Urinary Plasminogen as a Marker of Disease Progression in Human Glomerular Disease.

RATIONALE & OBJECTIVE: Glomerular disorders have a highly variable clinical course, and biomarkers that reflect the molecular mechanisms underlying their progression are needed. Based on our previous work identifying plasminogen as a direct cause of podocyte injury, we designed this study to test the association between urine plasmin(ogen) (ie, plasmin and its precursor plasminogen) and end-stage kidney disease (ESKD). STUDY DESIGN: Multicenter cohort study. SETTING & PARTICIPANTS: 1,010 patients enrolled in the CureGN Cohort with biopsy-proven glomerular disease (focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A nephropathy). PREDICTORS: The main predictor was urine plasmin(ogen) at baseline. Levels were measured by an electrochemiluminescent immunoassay developed de novo. Traditional clinical and analytical characteristics were used for adjustment. The ratio of urine plasmin(ogen)/expected plasmin(ogen) was evaluated as a predictor in a separate model. OUTCOME: Progression to ESKD. ANALYTICAL APPROACH: Cox regression was used to examine the association between urinary plasmin(ogen) and time to ESKD. Urinary markers were log2 transformed to approximate normal distribution and normalized to urinary creatinine (Log2uPlasminogen/cr, Log2 urinary protein/cr [UPCR]). Expected plasmin(ogen) was calculated by multiple linear regression. RESULTS: Adjusted Log2uPlasminogen/cr was significantly associated with ESKD (HR per doubling Log2 uPlasminogen/cr 1.31 [95% CI, 1.22-1.40], P<0.001). Comparison of the predictive performance of the models including Log2 uPlasminogen/cr, Log2 UPCR, or both markers showed the plasmin(ogen) model superiority. The ratio of measured/expected urine plasmin(ogen) was independently associated with ESKD: HR, 0.41 (95% CI, 0.22-0.77) if ratio<0.8 and HR 2.42 (95% CI, 1.54-3.78) if ratio>1.1 (compared with ratio between 0.8 and 1.1). LIMITATIONS: Single plasmin(ogen) determination does not allow for the study of changes over time. The use of a cohort of mostly white patients and the restriction to patients with 3 glomerular disorders limits the external validity of our analysis. CONCLUSIONS: Urinary plasmin(ogen) and the ratio of measured/expected plasmin(ogen) are independently associated with ESKD in a cohort of patients with glomerular disease. Taken together with our previous experimental findings, urinary plasmin(ogen) could be a useful biomarker in prognostic decision making and a target for the development of novel therapies in patients with proteinuria and glomerular disease. PLAIN-LANGUAGE SUMMARY: Glomerular diseases are an important cause of morbidity and mortality in patients of all ages. Knowing the individual risk of progression to dialysis or transplantation would help to plan the follow-up and treatment of these patients. Our work studies the usefulness of urinary plasminogen as a marker of progression in this context, since previous studies indicate that plasminogen may be involved in the mechanisms responsible for the progression of these disorders. Our work in a sample of 1,010 patients with glomerular disease demonstrates that urinary plasminogen (as well as the ratio of measured to expected plasminogen) is associated with the risk of progression to end-stage kidney disease. Urine plasminogen exhibited good performance and, if further validated, could enable risk stratification for timely interventions in patients with proteinuria and glomerular disease.

Urine Uromodulin as a Biomarker of Kidney Tubulointerstitial Fibrosis.

