Papio spp. Colon microbiome and its link to obesity in pregnancy.

INTRODUCTION: Gut microbial communities are critical players in the pathogenesis of obesity. Pregnancy is associated with increased bacterial load and changes in gut bacterial diversity. Sparse data exist regarding composition of gut microbial communities in obesity combined with pregnancy. MATERIAL AND METHODS: Banked tissues were collected under sterile conditions during necropsy, from three non-obese (nOb) and four obese (Ob) near-term pregnant baboons. Sequences were assigned taxonomy using the Ribosomal Database Project classifier. Microbiome abundance and its difference between distinct groups were assessed by a nonparametric test. RESULTS: Three families predominated in both the nOb and Ob colonic microbiome: Prevotellaceae (25.98% and 32.71% respectively), Ruminococcaceae (12.96% and 7.48%), and Lachnospiraceae (8.78% and 11.74%). Seven families of the colon microbiome displayed differences between Ob and nOb groups. CONCLUSION: Changes in gut microbiome in pregnant obese animals open the venue for dietary manipulation in pregnancy.

Psychological Flexibility Among Youth with Type 1 Diabetes: Relating Patterns of Acceptance, Adherence, and Stress to Adaptation.

Psychological flexibility, a complex concept encompassing both acceptance and action related factors, has been identified as a target for intervention for diabetes management. Research suggests acceptance, self-management, and stress, all factors that influence psychological flexibility, have an impact on adaptation to type 1 diabetes (T1D) by youth independently. However, yet to be explored is individually varying patterns of these variables and how they may relate to diabetes adaptation outcomes. The present study aimed to establish individual variations of patterns of these factors to derive profiles of psychological flexibility, and examine their relations to the adaptation outcomes of glycemic control and health-related quality of life. Youth (N = 162, aged 12-17 years) with T1D completed the Acceptance and Action Diabetes Questionnaire, Diabetes Stress Questionnaire, Self-Care Inventory, and Pediatric Quality of Life-Diabetes Module. Hemoglobin A1c values were abstracted from medical records. Latent profile analysis yielded three profiles: High Acceptance & Adherence/Low Stress, Low Acceptance/Moderate Adherence & Stress, and Low Acceptance & Adherence/High Stress. The High Acceptance & Adherence/Low Stress group displayed significantly higher health-related quality of life and lower HbA1c compared to other groups. Fluid psychological variables, such as acceptance and diabetes stress, and adherence behaviors may be salient targets to increase psychological flexibility for individual psychosocial interventions aimed at improving adaptation to type 1 diabetes in youth.

Patterns of Family Functioning and Diabetes-Specific Conflict in Relation to Glycemic Control and Health-Related Quality of Life Among Youth With Type 1 Diabetes.

Objectives: General and diabetes-specific family functioning may be associated with youth's adaptation to type 1 diabetes (T1D); however, empirically derived patterns of family functioning and diabetes-specific conflict among youth have not been explored in relation to T1D adaptation. Methods: Youth (N = 161, aged 12­18) with T1D and caregivers completed measures of family functioning and diabetes-specific conflict that served as indicators in latent profile analyses. Differences in glycemic control (measured by hemoglobin A1cs [HbA1c] and health-related quality of life [HRQoL]) were compared across profiles. Results: Four profiles that varied by levels of family functioning, diabetes-specific conflict, and congruence between youth and caregiver perspectives emerged and related to T1D adaptation differently. Greater agreement between caregiver and youth and lower diabetes-specific conflict was associated with lower HbA1c and greater HRQoL. Conclusions: Person-centered approaches are useful to quantify how many individuals fit into a particular pattern and determine how specific family dynamics may function together differently in relation to T1D adaptation for various subgroups of the population.

Physical Activity, Sedentary Behaviors, and Nutritional Risk Profiles and Relations to Body Mass Index, Obesity, and Overweight in Eighth Grade.

