bluuebunny/crossref_metadata_2025_split huggingface dataset:
APPL1 Counteracts Obesity-Induced Vascular Insulin Resistance and Endothelial Dysfunction by Modulating the Endothelial Production of Nitric Oxide and Endothelin-1 in Mice
Authors: Wang Yi , Cheng Kenneth K.Y. , Lam Karen S.L. , Wu Donghai , Wang Yu , Huang Yu , Vanhoutte Paul M. , Sweeney Gary , Li Yiming , Xu Aimin 
Published: September 2011

OBJECTIVE
Insulin stimulates both nitric oxide (NO)-dependent vasodilation and endothelin-1 (ET-1)–dependent vasoconstriction. However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear. This study aimed to investigate the roles of the multidomain adaptor protein APPL1 in modulating vascular actions of insulin in mice and in endothelial cells.

RESEARCH DESIGN AND METHODS
Both APPL1 knockout mice and APPL1 transgenic mice were generated to evaluate APPL1’s physiological roles in regulating vascular reactivity and insulin signaling in endothelial cells.

RESULTS
Insulin potently induced NO-dependent relaxations in mesenteric arteries of 8-week-old mice, whereas this effect of insulin was progressively impaired with ageing or upon development of obesity induced by high-fat diet. Transgenic expression of APPL1 prevented age- and obesity-induced impairment in insulin-induced vasodilation and reversed obesity-induced augmentation in insulin-evoked ET-1–dependent vasoconstriction. By contrast, genetic disruption of APPL1 shifted the effects of insulin from vasodilation to vasoconstriction. At the molecular level, insulin-elicited activation of protein kinase B (Akt) and endothelial NO synthase and production of NO were enhanced in APPL1 transgenic mice but were abrogated in APPL1 knockout mice. Conversely, insulin-induced extracellular signal–related kinase (ERK)1/2 phosphorylation and ET-1 expression was augmented in APPL1 knockout mice but was diminished in APPL1 transgenic mice. In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1.

CONCLUSIONS
APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium.
Fibroblast Growth Factor 21 (FGF21) in Human Cerebrospinal Fluid
Authors: Tan Bee K. , Hallschmid Manfred , Adya Raghu , Kern Werner , Lehnert Hendrik , Randeva Harpal S. 
Published: September 2011

OBJECTIVE
Reports of increased circulating fibroblast growth factor 21 (FGF21) levels in obesity indicate that FGF21 may be implicated in body weight homeostasis. We sought to investigate the existence of FGF21 in human cerebrospinal fluid (CSF) and, if present, the relationship between CSF FGF21 with body adiposity and metabolic parameters.

RESEARCH DESIGN AND METHODS
CSF and corresponding plasma FGF21 were measured by an enzyme-linked immunosorbent assay (18 men and 20 women, aged 19–80 years, and BMI 16.2–38.1 kg/m2) and correlated to body adiposity and metabolic parameters.

RESULTS
CSF and plasma FGF21 increased in particular with rising BMI and fat mass. In CSF, FGF21 was detectable at concentrations ~40% that of plasma levels. CSF and plasma FGF21 levels were significantly positively correlated with BMI and fat mass, body weight, plasma insulin, and homeostasis model assessment of insulin resistance. Plasma FGF21 levels were significantly negatively correlated with plasma adiponectin. When subjected to multiple regression analysis, only fat mass was predictive of plasma FGF21 (β = 0.758; P = 0.004) and CSF FGF21 (β = 0.767; P = 0.007). The CSF-to-plasma FGF21 ratio was significantly negatively correlated with BMI, fat mass, and plasma FGF21. Subjects in the highest plasma FGF21 quintile had a lower CSF-to-plasma FGF21 ratio (12.7% [9.7–14.9%]) compared with those in the lowest plasma FGF21 quintile (94.7% [37.3–99.8%]) (P &lt; 0.01).

CONCLUSIONS
Our observations have important implications with respect to the potential central actions of FGF21. Future research should seek to clarify whether FGF21 would be beneficial in the management of obesity and its metabolic complications.
Associations Between Paternally Transmitted Fetal IGF2 Variants and Maternal Circulating Glucose Concentrations in Pregnancy
Authors: Petry Clive J. , Seear Rachel V. , Wingate Dianne L. , Manico Lucy , Acerini Carlo L. , Ong Ken K. , Hughes Ieuan A. , Dunger David B. 
Published: September 2011

OBJECTIVE
To test the hypothesis that polymorphic variation in the paternally transmitted fetal IGF2 gene is associated with maternal glucose concentrations in the third trimester of pregnancy.