BACKGROUND AND OBJECTIVES: Uromodulin, produced exclusively in the kidney's thick ascending limb, is a biomarker of kidney tubular health. However, the relationship between urine uromodulin and histologic changes in the kidney tubulointerstitium has not been characterized. In this study, we test the association of urine uromodulin with kidney histologic findings in humans and mice. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We investigated the independent association of urine uromodulin measured at the time of kidney biopsy with histologic features in 364 participants at two academic medical centers from 2015 to 2018 using multivariable linear regression models. This relationship was further examined by comparison of uromodulin staining in murine models of kidney fibrosis and repair. RESULTS: We found urine uromodulin to be correlated with serum creatinine (rho=-0.43; P<0.001), bicarbonate (0.20; P<0.001), and hemoglobin (0.11; P=0.03) at the time of biopsy but not with urine albumin (-0.07; P=0.34). Multivariable models controlling for prebiopsy GFR, serum creatinine at biopsy, and urine albumin showed higher uromodulin to be associated with lower severity of interstitial fibrosis/tubular atrophy and glomerulosclerosis (interstitial fibrosis/tubular atrophy: -3.5% [95% confidence intervals, -5.7% to -1.2%] and glomerulosclerosis: -3.3% [95% confidence intervals, -5.9% to -0.6%] per two-fold difference in uromodulin). However, when both interstitial fibrosis/tubular atrophy and glomerulosclerosis were included in multivariable analysis, only interstitial fibrosis/tubular atrophy was independently associated with uromodulin (interstitial fibrosis/tubular atrophy: -2.5% [95% confidence intervals, -4.6% to -0.4%] and glomerulosclerosis: -0.9% [95% confidence intervals, -3.4% to 1.5%] per two-fold difference in uromodulin). In mouse kidneys, uromodulin staining was found to be lower in the fibrotic model than in normal or repaired models. CONCLUSIONS: Higher urine uromodulin is independently associated with lower tubulointerstitial fibrosis in both human kidney biopsies and a mouse model of fibrosis. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_08_10_CJN04360422.mp3.

Association of Financial Conflicts of Interest With Academic Productivity Among Junior Faculty in Hematology and Oncology

INTRODUCTION: Financial conflicts of interest (COIs) represent a common and complex issue in hematology and oncology. However, little is known about the timing of when COIs begin to develop during a career trajectory. We evaluated self-reported COIs for junior faculty members at top cancer centers to determine how these financial relationships correlated with measures of academic career productivity. METHODS: We analyzed data from 230 assistant professors at 10 academic cancer centers. Financial COIs were identified from the CMS Open Payments (Sunshine Act dollars) database. Self-reported COIs were obtained from American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) disclosures, and from disclosures in recent publications. Number of publications and h-index (defined as the largest number of publications [h] such that h publications each have at least h citations) were used as measures of academic productivity. Scatter plots and Spearman correlation coefficients were used to assess the relationship between COIs or Sunshine Act dollars with number of publications and h-index. Linear regression modeling was used to analyze the relationships between COIs or Sunshine Act dollars with number of publications and h-index, adjusting for years of experience since completing fellowship (YSF). RESULTS: A total of 46% of junior faculty had at least 1 COI. Number of COIs reported to ASCO/ASH was positively correlated with total Sunshine Act dollars (Spearman correlation, 0.53; P <.01). The number of COIs and the number of Sunshine Act dollars increased with years in practice (Spearman correlation, 0.38 and 0.25, respectively; P <.01 for both). COIs and Sunshine Act dollars correlated with h-index (Spearman correlation, 0.41 and 0.37, respectively; both P <.01). After adjusting for YSF, linear regression demonstrated that log-transformed h-index and number of publications were associated with Sunshine Act dollars (both P <.01) and COIs (ASCO/ASH) (both P = .01). CONCLUSIONS: Financial COIs increased with number of YSF. Measures of academic productivity were positively correlated with COIs (ASCO/ASH) and Sunshine Act dollars. These data suggest that the cultivation of industry relationships is associated with the early academic productivity of junior faculty.

Radiation Dose Reduction in Kidney Stone CT: A Randomized, Facility-Based Intervention.