The objective of this article was to determine (1) the existence of individually varying patterns of physical activity, sedentary behavior, and nutrition intake risk; and (2) how these risk-patterns relate to youth's demographics, Body mass index (BMI) and psychosocial functioning. Participants (N = 9,304) from the 2007 8th Grade Early Childhood Longitudinal Study Cohort completed the revised Self-Description Questionnaire II. Age, sex, height, and weight were used to calculate body mass index (BMI) z scores and percentiles. Three risk profiles emerged via Latent Profile Analyses: "Active + Healthy Diet" (AHD; 16.3% Obese); "Sedentary + Unbalanced Diet" (SUD; 21.3% Obese); and "Screen-Time + Recreational Food" (STRF; 25.0% Obese). Significant differences in BMIs, psychosocial factors, and demographic characteristics were found across the profiles. Differential patterns of physical activity, sedentary behavior, and nutritional choices were found to predict BMI and psychosocial functioning. These findings may be helpful to refine and develop modular-based prevention and weight control intervention programs.

Improvement in Fruit and Vegetable Consumption Associated with More Favorable Energy Density and Nutrient and Food Group Intake, but not Kilocalories.

BACKGROUND: Children generally do not consume adequate amounts of fruits and vegetables (F/V). Eating more F/V can improve energy density and overall diet quality. OBJECTIVE: Our aim was to investigate whether improvements in F/V consumption were associated with improvements in energy density, total calories, and dietary components related to F/V. DESIGN: We performed secondary analyses of dietary data from a successful four-group randomized controlled trial promoting F/V. Data were collected at baseline, immediately after gameplay, and 3 months post intervention. PARTICIPANTS/SETTING: Preadolescent child-parent dyads (n=400) were recruited. Eligibility criteria were 4th- or 5th-grade child (approximately 9 to 11 years old) with Internet access and a parent willing to participate in the intervention. Complete dietary data were collected on 387 of the 400 child participants. The videogame was available online on a secure, password-protected website. MAIN OUTCOME MEASURES: Dietary intake was assessed with three unannounced dietary recalls collected at each data-collection period via telephone by trained staff using Nutrition Data System for Research software. Energy density and F/V, nutrient, and food consumption were calculated. STATISTICAL ANALYSIS PERFORMED: A 4×3 (group by time) repeated measures analysis of covariance with mixed-effect linear models was used. Covariates included child's sex, race/ethnicity, and total energy intake as well as parent's age and household education. Energy was excluded as a covariate in the energy density and energy models. RESULTS: Significant changes occurred in energy density. A significant interaction (group by time) was observed (F6, 515=2.40; P<0.05) in energy density from food only, while a significant time effect was observed for energy density from all foods and beverages (F2, 388=13.75; P<0.0001). Desirable changes were also observed in F/V-related dietary components. CONCLUSIONS: Increasing F/V consumption improved energy density and diet quality considerably in preadolescent children.

Medicaid managed care reduces readmissions for youths with type 1 diabetes.

OBJECTIVES: To determine whether the likelihood of readmission (adjusted for severity on first admission) for pediatric type 1 diabetes (T1D) differs between Medicaid managed care and non-managed care. STUDY DESIGN: De-identified patients were retrospectively selected from the Pediatric Health Information Systems database of the Children's Hospital Association (CHA). The cohort of 42 hospitals across 25 states included discharges between 2008 and 2011 for patients who were receiving Medicaid at the time of service and had T1D as their diagnosis. METHODS: Multiple factors and co-variants for readmission were analyzed by logistic regression, including age, race, gender, severity of illness, and state of admission. RESULTS: Of 14,544 T1D discharges with Medicaid, 4985 were readmitted, including 1792 readmitted for diabetic ketoacidosis (DKA). Despite similar rates of DKA between the managed care and non-managed care cohorts, overall 90-day readmission was 1.12 times more likely for Medicaid patients on non-managed care plans than those on managed care (odds ratio, 1.12; range = 1.04-1.20; both adjusted for severity of illness). Significant contributors were race, age, and gender; the relationship of location (state) and days between readmissions was also significant. The conservative estimate of cost reduction from Medicaid managed care related to lower readmission rate for pediatric T1D across CHA institutions between 2008 and 2011 was $2.6 million. CONCLUSIONS: From the largest, national, defined cohort available for contemporary study, youths with T1D on Medicaid managed care plans were less likely to be readmitted within 90 days of discharge.