RESEARCH DESIGN AND METHODS
A total of 17 haplotype tag single nucleotide polymorphisms in the IGF2 gene region were genotyped in 1,160 mother/partner/offspring trios from the prospective Cambridge Baby Growth Study (n = 845 trios) and the retrospective Cambridge Wellbeing Study (n = 315 trios) (3,480 samples in total). Associations were tested between inferred parent-of-origin fetal alleles, z scores of maternal glucose concentrations 60 min. after an oral glucose load performed at week 28 of pregnancy, and offspring birth weights.

RESULTS
Using the minimum P value test, paternally transmitted fetal IGF2 polymorphisms were associated with maternal glucose concentrations; specifically, paternally transmitted fetal rs6578987 (P = 0.006), rs680 (P = 0.01), rs10770125 (P = 0.0002), and rs7924316 (P = 0.01) alleles were associated with increased maternal glucose concentrations in the third trimester of pregnancy and placental IGF-II contents at birth (P = 0.03). In contrast, there were no associations between maternal glucose concentrations and maternal or maternally transmitted fetal IGF2 genotypes.

CONCLUSIONS
Polymorphic variation in paternally transmitted fetal IGF2 is associated with increased maternal glucose concentrations in pregnancy and could potentially alter the risk of gestational diabetes in the mother. The association may be at least partially mediated by changes in placental IGF2 expression.
Loss of Intra-Islet CD20 Expression May Complicate Efficacy of B-Cell–Directed Type 1 Diabetes Therapies
Authors: Serreze David V. , Chapman Harold D. , Niens Marijke , Dunn Robert , Kehry Marilyn R. , Driver John P. , Haller Michael , Wasserfall Clive , Atkinson Mark A. 
Published: September 2011

OBJECTIVEConsistent with studies in NOD mice, early clinical trials addressing whether depletion of B cells by the Rituximab CD20-specific antibody provides an effective means for type 1 diabetes reversal have produced promising results. However, to improve therapeutic efficacy, additional B-cell–depleting agents, as well as attempts seeking diabetes prevention, are being considered.RESEARCH DESIGN AND METHODSAutoantibodies, including those against insulin (IAAs), are used to identify at-risk subjects for inclusion in diabetes prevention trials. Therefore, we tested the ability of anti-CD20 to prevent diabetes in NOD mice when administered either before or after IAA onset.RESULTSThe murine CD20-specific 18B12 antibody that like Rituximab, depletes the follicular (FO) but not marginal zone subset of B cells, efficiently inhibited diabetes development in NOD mice in a likely regulatory T-cell–dependent manner only when treatment was initiated before IAA detection. One implication of these results is that the FO subset of B cells preferentially contributes to early diabetes initiation events. However, most important, the inefficient ability of anti-CD20 treatment to exert late-stage diabetes prevention was found to be attributable to downregulation of CD20 expression upon B cell entry into pancreatic islets.CONCLUSIONSThese findings provide important guidance for designing strategies targeting B cells as a potential means of diabetes intervention.
High-Resolution Magnetic Resonance Imaging Quantitatively Detects Individual Pancreatic Islets
Authors: Lamprianou Smaragda , Immonen Riikka , Nabuurs Christine , Gjinovci Asllan , Vinet Laurent , Montet Xavier C.R. , Gruetter Rolf , Meda Paolo 
Published: September 2011

OBJECTIVE
We studied whether manganese-enhanced high-field magnetic resonance (MR) imaging (MEHFMRI) could quantitatively detect individual islets in situ and in vivo and evaluate changes in a model of experimental diabetes.

RESEARCH DESIGN AND METHODS
Whole pancreata from untreated (n = 3), MnCl2 and glucose-injected mice (n = 6), and mice injected with either streptozotocin (STZ; n = 4) or citrate buffer (n = 4) were imaged ex vivo for unambiguous evaluation of islets. Exteriorized pancreata of MnCl2 and glucose-injected mice (n = 6) were imaged in vivo to directly visualize the gland and minimize movements. In all cases, MR images were acquired in a 14.1 Tesla scanner and correlated with the corresponding (immuno)histological sections.

RESULTS
In ex vivo experiments, MEHFMRI distinguished different pancreatic tissues and evaluated the relative abundance of islets in the pancreata of normoglycemic mice. MEHFMRI also detected a significant decrease in the numerical and volume density of islets in STZ-injected mice. However, in the latter measurements the loss of β-cells was undervalued under the conditions tested. The experiments on the externalized pancreata confirmed that MEHFMRI could visualize native individual islets in living, anesthetized mice.

