricular hearts followed primarily at our institution who had completed a staged construction of the Fontan circulation between January 1990 and December 1995. Measurements were available on all children prior to surgery, and annually for three years following the Fontan operation. Data was obtained on siblings and parents for comparative purposes. The criterions of eligibility for inclusion were satisfied by 65 patients. The mean Z score for weight was -1.5 +/- 1.2 at the time of the hemi-Fontan operation. Weight improved by the time of completion of the Fontan circulation (-0.91 +/- 0.99), and for the first two years following the Fontan operation, but never normalized. The mean Z scores for height at the hemi-Fontan and Fontan operations were -0.67 +/- 1.1 and -0.89 +/- 1.2 respectively. At most recent follow-up, with a mean age of 6.1 +/- 1.3 years, and a mean time from the Fontan operation of 4.4 +/- 1.4 years, the mean Z score for height was -1.15 +/- 1.2, and was significantly less than comparable Z scores for parents and siblings. In our experience, children with functionally univentricular hearts who have been palliated with a Fontan operation are significantly underweight and shorter than the general population and their siblings.

Calcium-stimulated insulin secretion in diffuse and focal forms of congenital hyperinsulinism.

OBJECTIVES: To identify infants with hyperinsulinism caused by defects of the beta-cell adenosine triphosphate-dependent potassium channel complex and to distinguish focal and diffuse forms of hyperinsulinism caused by these mutations. STUDY DESIGN: The acute insulin response to intravenous calcium stimulation (CaAIR) was determined in 9 patients <20 years with diffuse hyperinsulinism caused by defective beta-cell sulfonylurea receptor (SUR1(-/-)), 3 patients with focal congenital hyperinsulinism (6 weeks to 18 months), a 10-year-old with insulinoma, 5 with hyperinsulinism/hyperammonemia syndrome caused by defective glutamate dehydrogenase (6 months to 28 years), 4 SUR1(+/-) heterozygotes with no symptoms, and 9 normal adults. Three infants with congenital focal disease, 1 with diffuse hyperinsulinism, and the child with insulinoma underwent selective pancreatic intra-arterial calcium stimulation with hepatic venous sampling. RESULTS: Children with diffuse SUR1(-/-) disease and infants with congenital focal hyperinsulinism responded to CaAIR, whereas the normal control group, patients with hyperinsulinism/hyperammonemia syndrome, and SUR1(+/-) carriers did not. Selective arterial calcium stimulation of the pancreas with hepatic venous sampling revealed selective, significant step-ups in insulin secretion that correlated anatomically with the location of solitary lesions confirmed surgically in 2 of 3 infants with congenital focal disease and in the child with insulinoma. Selective arterial calcium stimulation of the pancreas with hepatic venous sampling demonstrated markedly elevated baseline insulin levels throughout the pancreas of the infant with diffuse hyperinsulinism. CONCLUSIONS: The intravenous CaAIR is a safe and simple test for identifying infants with diffuse SUR1(-/-) hyperinsulinism or with focal congenital hyperinsulinism. Preoperative selective arterial calcium stimulation of the pancreas with hepatic venous sampling can localize focal lesions causing hyperinsulinism in children. The combination of these calcium stimulation tests may help distinguish focal lesions suitable for cure by local surgical resection.

Suppression of insulin oversecretion by subcutaneous recombinant human insulin-like growth factor I in children with congenital hyperinsulinism due to defective beta-cell sulfonylurea receptor.