Effect of Low-Magnitude, High-Frequency Mechanical Stimulation on BMD Among Young Childhood Cancer Survivors: A Randomized Clinical Trial.

IMPORTANCE: Bone accrual during youth is critical to establish sufficient strength for lifelong skeletal health. Children with cancer may develop low bone mineral density (BMD) any time before or after diagnosis. OBJECTIVE: To evaluate the ability of low-magnitude, high-frequency mechanical stimulation to enhance BMD among childhood cancer survivors. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized clinical trial conducted at St Jude Children's Research Hospital from June 1, 2010, to January 22, 2013, using cancer survivors, ages 7 to 17 years, who were previously treated at St Jude Children's Research Hospital, were in remission, and at least 5 years from diagnosis, with whole-body or lumbar spine BMD z scores of -1.0 or lower. Participants were randomized (stratified by sex and Tanner stage) to either a placebo device or low-magnitude, high-frequency mechanical stimulation device, which was used at home. INTERVENTIONS: Placebo or low-magnitude, high-frequency mechanical stimulation (0.3 g; 32-37 Hz) for 2 sessions lasting 10 minutes each, 7 days per week for 1 year. All participants were prescribed daily cholecalciferol (vitamin D) and calcium. MAIN OUTCOMES AND MEASURES: Changes in areal and volumetric BMD and bone biomarkers were compared by analysis of variance, adjusted for strata. RESULTS: Of the 65 participants, 32 were randomized to the intervention group (mean [SD] age was 13.6 [3.7] years, 18 [56.2%] were male, and 27 [84.4%] were white), and 33 were randomized to the placebo group (mean [SD] age was 13.6 [2.9] years, 17 [51.5%] were male, and 26 [78.8%] were white). Forty-eight participants completed the trial, 22 in the intervention group and 26 in the placebo group with median adherence of 70.1% for intervention and 63.7% for placebo groups. With intention-to-treat analysis, mean (SD) whole-body BMD z score by dual x-ray absorptiometry improved by 0.25 (0.78) in the intervention (n = 22), but decreased by -0.19 (0.79) in the placebo group (n = 26, P = .05). Circulating osteocalcin at 12 months correlated with change in total body BMD (r = 0.35, P = .02). Tibial trabecular bone among participants completing 70% or more of the prescribed sessions increased by a mean of 11.2% (95% CI, 5.2 to 17.2%) compared with those completing less than 70% who decreased by a mean of -1.3% (95% CI, -7.3 to 4.7%; P = .02). Change in circulating receptor activator of nuclear factor κ-B ligand was higher in the intervention than in the placebo group (0.06 [0.16] vs -0.04 [0.17] pmol/L) (P = .04). CONCLUSIONS AND RELEVANCE: Pediatric cancer survivors with low BMD may benefit from low-magnitude, high-frequency mechanical stimulation as a novel and safe intervention to optimize peak bone mass during youth, alone or in conjunction with other therapies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01010230.

Gestational Vitamin 25(OH)D Status as a Risk Factor for Receptive Language Development: A 24-Month, Longitudinal, Observational Study.

Emerging data suggest that vitamin D status during childhood and adolescence can affect neurocognitive development. The purpose of this study was to investigate whether gestational 25(OH)D status is associated with early childhood cognitive and receptive language development. The Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study (CANDLE) study enrolled 1503 mother-child dyads during the second trimester of healthy singleton pregnancies from Shelby County TN. Among 1020 participants of the total CANDLE cohort for whom 25(OH)D levels were available, mean gestational 25(OH)D level during the second trimester was 22.3 ng/mL (range 5.9-68.4), with 41.7% of values <20 ng/dL. Cognitive and language scaled scores increased in a stair-step manner as gestational 25(OH)D levels in the second trimester rose from <20 ng/dL, through 20-29.99 ng/dL, to ≥30 ng/dL. When controlling for socioeconomic status, race, use of tobacco products, gestational age of the child at birth, and age at the 2-year assessment, the gestational 25(OH)D was positively related to receptive language development (p < 0.017), but not cognitive or expressive language.