CONCLUSIONS
Data show that MEHFMRI quantitatively visualizes individual islets in the intact mouse pancreas, both ex vivo and in vivo.
Normal Glucagon Signaling and β-Cell Function After Near-Total α-Cell Ablation in Adult Mice
Authors: Thorel Fabrizio , Damond Nicolas , Chera Simona , Wiederkehr Andreas , Thorens Bernard , Meda Paolo , Wollheim Claes B. , Herrera Pedro L. 
Published: September 2011

OBJECTIVE
To evaluate whether healthy or diabetic adult mice can tolerate an extreme loss of pancreatic α-cells and how this sudden massive depletion affects β-cell function and blood glucose homeostasis.

RESEARCH DESIGN AND METHODS
We generated a new transgenic model allowing near-total α-cell removal specifically in adult mice. Massive α-cell ablation was triggered in normally grown and healthy adult animals upon diphtheria toxin (DT) administration. The metabolic status of these mice was assessed in 1) physiologic conditions, 2) a situation requiring glucagon action, and 3) after β-cell loss.

RESULTS
Adult transgenic mice enduring extreme (98%) α-cell removal remained healthy and did not display major defects in insulin counter-regulatory response. We observed that 2% of the normal α-cell mass produced enough glucagon to ensure near-normal glucagonemia. β-Cell function and blood glucose homeostasis remained unaltered after α-cell loss, indicating that direct local intraislet signaling between α- and β-cells is dispensable. Escaping α-cells increased their glucagon content during subsequent months, but there was no significant α-cell regeneration. Near-total α-cell ablation did not prevent hyperglycemia in mice having also undergone massive β-cell loss, indicating that a minimal amount of α-cells can still guarantee normal glucagon signaling in diabetic conditions.

CONCLUSIONS
An extremely low amount of α-cells is sufficient to prevent a major counter-regulatory deregulation, both under physiologic and diabetic conditions. We previously reported that α-cells reprogram to insulin production after extreme β-cell loss and now conjecture that the low α-cell requirement could be exploited in future diabetic therapies aimed at regenerating β-cells by reprogramming adult α-cells.
Arginase-2 Mediates Diabetic Renal Injury
Authors: Morris Sidney M. , Gao Ting , Cooper Timothy K. , Kepka-Lenhart Diane , Awad Alaa S. 
Published: September 2011

OBJECTIVE
To determine 1) whether renal arginase activity or expression is increased in diabetes and 2) whether arginase plays a role in development of diabetic nephropathy (DN).

RESEARCH DESIGN AND METHODS
The impact of arginase activity and expression on renal damage was evaluated in spontaneously diabetic Ins2Akita mice and in streptozotocin (STZ)-induced diabetic Dilute Brown Agouti (DBA) and arginase-2–deficient mice (Arg2−/−).

RESULTS
Pharmacological blockade or genetic deficiency of arginase-2 conferred kidney protection in Ins2Akita mice or STZ-induced diabetic renal injury. Blocking arginases using S-(2-boronoethyl)-l-cysteine for 9 weeks in Ins2Akita mice or 6 weeks in STZ-induced diabetic DBA mice significantly attenuated albuminuria, the increase in blood urea nitrogen, histopathological changes, and kidney macrophage recruitment compared with vehicle-treated Ins2Akita mice. Furthermore, kidney arginase-2 expression increased in Ins2Akita mice compared with control. In contrast, arginase-1 expression was undetectable in kidneys under normal or diabetes conditions. Arg2−/− mice mimicked arginase blockade by reducing albuminuria after 6 and 18 weeks of STZ-induced diabetes. In wild-type mice, kidney arginase activity increased significantly after 6 and 18 weeks of STZ-induced diabetes but remained very low in STZ-diabetic Arg2−/− mice. The increase in kidney arginase activity was associated with a reduction in renal medullary blood flow in wild-type mice after 6 weeks of STZ-induced diabetes, an effect significantly attenuated in diabetic Arg2−/− mice.

CONCLUSIONS
These findings indicate that arginase-2 plays a major role in induction of diabetic renal injury and that blocking arginase-2 activity or expression could be a novel therapeutic approach for treatment of DN.
Diagnostic Testing for Diabetes Using HbA1c in the Abu Dhabi Population
Authors: Hajat Cother , Harrison Oliver , Al Siksek Zaid 
Published: September 2011

OBJECTIVE
The validity of HbA1c as a population diagnostic tool was tested against oral glucose tolerance testing in Abu Dhabi nationals.

RESEARCH DESIGN AND METHODS
The screening tool of HbA1c and random glucose was validated against the “gold standard” oral glucose tolerance test according to World Health Organization criteria.