OBJECTIVE: Kidney stones are common, tend to recur, and afflict a young population. Despite evidence and recommendations, adoption of reduced-radiation dose CT (RDCT) for kidney stone CT (KSCT) is slow. We sought to design and test an intervention to improve adoption of RDCT protocols for KSCT using a randomized facility-based intervention. METHODS: Facilities contributing at least 40 KSCTs to the American College of Radiology dose index registry (DIR) during calendar year 2015 were randomized to intervention or control groups. The Dose Optimization for Stone Evaluation intervention included customized CME modules, personalized consultation, and protocol recommendations for RDCT. Dose length product (DLP) of all KSCTs was recorded at baseline (2015) and compared with 2017, 2018, and 2019. Change in mean DLP was compared between facilities that participated (intervened-on), facilities randomized to intervention that did not participate (intervened-off), and control facilities. Difference-in-difference between intervened-on and control facilities is reported before and after intervention. RESULTS: Of 314 eligible facilities, 155 were randomized to intervention and 159 to control. There were 25 intervened-on facilities, 71 intervened-off facilities, and 96 control facilities. From 2015 to 2017, there was a drop of 110 mGy ∙ cm (a 16% reduction) in the mean DLP in the intervened-on group, which was significantly lower compared with the control group (P < .05). The proportion of RDCTs increased for each year in the intervened-on group relative to the other groups for all 3 years (P < .01). DISCUSSION: The Dose Optimization for Stone Evaluation intervention resulted in a significant (P < .05) and persistent reduction in mean radiation doses for engaged facilities performing KSCTs.

Automated Lung Ultrasound B-Line Assessment Using a Deep Learning Algorithm.

Shortness of breath is a major reason that patients present to the emergency department (ED) and point-of-care ultrasound (POCUS) has been shown to aid in diagnosis, particularly through evaluation for artifacts known as B-lines. B-line identification and quantification can be a challenging skill for novice ultrasound users, and experienced users could benefit from a more objective measure of quantification. We sought to develop and test a deep learning (DL) algorithm to quantify the assessment of B-lines in lung ultrasound. We utilized ultrasound clips ( n = 400 ) from an existing database of ED patients to provide training and test sets to develop and test the DL algorithm based on deep convolutional neural networks. Interpretations of the images by algorithm were compared to expert human interpretations on binary and severity (a scale of 0-4) classifications. Our model yielded a sensitivity of 93% (95% confidence interval (CI) 81%-98%) and a specificity of 96% (95% CI 84%-99%) for the presence or absence of B-lines compared to expert read, with a kappa of 0.88 (95% CI 0.79-0.97). Model to expert agreement for severity classification yielded a weighted kappa of 0.65 (95% CI 0.56-074). Overall, the DL algorithm performed well and could be integrated into an ultrasound system in order to help diagnose and track B-line severity. The algorithm is better at distinguishing the presence from the absence of B-lines but can also be successfully used to distinguish between B-line severity. Such methods could decrease variability and provide a standardized method for improved diagnosis and outcome.

Imaging in Suspected Renal Colic: Systematic Review of the Literature and Multispecialty Consensus.

STUDY OBJECTIVE: Renal colic is common and computed tomography (CT) is frequently used when the diagnosis of kidney stone is suspected. CT is accurate but exposes patients to ionizing radiation and has not been shown to alter either interventional approaches or hospital admission rates. This multiorganizational transdisciplinary collaboration seeks evidence-based, multispecialty consensus on optimal imaging across different clinical scenarios in patients with suspected renal colic in the acute setting. METHODS: In conjunction with the American College of Emergency Physicians (ACEP) Emergency Quality Network, we formed a 9-member panel with 3 physician representatives each from ACEP, the American College of Radiology, and the American Urology Association. A systematic literature review was used as the basis for a 3-step modified Delphi process to seek consensus on optimal imaging in 29 specific clinical scenarios. RESULTS: From an initial search yielding 6,337 records, there were 232 relevant articles of acceptable evidence quality to guide the literature summary. At the completion of the Delphi process consensus, out of the 29 scenarios agreement was rated as perfect in 15 (52%), excellent in 8 (28%), good in 3 (10%), and moderate in 3 (10%). There were no scenarios in which at least moderate consensus was not reached. CT was recommended in 7 scenarios (24%), with ultrasonography in 9 (31%) and no further imaging needed in 12 (45%). CONCLUSION: Evidence and multispecialty consensus support ultrasonography or no further imaging in specific clinical scenarios, with reduced-radiation-dose CT to be used when CT is needed for patients with suspected renal colic.

Imaging in Suspected Renal Colic: Systematic Review of the Literature and Multispecialty Consensus.

