Effects of Different SARS-CoV-2 Testing Strategies in the Emergency Department on Length of Stay and Clinical Outcomes: A Randomised Controlled Trial.

The turn-around-time (TAT) of diagnostic and screening measures such as testing for SARS-CoV-2 can affect a patient's length of stay (LOS) in the hospital as well as the emergency department (ED). This, in turn, can affect clinical outcomes. Therefore, a reliable and time-efficient SARS-CoV-2 testing strategy is necessary, especially in the ED. In this randomised controlled trial, n = 598 ED patients presenting to one of three university hospital EDs in Berlin, Germany, and needing hospitalisation were randomly assigned to two intervention groups and one control group. Accordingly, different SARS-CoV-2 testing strategies were implemented: rapid antigen and point-of-care (POC) reverse transcription polymerase chain reaction (rtPCR) testing with the Roche cobas® Liat® (LIAT) (group one n = 198), POC rtPCR testing with the LIAT (group two n = 197), and central laboratory rtPCR testing (group three, control group n = 203). The median LOS in the hospital as an inpatient across the groups was 7 days. Patients' LOS in the ED of more than seven hours did not differ significantly, and furthermore, no significant differences were observed regarding clinical outcomes such as intensive care unit stay or death. The rapid and POC test strategies had a significantly (p < 0.01) shorter median TAT (group one 00:48 h, group two 00:21 h) than the regular central laboratory rtPCR test (group three 06:26 h). However, fast SARS-CoV-2 testing strategies did not reduce ED or inpatient LOS significantly in less urgent ED admissions. Testing strategies should be adjusted to the current circumstances including crowding, SARS-CoV-2 incidences, and patient cohort. This trial is registered with DRKS00023117.

Patients pathways before and after treatments in emergency departments: A retrospective analysis of secondary data in Germany.

Increasing emergency department (ED) utilization induces considerable pressure on ED staff and organization in Germany. Reasons for certain ED attendances are seen partly in insufficient continuity of care outside of hospitals. To explore the health care patterns before and after an ED attendance in Germany, we used claims data from nine statutory health insurance funds, covering around 25 % of statutory health insurees (1). We descriptively analyzed ED attendances for adult patients in 2016 according to their sociodemographic characteristics and diagnoses (2). Based on the ED attendance as initial event, we investigated health care provider utilization 180 days before and after the respective ED treatment and are presented by means of Sankey diagrams. In total, 4,757,536 ED cases of 3,164,343 insured individuals were analyzed. Back pain was the most frequent diagnosis in outpatient ED cases (5.0 %), and 80.2 % of the patients visited primary care physicians or specialists 180 days before and 78.8 % 180 days after ED treatment. Among inpatient cases, heart failure (4.6 %) was the leading diagnosis and 74.6 % used primary care physicians or specialists 180 days before and 65.1 % 180 days after ED treatment. The ED re-attendance slightly increased for back pain (4.9 % to 7.9 %) and decreased for heart failure (13.4 % to 12.6 %).

Identification of low-acuity attendances in routine clinical information documented in German Emergency Departments.

INTRODUCTION: It has not yet been possible to ascertain the exact proportion, characterization or impact of low-acuity emergency department (ED) attendances on the German Health Care System since valid and robust definitions to be applied in German ED routine data are missing. METHODS: Internationally used methods and parameters to identify low-acuity ED attendances were identified, analyzed and then applied to routine ED data from two EDs of the tertiary care hospitals Charité-Universitätsmedizin Berlin, Campus Mitte (CCM) and Campus Virchow (CVK). RESULTS: Based on the three routinely available parameters `disposition´, `transport to the ED´ and `triage´ 33.2% (n = 30 676) out of 92 477 presentations to the two EDs of Charité-Universitätsmedizin Berlin (CVK, CCM) in 2016 could be classified as low-acuity presentations. CONCLUSION: This study provides a reliable and replicable means of retrospective identification and quantification of low-acuity attendances in German ED routine data. This enables both intra-national and international comparisons of figures across future studies and health care monitoring.

Recording early deaths following emergency department visits in inpatient data: An observational study using data of 16 German hospitals.