Nedd4 haploinsufficient mice display moderate insulin resistance, enhanced lipolysis, and protection against high-fat diet-induced obesity.

Neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) is the prototypical protein in the Nedd4 ubiquitin ligase (E3) family, which governs ubiquitin-dependent endocytosis and/or degradation of plasma membrane proteins. Loss of Nedd4 results in embryonic or neonatal lethality in mice and reduced insulin/IGF-1 signaling in embryonic fibroblasts. To delineate the roles of Nedd4 in vivo, we examined the phenotypes of heterozygous knockout mice using a high-fat diet-induced obesity (HFDIO) model. We observed that Nedd4+/- mice are moderately insulin resistant but paradoxically protected against HFDIO. After high-fat diet feeding, Nedd4+/- mice showed less body weight gain, less fat mass, and smaller adipocytes vs the wild type. Despite ameliorated HFDIO, Nedd4+/- mice did not manifest improvement in glucose tolerance vs the wild type in both genders. Nedd4+/- male, but not female, mice displayed significantly lower fasting blood glucose levels and serum insulin levels. Under obesogenic conditions, Nedd4+/- mice displayed elevated stimulated lipolytic activity, primarily through a ß2-adrenergic receptor. Combined, these data support novel complex roles for Nedd4 in metabolic regulation involving altered insulin and ß-adrenergic signaling pathways.

Assessing measurement invariance of the diabetes stress questionnaire in youth with type 1 diabetes.

OBJECTIVE: To evaluate the factor structure and measurement invariance of the Diabetes Stress Questionnaire (DSQ), a measure of diabetes-specific stress, across sex, age (<9th grade vs. ≥9th grade), and glycemic control (optimal vs. suboptimal). METHODS: Data from 318 adolescent participants were pooled from four archival data sets and the ongoing Predicting Resiliency in Youth with Type 1 Diabetes study in which the DSQ was completed. Confirmatory factor and measurement invariance analyses were conducted to confirm the proposed factor structure and measurement invariance across sex, age, and glycemic control. RESULTS: The DSQ factor structure was found to have an acceptable fit, which was invariant across sex, age, and glycemic control. CONCLUSIONS: When using the DSQ, differences in diabetes-related stress with respect to sex, age, or glycemic control can be considered meaningful. This study supports the DSQ as an evidence-based and well-established assessment of perceived diabetes stress in youth with type 1 diabetes.

Real-time support of pediatric diabetes self-care by a transport team.

OBJECTIVE The study seeks to improve access for underserved patients via novel integration of Pedi-Flite (a critical care transport team) and to validate whether this safely enhances diabetes care and effectively expands the endocrine workforce. RESEARCH DESIGN AND METHODS The study retrospectively analyzed pager service use in a cohort of established diabetic patients (n = 979) after inception of Pedi-Flite support. Outcomes included incidence and severity of recurrent diabetic ketoacidosis (DKA) and cost savings generated from reduced referrals to the emergency department (ED) and on-call endocrinologist. We generated descriptive statistics to characterize the study population and ED visits for DKA and constructed logistic regression models to examine associations of pager use and likelihood of ED visitation and nonelective inpatient admission from an ED for DKA. RESULTS Pager users comprised 30% of the patient population. They were younger but had more established diabetes than nonusers. While pager users were 2.75 times more likely than nonusers to visit the ED for DKA (P < 0.0001), their visits were less likely to lead to inpatient admissions (odds ratio 0.58; P < 0.02). More than half (n = 587) of all calls to the pager were resolved without need for further referral. Estimates suggest that 439 ED visits and 115 admissions were avoided at a potential cost savings exceeding 760,000 USD. CONCLUSIONS Integration of a transport service provides a novel, cost-effective approach to reduce disparities in diabetes care. Advantages include scalability, applicability to other disease areas and settings, and low added costs. These findings enrich an emerging evidence base for telephonic care-management models supported by allied health personnel.

Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial.

Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8-17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose.

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial.

BACKGROUND: Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve ß-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. METHODS: In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. FINDINGS: 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). INTERPRETATION: Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in ß-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. FUNDING: MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Association of muscle strength and bone mineral density in adult survivors of childhood acute lymphoblastic leukemia.

OBJECTIVES: To investigate the association between bone mineral density (BMD) and muscle strength in survivors of childhood acute lymphoblastic leukemia (ALL), a population at increased risk for both decreased BMD and muscle strength from cancer and its treatment. DESIGN: Cohort data from the St Jude Lifetime Cohort (SJLIFE) study. SETTING: Department of Cancer Control at St Jude Children's Research Hospital. PARTICIPANTS: Subjects were adults enrolled in St Jude Lifetime Cohort study and treated for childhood ALL between 1962 and 1999. As part of a comprehensive evaluation, participants had dual energy x-ray absorptiometry (DEXA) scans and muscle strength testing. The participants consisted of 261 women and 232 men who were 20.4 to 49.8 years old (median, 35.7y), and 12.7 to 46.5 years from diagnosis of childhood ALL (median, 27.2y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: BMD was determined by DEXA scan. Muscle strength of upper and lower extremities was assessed with physical performance testing. RESULTS: After adjusting for covariates, we found significant (P<0.005) associations between BMD and muscle strength in lower extremities (R(2) range, 0.33-0.40) and strong, significant associations in upper extremities (left-side R(2)=0.558; right-side R(2)=0.560). CONCLUSIONS: Muscle strength was associated with BMD in the extremities of long-term survivors of childhood ALL, a finding suggesting that muscle strengthening interventions may improve bone health in them.

Treatment of transient neonatal diabetes mellitus with subcutaneous insulin glargine in an extremely low birth weight neonate.

Neonatal diabetes mellitus (NDM) results from impaired insulin secretion. While rare, NDM presents complex challenges with regard to the management of glycemic control. NDM is classified as transient neonatal diabetes mellitus (TNDM) or permanent neonatal diabetes mellitus (PNDM). Determination of TNDM vs. PNDM is usually possible only after medical management has been initiated. Management of NDM begins with insulin; however, the correct dose, choice of formulation, and route of administration are complicated by the risk of neonatal hypoglycemia. For the first time, the successful management of TNDM in an extremely low birth weight (ELBW) neonate with the long-acting subcutaneous insulin analog, insulin glargine, is reported. In addition, potential pharmacokinetic barriers to treating ELBW neonates diagnosed with NDM with subcutaneous insulin products are discussed.

Causes of unplanned hospital admissions: implications for practice and policy.

Unplanned hospitalizations among home health patients were reviewed to identify preventable hospital admissions and their causes. Study methods included treatment record review; interviews with home health visit staff, supervisors, and managers; and review of orientation materials and policies. Findings from this study suggest focus areas for home health agencies and other stakeholders to reduce acute care hospitalization rates and in other quality improvement initiatives.

The prolonged effect of repeated maternal glucocorticoid exposure on the maternal and fetal leptin/insulin-like growth factor axis in Papio species.

BACKGROUND: Maternal obesity represents a risk factor for pregnancy-related complications. Glucocorticoids are known to promote obesity in adults. METHODS: We evaluated maternal and fetal metabolic changes during and after 3 weekly courses of betamethasone administered to pregnant baboons (Papio subspecies) at doses equivalent to those given to pregnant women. RESULTS: Betamethasone administration during the second half of pregnancy increased maternal weight but neither maternal food intake nor fetal weight, as assessed at the end of gestation. Betamethasone increased maternal serum glucose concentration, the ratio of insulin-like growth factor-I and insulin-like growth factor binding protein-3, and serum leptin during treatment (normalized by 17, 35, and 45 days posttreatment, respectively, for each parameter). Maternal and fetal serum leptin concentrations did not differ between groups at the end of gestation. CONCLUSION: Prolonged maternal hyperleptinemia caused by betamethasone administration in the second half of gestation did not change fetal metabolic parameters measured and placental leptin distribution at the end of gestation.