BACKGROUND: Renal colic is common, and CT is frequently utilized when the diagnosis of kidney stones is suspected. CT is accurate but exposes patients to ionizing radiation and has not been shown to alter either interventional approaches or hospital admission rates. This multi-organizational transdisciplinary collaboration sought evidence-based, multispecialty consensus on optimal imaging across different clinical scenarios in patients with suspected renal colic in the acute setting. METHODS: In conjunction with the American College of Emergency Physicians (ACEP) eQual network, we formed a nine-member panel with three physician representatives each from ACEP, the ACR, and the American Urology Association. A systematic literature review was used as the basis for a three-step modified Delphi process to seek consensus on optimal imaging in 29 specific clinical scenarios. RESULTS: From an initial search yielding 6,337 records, there were 232 relevant articles of acceptable evidence quality to guide the literature summary. At the completion of the Delphi process consensus, agreement was rated as perfect in 15 (52%), excellent in 8 (28%), good in 3 (10%), and moderate in 3 (10%) of the 29 scenarios. There were no scenarios where at least moderate consensus was not reached. CT was recommended in 7 scenarios (24%), with ultrasound in 9 (31%) and no further imaging needed in 12 (45%). SUMMARY: Evidence and multispecialty consensus support ultrasound or no further imaging in specific clinical scenarios, with reduced-radiation dose CT to be employed when CT is needed in patients with suspected renal colic.

Imaging in Suspected Renal Colic: Systematic Review of the Literature and Multispecialty Consensus.

PURPOSE: Renal colic is common and CT (computerized tomography) is frequently utilized when the diagnosis of kidney stone is suspected. CT is accurate, but exposes patients to ionizing radiation and has not been shown to alter either interventional approaches or hospital admission rates. This multi-organizational transdisciplinary collaboration sought evidence-based, multispecialty consensus on optimal imaging across different clinical scenarios in patients with suspected renal colic in the acute setting. MATERIALS AND METHODS: In conjunction with the ACEP (American College of Emergency Physicians®) E-QUAL (Emergency Quality Network) we formed a nine-member panel with three physician representatives each from the ACEP, the ACR® (American College of Radiology) and the AUA (American Urological Association). A systematic literature review was used as the basis for a 3-step modified Delphi process to seek consensus on optimal imaging in 29 specific clinical scenarios. RESULTS: From an initial search yielding 6,337 records there were 232 relevant articles of acceptable evidence quality to guide the literature summary. At the completion of the Delphi process consensus, agreement was rated as perfect in 15 (52%), excellent in 8 (28%), good in 3 (10%) and moderate in 3 (10%) of the 29 scenarios. There were no scenarios where at least moderate consensus was not reached. CT was recommended in 7 scenarios (24%) with ultrasound in 9 (31%) and no further imaging needed in 13 (45%). CONCLUSIONS: Evidence and multispecialty consensus support ultrasound or no further imaging in specific clinical scenarios, with reduced-radiation dose CT to be employed when CT is needed in patients with suspected renal colic.

Tropicamide has limited clinical effect on cycloplegia and mydriasis when combined with cyclopentolate and phenylephrine.

PURPOSE: To examine the cycloplegic and mydriatic effect of tropicamide omission from a common pediatric eye drop combination. METHODS: Consecutive children examined at the Ann & Robert H. Lurie Children's Hospital of Chicago from June 8, 2017 to September 6, 2017 were enrolled prospectively. Tropicamide, cyclopentolate, and phenylephrine (TCP) was instilled in one eye; cyclopentolate and phenylephrine (CP), in the other. Spherical equivalent, maximum pupil size, and pupillary constriction in response to photostimulation were measured before and 30 minutes after instillation using an autorefractor and pupillometer. Iris pigmentation was examined as a between-subjects variable. RESULTS: A total of 75 children 4-11 years of age were included. Mean differences in spherical equivalent between TCP and CP were not statistically significant (P = 0.95). Significant interactions between eye drop regimen and iris pigmentation were observed for pupil size (P = 0.001) and constriction percentage (P = 0.02). Among only patients with dark irides, TCP yielded slightly larger pupils (7.70 vs 7.31 mm [P < 0.001]) that were less responsive to light (5.75% vs 8.07% [P = 0.002]). All pupils dilated to ≥6.0 mm, with equivalent proportions achieving ≥7.0 mm for TCP and CP (P = 0.18). CONCLUSIONS: TCP and CP elicited equivalent cycloplegic effects. Mydriatic differences between the regimens, although statistically significant in dark irides, were of limited clinical magnitude, and all pupils achieved sufficient dilation for funduscopy.

Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study.

UNLABELLED: We assessed the association between the single-nucleotide polymorphism (SNP) rs58542926 in the transmembrane 6 superfamily member 2 (TM6SF2) gene and fatty liver disease in obese youth. We genotyped the TM6SF2 rs58542926 SNP in a multiethnic cohort of 957 obese children and adolescents (42% Caucasians, 28% African Americans, 30% Hispanics). All underwent an oral glucose tolerance test, a liver panel, and a lipid profile. Of them, 454 children underwent a magnetic resonance imaging study to assess hepatic fat content and 11 underwent liver biopsy to assess the degree of disease severity. The minor allele of the rs58542926 SNP was associated with high hepatic fat content in Caucasians and African Americans (all P < 0.05), with high alanine aminotransferase levels in Hispanics (P < 0.05) and a more favorable lipoprotein profile (lower low-density lipoprotein, small dense low-density lipoprotein, and very small low-density lipoprotein) in Caucasians and Hispanics (all P < 0.05). The liver biopsy showed a higher prevalence of fibrosis (P = 0.04) and a higher nonalcoholic fatty liver disease activity score (P = 0.05) in subjects carrying the minor allele than in those homozygous for the common allele. Moreover, we observed a joint effect among the TM6SF2 rs58542926, the PNPLA3 rs738409, and the GCKR rs1260326 SNPs in determining intrahepatic fat accumulation (P < 0.05). CONCLUSION: The rs58542926 SNP in the TM6SF2 gene is associated with pediatric nonalcoholic fatty liver disease but may confer protection against cardiovascular risk.

The role of multicellular aggregation in the survival of ErbB2-positive breast cancer cells during extracellular matrix detachment.

The metastasis of cancer cells from the site of the primary tumor to distant sites in the body represents the most deadly manifestation of cancer. In order for metastasis to occur, cancer cells need to evade anoikis, which is defined as apoptosis caused by loss of attachment to extracellular matrix (ECM). Signaling from ErbB2 has previously been linked to the evasion of anoikis in breast cancer cells but the precise molecular mechanisms by which ErbB2 blocks anoikis have yet to be unveiled. In this study, we have identified a novel mechanism by which anoikis is inhibited in ErbB2-expressing cells: multicellular aggregation during ECM-detachment. Our data demonstrate that disruption of aggregation in ErbB2-positive cells is sufficient to induce anoikis and that this anoikis inhibition is a result of aggregation-induced stabilization of EGFR and consequent ERK/MAPK survival signaling. Furthermore, these data suggest that ECM-detached ErbB2-expressing cells may be uniquely susceptible to targeted therapy against EGFR and that this sensitivity could be exploited for specific elimination of ECM-detached cancer cells.

Oxidized fatty acids: A potential pathogenic link between fatty liver and type 2 diabetes in obese adolescents?

In this study, we sought to investigate the putative association of the oxidized metabolites derived from linoleic acid (OXFAs) with pediatric nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We studied 80 obese adolescents (age 13.3 ± 3.31 years; body mass index 33.0 ± 6.79 kg/m(2)), who underwent an oral glucose tolerance test, a magnetic resonance imaging (MRI) to measure the hepatic fat content, and the measurement of OXFAs and caspase-cleaved Citokeratin18 fragment (CK-18), a robust biomarker of liver injury. In this study, we show that only in subjects with hepatic steatosis, the OXFAs are associated with the CK-18 and that this association is modulated by the PNPLA3 rs738409 variant. We also show that most of the OXFAs are associated with a lower insulin secretion and that adolescents with T2D have higher levels of OXFAs than subjects with impaired or normal glucose tolerance. These observations lead to the hypothesis that the OXFAs may be the pathogenic link between liver injury and T2D and that the novel therapeutic opportunities targeting the OXFAs are possible in adolescents with early-onset NAFLD and T2D.