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants under 1 yr of age. HI is most often due to defective glucose-insulin coupling by the beta-cell sulfonylurea receptor (SUR1) or glutamate dehydrogenase. HI-induced hypoglycemia carries significant morbidity, and current therapies are suboptimal. Insulin-like growth factor I (IGF-I) decreases insulin secretion in vitro and in healthy adults in vivo. We postulated that recombinant human IGF-I (rhIGF-I) could benefit children with HI and hypoglycemia by decreasing insulin levels and improving fasting tolerance. We enrolled nine subjects in an open label trial of rhIGF-I: eight children, ages 1 month to 11 yr, with HI due to identified mutations of SUR1 (n = 5) or clinically unresponsive to diazoxide, which acts via the SUR (n = 3), and one adult, age 32 yr, with HI due to defective glutamate dehydrogenase-1. All had suboptimal glycemic control and served as their own controls. Subjects underwent 24-h glucose monitoring under their home regimens, followed by a supervised fasting study. The controlled fast was terminated when the subject became hypoglycemic (blood glucose, <50 mg/dL) or developed symptoms consistent with hypoglycemia. The fast was repeated 2 days later with administration of rhIGF-I at 40 microg/kg, s.c., every 12 h. At the start of fasting rhIGF-I lowered the mean serum insulin level by 70% (21.0 +/- 11.1 vs. 6.3 +/- 2.2 microIU/mL; P < 0.04) and lowered the mean serum C peptide level by 43% (2.1 +/- 0.7 vs. 1.2 +/- 0.6 ng/mL; P < 0.04). rhIGF-I suppression of insulin and C peptide persisted throughout the fast. The duration of fasting did not change significantly with rhIGF-I treatment. We have directly demonstrated that rhIGF-I inhibits insulin oversecretion in children with HI due to defective SUR1. Our data suggest that IGF inhibition of insulin secretion does not require an intact SUR. rhIGF-I is unlikely to be effective monotherapy for HI, but may provide synergy to inhibit insulin secretion when combined with agents acting via IGF-independent mechanisms.

Serum IGF-I and IGFBP-3 concentrations do not accurately predict growth hormone deficiency in children with brain tumours.

OBJECTIVE: The growth hormone (GH)-dependent growth factors insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) may be superior to provocative GH testing in diagnosing GH deficiency (GHD) in children. In adults with brain tumours (BT) and GHD, however, provocative GH testing more accurately reflects GHD than either IGF-I or IGFBP-3. We assessed growth factor levels in children with GHD due to BT with respect to brain tumour type, pubertal stage, growth velocity, bone age delay, and body mass index (BMI). DESIGN: Retrospective case review of all patients followed at our centre with GHD following treatment of BT. PATIENTS: 72 children (51 M, 21 F) with BT diagnosed with GHD by clinical and auxological criteria, including provocative GH testing, in whom pre-GH treatment IGF-I and IGFBP-3 levels were obtained. MEASUREMENTS: Auxological data, including height, weight, growth velocity, and pubertal stage; and biochemical data, including GH response to provocative GH testing and pre-GH treatment serum IGF-I and IGFBP-3 concentrations. RESULTS: IGF-I levels were normal (above -2 SD) in 19 of 70 children (27%), and IGFBP-3 levels were normal in 21 of 42 (50%). In children with GHD, pubertal stage correlated significantly with both IGF-I (r = 0.328, p < 0.006) and IGFBP-3 (r = 0.364, P < 0.02). Normal IGF-1 levels were found in 1/15 children with craniopharyngioma (Cranio) (7%), 10/30 with primitive neuroectodermal tumours (PNET) (33%), and 5/12 children with hypothalamic/chiasmatic glioma (HCG) (42%) (P < 0. 05). IGFBP-3 levels were normal in 4/13 Cranio patients (31%), 8/15 PNET patients (53%), and 6/8 HCG patients (75%) (P = ns). Tanner staging varied significantly among tumour types: mode = 1 for Cranio and PNET vs. mode = 3 for HCG (P < 0.03). BMI did not differ between patients with low vs. normal growth factor levels. CONCLUSIONS: Low IGF-I levels were more predictive of growth hormone deficiency than low IGFBP-3 levels in our brain tumour patients, but both were poor predictors of growth hormone deficiency in children with hypothalamic-chiasmatic glioma and in pubertal children. Serum IGF-I and IGFBP-3 levels, therefore, do not always reflect growth hormone deficiency in children with brain tumours, particularly in those with hypothalamic-chiasmatic glioma or those already in puberty.