Patient-based cultural competency curriculum for pre-health professionals.

BACKGROUND AND OBJECTIVES: The diverse US population requires medical cultural competency education for health providers throughout their pre-professional and professional years. We present a curriculum to train pre-health professional undergraduates by combining classroom education in the humanities and cross-cultural communication skills with volunteer clinical experiences at the University of California, Los Angeles (UCLA) hospital. METHODS: The course was open to a maximum of 15 UCLA junior and senior undergraduate students with a pre-health or humanities major and was held in the spring quarters of 2002--2004. The change in students' knowledge of cultural competency was evaluated using the Provider's Guide to Quality and Culture Quiz (QCQ) and through students' written assignments and evaluations. RESULTS: Trainees displayed a statistically significant improvement in scores on the QCQ. Participants' written assignments and subjective evaluations confirmed an improvement in awareness and a high motivation to continue learning at the graduate level. CONCLUSIONS: This is the first evaluated undergraduate curriculum that integrates interdisciplinary cultural competency training with patient volunteering in the medical field. The didactic, volunteering, and writing components of the course comprise a broadly applicable tool for training future health care providers at other institutions.

Novel roles of the IGF-IGFBP axis in etiopathophysiology of diabetic nephropathy.

Mechanisms contributing to development of diabetic nephropathy (DN) remain unclear. High ambient glucose level transforms intracellular pathways, promoting stable phenotypic changes in the glomerulus such as mesangial cell hypertrophy, podocyte apoptosis, and matrix expansion. Insulin-like growth factors (IGFs) and the high affinity IGF binding proteins (IGFBPs) exert major effects on cell growth and metabolism. Compared with diabetic patients without microalbuminuria (MA), MA diabetic patients display perturbed GH-IGF-IGFBP homeostasis, including increased circulating IGF-I and IGFBP-3 protease activity, increased excretion of bioactive GH, IGF-I, and IGFBP-3, but decreased circulating IGFBP-3 levels. In diabetic animal models, expression of IGF-I and IGFBP-1 to -4 increases in key renal tissues and glomerular ulrafiltrate. Epithelial, mesangial, and endothelial cells derived from the kidney respond to IGF-I binding with increased protein synthesis, migration, and proliferation. This article reviews classic and emerging concepts for the roles of the GH-IGF-IGFBP axis in the etiopathophysiology, treatment, and prevention of diabetic renal disease. We report IGF-independent actions of IGFBP-3 in the podocyte for the first time.

Novel actions of IGFBP-3 on intracellular signaling pathways of insulin-secreting cells.

Understanding mechanisms underlying apoptotic destruction of insulin-secreting cells is critical to validate therapeutic targets for type 1 diabetes mellitus. We recently reported insulin-like growth factor binding protein-3 (IGFBP-3) as a novel mediator of apoptosis in insulin-secreting cells. In light of emerging IGF-independent roles for IGFBP-3, we investigated the mechanisms underlying actions of the novel, recombinant human mutant G(56)G(80)G(81)-IGFBP-3, which lacks intrinsic IGF binding affinity. Using the rat insulinoma RINm5F cell line, we report the first studies in insulin-secreting cells that IGFBP-3 selectively suppresses multiple, key intracellular phosphorelays. By immunoblot, we demonstrate that G(56)G(80)G(81)-IGFBP-3 suppresses phosphorylation of c-raf-MEK-ERK pathway and p38 kinase in time-dependent and dose-dependent manners. SAPK/JNK signaling was unaffected. These data delineate several novel intracellular sites of action for IGFBP-3 in insulin-secreting cells.