Co-occurrence of risk alleles in or near genes modulating insulin secretion predisposes obese youth to prediabetes.

OBJECTIVE: Paralleling the rise of pediatric obesity, the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) is increasing among youth. In this study, we asked whether the co-occurrence of risk alleles in or near five genes modulating insulin secretion (TCF7L2 rs7903146, IGF2BP2 rs4402960, CDKAL1 rs7754840, HHEX rs1111875, and HNF1A rs1169288) is associated with a higher risk of IGT/T2D in obese children and adolescents. RESEARCH DESIGN AND METHODS: We studied 714 obese subjects (290 boys and 424 girls; mean age 13.6 ± 3.1 years; mean z score BMI 2.2 ± 0.4) and evaluated the insulin secretion by using the oral minimal model and, in a subgroup of 37 subjects, the hyperglycemic clamp. Also, 203 subjects were followed up for a mean of 2.1 years. RESULTS: We observed that the increase of risk alleles was associated with a progressive worsening of insulin secretion (P < 0.001) mainly due to an impairment of the dynamic phase of insulin secretion (P = 0.004); the higher the number of the risk alleles, the higher the chance of progression from normal glucose tolerance (NGT) to IGT/T2D (P = 0.022). Also, for those who were IGT at baseline, a higher risk score was associated with a lower odds to revert to NGT (P = 0.026). CONCLUSIONS: Obese children and adolescents developing IGT/T2D have a higher genetic predisposition than those who do not show these diseases, and this predisposition is mainly related to gene variants modulating the early phase of insulin secretion. Although these data are very interesting, they need to be replicated in other cohorts.

Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake.

BACKGROUND: A single nucleotide polymorphism (SNP), the rs738409, in the patatin like phospholipase 3 gene (PNPLA3) has been recently associated with increased hepatic steatosis and ALT levels in adults and children. Given the potential role of PNPLA3 in fatty liver development, we aimed to explore whether the influence of PNPLA3 genotype on hepatic fat in obese youth might be modulated by dietary factors such as essential omega polyunsaturated fatty acids (PUFA) intake. MATERIALS AND METHODS: We studied 127 children and adolescents (56 boys, 71 girls; 58 Caucasians; 30 African Americans and 39 Hispanics; mean age 14.7±3.3; mean BMI 30.7±7.2). The dietary composition was assessed by the Nutrition Data System for Research (NDS-R version 2011). The patients underwent a MRI study to assess the liver fat content (HFF%), ALT measurement and the genotyping of the rs738409 SNP by automatic sequencing. RESULTS: As previously observed, HFF% and ALT levels varied according to the genotype in each ethnicity. ALT levels and HFF% were significantly influenced by the interaction between genotype and omega-6/omega-3 PUFA ratio (n-6/n-3), p = 0.003 and p = 0.002, respectively. HFF% and ALT levels were, in fact, related to the n-6/n-3 consumption only in subjects homozygote for the G allele of the rs738409 (r2 = 0.45, p =  0.001 and r2 = 0.40, p = 0.006, respectively). CONCLUSIONS: These findings suggest that the association of a high dietary n-6/n-3 PUFA with fatty liver and liver damage in obese youths may be driven by a predisposing genotype.

Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents.