Congenital hyperinsulinism and the surgeon: lessons learned over 35 years.

BACKGROUND/PURPOSE: Congenital hyperinsulinism induces severe and unremitting hypoglycemia in newborns and infants. If poorly controlled, seizures and irreversible brain damage may result. Subtotal (<95%) or near-total (95% to 98%) pancreatectomy have been performed for glycemic control in babies who do not respond to aggressive medical therapy. Because hypoglycemia often persists after subtotal resection, 95% pancreatectomy has emerged as the procedure of choice. To define the effect of more or less extensive pancreatectomy on the management and outcome of refractory congenital hyperinsulinism, the authors examined our single institutional experience. METHODS: The records of children treated between 1963 and 1998 for congenital hyperinsulinism, and who required pancreatectomy, were reviewed. Outcome parameters included glycemic response to surgery, need for reresection, surgical morbidity, surgical and long-term mortality, and development of diabetes mellitus (DM). A complete response was defined as discharge to home on no glycemic medications, no continuous feedings, and without DM. Histological reports were reviewed and categorized as either diffuse or focal disease. RESULTS: Of 101 children treated for congenital hyperinsulinism during this period, 53 (50%) required pancreatectomy for glucose control. Mean follow-up for the study population was 9.8 +/- 1.1 years. Overall, 23 children (43%) showed a complete response, occurring in 50% of patients having > or = 95% pancreatectomy (n = 34), but in only 19% having less than 95% resection (n = 16). The remaining three babies had local excision of a solitary focal lesion, and each showed a complete response. Histopathology showed diffuse islet abnormalities in 42 specimens (79%) and solitary focal lesions in 11 (21%). A complete response was observed for 82% of focal but only 33% of diffuse lesions. Eight patients (15%) required reresection for persistent hypoglycemia, seven having diffuse lesions and one focal. Surgical morbidity occurred in 13 cases (26%), and the 30-day surgical mortality rate was 6%, each death (n = 3) occurring before 1975. DM developed in seven children (14%), each having diffuse lesions, and was independent of resection type. CONCLUSION: Because euglycemia is more readily restored, and because the risks for surgical complications and DM do not appear increased, the authors recommend 95% pancreatectomy as the initial procedure of choice for newborns and infants with congenital hyperinsulinism.

Insulin-like growth factor binding proteins: new proteins, new functions.

The insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and IGFBP proteases regulate somatic growth and cellular proliferation both in vivo and in vitro. IGFs are potent mitogens whose actions are determined by the availability of free IGFs to interact with IGF receptors. IGFBPs comprise a family of six proteins that bind IGFs with high affinity and specificity and thereby regulate IGF-dependent actions. IGFBPs have recently emerged as IGF-independent regulators of cell growth. Cleavage of IGFBPs by specific proteases modulate levels of free IGFs and IGFBPs and thereby their actions. IGFBP-related proteins (IGFBP-rPs) bind IGFs with low affinity and also play important roles in cell growth and differentiation. The GH-IGF-IGFBP axis is complex and powerful. Future research on its physiology promises exciting insights into cell biology as well as therapies for diseases such as cancer and diabetes mellitus.

Cellular actions of insulin-like growth factor binding proteins.

The insulin-like growth factors (IGFs), insulin-like growth factor binding proteins (IGFBPs), and the IGFBP proteases are involved in the regulation of somatic growth and cellular proliferation both in vivo and in vitro. IGFs are potent mitogenic agents whose actions are determined by the availability of free IGFs to interact with the IGF receptors. IGFBPs comprise a family of proteins that bind IGFs with high affinity and specificity and thereby regulate IGF-dependent actions. IGFBPs have recently emerged as IGF-independent regulators of cell growth. Various IGFBP association proteins as well as cleavage of IGFBPs by specific proteases modulate levels of free IGFs and IGFBPs. The ubiquity and complexity of the IGF axis promise exciting discoveries and applications for the future.