RESULTS
The HbA1c threshold of 6.4% provided the optimum balance between sensitivity (72.0%) and specificity (84.3%) with positive and negative predictive values of 47.9 and 93.7% and area under the receiver operating characteristics curve of 0.78. This threshold compares with a threshold of 6.5% recommended by the International Scientific Committee and American Diabetes Association and of 6.3% in a recent study in China.

CONCLUSIONS
This study successfully validates the feasibility and threshold of HbA1c for diagnosis of diabetes at the population level in a Middle-Eastern population. This result is a major step in the fight to tackle the increasing burden of diabetes in the United Arab Emirates.
Association of Increased Upper Trunk and Decreased Leg Fat With 2-h Glucose in Control and HIV-Infected Persons
Authors: Kosmiski Lisa A. , Scherzer Rebecca , Heymsfield Steven B. , Rimland David , Simberkoff Michael S. , Sidney Stephen , Shlipak Michael G. , Bacchetti Peter , Biggs Mary L. , Grunfeld Carl ,   for the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM)
Published: September 2011

OBJECTIVE
Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects.

RESEARCH DESIGN AND METHODS
A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters.

RESULTS
The prevalence of impaired fasting glucose (IFG) (&gt;110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants.

CONCLUSIONS
In HIV infection, increased upper trunk SAT and decreased leg SAT are associated with higher 2-h glucose. These body fat characteristics may identify HIV-infected patients with normal fasting glucose but nonetheless at increased risk for diabetes.
Reducing Rates of Severe Hypoglycemia in a Population-Based Cohort of Children and Adolescents With Type 1 Diabetes Over the Decade 2000–2009
Authors: O'Connell Susan M. , Cooper Matthew N. , Bulsara Max K. , Davis Elizabeth A. , Jones Timothy W. 
Published: September 2011

OBJECTIVE
To examine rates of severe hypoglycemia (SH) in a large population-based cohort of children with type 1 diabetes and relationships to HbA1c.

RESEARCH DESIGN AND METHODS
Data from 1,683 children (mean [SD] age at diagnosis 10.5 [4.2]; range 1–18 years) from 2000 to 2009 were analyzed from the Western Australian Children's Diabetes Database. Rates of SH were related to HbA1c using negative binomial regression.

RESULTS
A total of 7,378 patient-years of data and 780 SH events were recorded. The rate of SH per 100 patient-years peaked at 17.3 in 2001 and then declined from 2004 to a nadir of 5.8 in 2006. HbA1c &lt;7% was not associated with higher risk of SH (incidence rate ratio 1.2 [95% CI 0.9–1.6], P = 0.29) compared with HbA1c of 8–9%.

CONCLUSIONS
In a sample of youth with type 1 diabetes, there has been a decrease in rates of SH and a weaker relationship with glycemic control than previously observed.
Sleep Disturbances and Their Relationship to Glucose Tolerance in Pregnancy
Authors: Reutrakul Sirimon , Zaidi Nausheen , Wroblewski Kristen , Kay Helen H. , Ismail Mahmoud , Ehrmann David A. , Van Cauter Eve 
Published: September 2011

OBJECTIVE
To explore relationships among sleep disturbances, glucose tolerance, and pregnancy outcomes.

RESEARCH DESIGN AND METHODS
Four validated sleep questionnaires were administered to 169 pregnant women at the time of 50-g oral glucose tolerance testing (OGTT) during the second trimester. Pregnancy outcomes were analyzed in 108 women with normal glucose tolerance (NGT).

RESULTS
Of the participants, 41% had excessive daytime sleepiness (Epworth Sleepiness Scale [ESS] &gt;8); 64% had poor sleep quality; 25% snored frequently; 29% had increased risk of sleep-disordered breathing (SDB); 52% experienced short sleep (SS); 19% had both increased SDB risk and SS (SDB/SS); and 14% had daytime dysfunction. Reported sleep duration inversely correlated with glucose values from 50-g OGTT (r = −0.21, P &lt; 0.01). Each hour of reduced sleep time was associated with a 4% increase in glucose levels. Increased likelihood of gestational diabetes mellitus (GDM) was found in subjects with increased SDB risk (odds ratio 3.0 [95% CI 1.2–7.4]), SS (2.4 [1.0–5.9]), SDB/SS (3.4 [1.3–8.7]), and frequent snoring (3.4 [1.3–8.8], after adjustment for BMI). Among NGT subjects, preterm delivery was more frequent in those with increased ESS (P = 0.02), poor sleep quality (P = 0.02), and SS (P = 0.03). Neonatal intensive care unit admissions were associated with increased ESS (P = 0.03), SDB/SS (P = 0.03), and daytime dysfunction (P &lt; 0.01) in mothers.