UNLABELLED: Recently, the single nucleotide polymorphism (SNP) identified as rs1260326, in the glucokinase regulatory protein (GCKR), was associated with hypertriglyceridemia in adults. Because accumulation of triglycerides in hepatocytes represents the hallmark of steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, because recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans, and 135 Hispanics). All underwent an oral glucose tolerance test and fasting lipoprotein subclasses measurement by proton nuclear magnetic resonance. A subset of 142 children underwent a fast gradient magnetic resonance imaging to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians P = 0.00014; African Americans P = 0.00417), large very low-density lipoprotein (VLDL) (Caucasians P = 0.001; African Americans, P = 0.03), and with fatty liver (Caucasians P = 0.034; African Americans P = 0.00002; and Hispanics P = 0.016). The PNPLA3, but not the APOC3 rs2854116 SNP, was associated with fatty liver but not with triglyceride levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance in Caucasians (P = 0.00161), 39.0% in African Americans (P = 0.00000496), and 15% in Hispanics (P = 0.00342). CONCLUSION: The rs1260326 in GCKR is associated with hepatic fat accumulation along with large VLDL and triglyceride levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths.

Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children and adolescents.

OBJECTIVE: Hemoglobin A(1c) (A1C) has emerged as a recommended diagnostic tool for identifying diabetes and subjects at risk for the disease. This recommendation is based on data in adults showing the relationship between A1C with future development of diabetes and microvascular complications. However, studies in the pediatric population are lacking. RESEARCH DESIGN AND METHODS: We studied a multiethnic cohort of 1,156 obese children and adolescents without a diagnosis of diabetes (male, 40%/female, 60%). All subjects underwent an oral glucose tolerance test (OGTT) and A1C measurement. These tests were repeated after a follow-up time of ∼2 years in 218 subjects. RESULTS: At baseline, subjects were stratified according to A1C categories: 77% with normal glucose tolerance (A1C <5.7%), 21% at risk for diabetes (A1C 5.7-6.4%), and 1% with diabetes (A1C >6.5%). In the at risk for diabetes category, 47% were classified with prediabetes or diabetes, and in the diabetes category, 62% were classified with type 2 diabetes by the OGTT. The area under the curve receiver operating characteristic for A1C was 0.81 (95% CI 0.70-0.92). The threshold for identifying type 2 diabetes was 5.8%, with 78% specificity and 68% sensitivity. In the subgroup with repeated measures, a multivariate analysis showed that the strongest predictors of 2-h glucose at follow-up were baseline A1C and 2-h glucose, independently of age, ethnicity, sex, fasting glucose, and follow-up time. CONCLUSIONS: The American Diabetes Association suggested that an A1C of 6.5% underestimates the prevalence of prediabetes and diabetes in obese children and adolescents. Given the low sensitivity and specificity, the use of A1C by itself represents a poor diagnostic tool for prediabetes and type 2 diabetes in obese children and adolescents.

Rosiglitazone improves glucose metabolism in obese adolescents with impaired glucose tolerance: a pilot study.

Impaired glucose tolerance (IGT) is a prediabetic state fueling the rising prevalence of type 2 diabetes mellitus (T2DM) in adolescents with marked obesity. Given the importance of insulin resistance, the poor ß-cell compensation and the altered fat partitioning as underlying defects associated with this condition, it is crucial to determine the extent to which these underlying abnormalities can be reversed in obese adolescents. We tested, in a pilot study, whether rosiglitazone (ROSI) restores normal glucose tolerance (NGT) in obese adolescents with IGT by improving insulin sensitivity and ß-cell function. In a small randomized, double-blind, placebo (PLA)-controlled study, lasting 4 months, 21 obese adolescents with IGT received either ROSI (8 mg daily) (n = 12, 5M/7F, BMI z-score 2.44 ± 0.11) or PLA (n = 9, 4M/5F, BMI z-score 2.41 ± 0.09). Before and after treatment, all subjects underwent oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, magnetic resonance imaging, and (1)H NMR assessment. After ROSI treatment, 58% of the subjects converted to NGT compared to 44% in the PLA group (P = 0.528). Restoration of NGT was associated with a significant increase in insulin sensitivity (P < 0.04) and a doubling in the disposition index (DI) (P < 0.04), whereas in the PLA group, these changes were not significant. The short-term use of ROSI appears to be safe in obese adolescents with IGT. ROSI restores NGT by increasing peripheral insulin sensitivity and ß-cell function, two principal pathophysiological abnormalities of IGT.

A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents.

UNLABELLED: The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPARγ2(peroxisome proliferator-activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04). CONCLUSION: A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size.