CONCLUSIONS
Pregnant women experience significant sleep disturbances that are associated with increased risk of GDM and unfavorable pregnancy outcomes. Pregnant women with increased SDB risk, frequent snoring, and sleep duration of &lt;7 h/night have increased risk of developing GDM.
Hepatic Insulin Resistance Is an Early Determinant of Declining β-Cell Function in the First Year Postpartum After Glucose Intolerance in Pregnancy
Authors: Retnakaran Ravi , Qi Ying , Ye Chang , Hanley Anthony J.G. , Connelly Philip W. , Sermer Mathew , Zinman Bernard 
Published: September 2011

OBJECTIVEThe increased risk of type 2 diabetes in women with glucose intolerance in pregnancy is mediated by deterioration of their β-cell function, which occurs as early as the first year postpartum. We thus sought to identify early determinants of their declining β-cell function.RESEARCH DESIGN AND METHODSWomen with recent gestational glucose intolerance (166) underwent oral glucose tolerance test at 3 and 12 months postpartum. They were stratified into those in whom β-cell function (Insulin Secretion-Sensitivity Index-2 [ISSI-2]) declined over this time (decliners; n = 92) and those in whom it did not (nondecliners; n = 74).RESULTSBetween 3 and 12 months, hepatic insulin sensitivity (1/homeostasis model assessment of insulin resistance [HOMA-IR]) decreased in decliners but not in nondecliners. Over this time, the change in 1/HOMA-IR emerged as an independent predictor of the change in ISSI-2 (t = 5.5; P &lt; 0.0001). Increased hepatic insulin sensitivity independently predicted a lower likelihood of declining β-cell function (odds ratio = 0.13 [95% CI 0.06–0.29]; P &lt; 0.0001).CONCLUSIONSHepatic insulin resistance is an early determinant of declining β-cell function after gestational dysglycemia.
Age and Sex Influence Cystatin C in Adolescents With and Without Type 1 Diabetes
Authors: Maahs David M. , Prentice Nicole , McFann Kim , Snell-Bergeon Janet K. , Jalal Diana , Bishop Franziska K. , Aragon Brittany , Wadwa R. Paul 
Published: September 2011

OBJECTIVE
To compare serum cystatin C levels, a novel biomarker of renal function, in adolescents with and without type 1 diabetes and to determine what factors affect cystatin C levels.

RESEARCH DESIGN AND METHODS
Cystatin C was measured in youth 12–19 years of age with (n = 259, diabetes duration 9 ± 3 years, HbA1c 8.9 ± 1.6%) and without diabetes (n = 78). Data were compared by diabetes status, and linear regression was used to determine factors affecting cystatin C.

RESULTS
Cystatin C (0.698 ± 0.083 vs. 0.688 ± 0.127 mg/L, P = 0.40) was similar by diabetes status. In multiple linear regression, cystatin C was associated with age and serum creatinine in nondiabetic subjects and sex, age, and serum creatinine in subjects with diabetes (P &lt; 0.05).

CONCLUSIONS
These data suggest sex differences and age-related changes in cystatin C in adolescents with type 1 diabetes. An understanding of these changes is needed to determine the potential role of cystatin C as a marker of renal function in this population.
Associations Between Media Consumption Habits, Physical Activity, Socioeconomic Status, and Glycemic Control in Children, Adolescents, and Young Adults With Type 1 Diabetes
Authors: Galler Angela , Lindau Maren , Ernert Andrea , Thalemann Ralf , Raile Klemens 
Published: September 2011

OBJECTIVE
To evaluate the relationship between media consumption habits, physical activity, socioeconomic status, and glycemic control in youths with type 1 diabetes.

RESEARCH DESIGN AND METHODS
In the cross-sectional study, self-report questionnaires were used to assess media consumption habits, physical activity, and socioeconomic status in 296 children, adolescents, and young adults with type 1 diabetes. Clinical data and HbA1c levels were collected. Risk factors were analyzed by multiple regression.

RESULTS
Youths with type 1 diabetes (aged 13.7 ± 4.1 years, HbA1c 8.7 ± 1.6%, diabetes duration 6.1 ± 3.3 years) spent 2.9 ± 1.8 h per day watching television and using computers. Weekly physical activity was 5.1 ± 4.5 h. Multiple regression analysis identified diabetes duration, socioeconomic status, and daily media consumption time as significant risk factors for glycemic control.

CONCLUSIONS
Diabetes duration, socioeconomic status, and daily media consumption time, but not physical activity, were significant risk factors for glycemic control in youths with type 1 diabetes.