OBJECTIVE: In German hospital emergency departments (EDs), no definite reimbursement rules exist for patients who die within 24 hours after arrival. Our study aimed to assess whether these cases were recorded and billed as inpatient stays. Furthermore, characteristics of patients who die within 24 hours following arrival at the ED were investigated for all ED visits, as well as for the subgroup of ED visits with an ED diagnosis or inpatient principal diagnosis of acute myocardial infarction. METHODS: This study was part of the INDEED project, which aimed to explore utilization and trans-sectoral patterns of care for patients treated in EDs in Germany. The study population includes ED visits of adult patients in 2016 in 16 German hospitals participating in the project. In the data set of combined ED, inpatient, and outpatient treatment information early deaths were classified as patients who died in the ED or in the hospital within 24 hours after arrival. Characteristics of visits followed by early death were analyzed descriptively. Mode of billing as inpatient or outpatient was validated by identifying corresponding billing information using linked inpatient and outpatient data. RESULTS: In 2016, 454,747 ED visits of adult patients occurred in the participating hospitals and 42.8% resulted in inpatient admission. Among these inpatients 8,317 (4.3%) died during the overall hospital stay, and 1,302 (0.7%) died within 24 hours following arrival. The proportion of early deaths among all deaths in patients with a diagnosis of acute myocardial infarction was higher (27%) compared to the overall patient population (16%). Although all cases of early death were classified as inpatients the corresponding inpatient data was missing in 1.9% of all early deaths and in 3.4% of early deaths with a diagnosis of acute myocardial infarction. Outpatient billing information suggesting that these cases were billed as outpatients, was found in 0.3% of all early deaths and in 0.8 to 1.7% of early deaths with a diagnosis of acute myocardial infarction, respectively. CONCLUSION: In-hospital mortality might be biased by incomplete recording of early deaths in inpatient data. However, the proportion of patients with early death who were billed as outpatients was marginal in the investigated study population of 16 hospitals. Although the study results are limited by restricted generalizability and subpar data quality, this finding indicates that early deaths might be almost completely recorded in German inpatient data. Nevertheless, data quality should be enhanced by establishing general billing rules for cases with a short treatment duration due to early death.

The Abdominal Pain Unit (APU). Study protocol of a standardized and structured care pathway for patients with atraumatic abdominal pain in the emergency department: A stepped wedged cluster randomized controlled trial.

This study aims to improve emergency department (ED) care for patients suffering from atraumatic abdominal pain. An application-supported pathway for the ED will be implemented, which supports quick, evidence-based, and standardized diagnosis and treatment steps for patients with atraumatic abdominal pain at the ED. A mixed-methods multicentre cluster randomized controlled stepped wedge trial design will be applied. A total of 10 hospitals with EDs (expected n = 2.000 atraumatic abdominal pain patients) will consecutively (every 4 months) be randomized to apply the intervention. Inclusion criteria for patients are a minimum age of 18 years, suffering from atraumatic abdominal pain and being insured with a German statutory health insurance. Primary outcomes: acute pain score at time of discharge from ED, duration of treatment at the ED, patient-reported satisfaction. Secondary endpoints include patient safety and quality of care parameters, process evaluation parameters, and costs and cost-effectiveness parameters. Quantitative data will be gathered from patient-surveys, clinical records, and routine data from hospital information systems as well as from a participating German statutory health insurance. Descriptive and analytic statistical analysis will be performed to provide summaries and associations for primary patient-reported outcomes, process measures, quality measures, and costs. Qualitative data collection consists of participatory patient observations and semi-structured expert interviews, which will be inductively analysed. Findings will be disseminated in publications in peer-reviewed journals, on conferences, as well as via a project website. To ensure data protection, appropriate technical and organisational measures will be taken. Trial registration: DRKS00021052.

Influence of Weekday and Seasonal Trends on Urgency and In-hospital Mortality of Emergency Department Patients.

Background: Given the scarcity of resources, the increasing use of emergency departments (ED) represents a major challenge for the care of emergency patients. Current health policy interventions focus on restructuring emergency care with the help of patient re-direction into outpatient treatment structures. A precise analysis of ED utilization, taking into account treatment urgency, is essential for demand-oriented adjustments of emergency care structures. Methods: Temporal and seasonal trends in the use of EDs were investigated, considering treatment urgency and hospital mortality. Secondary data of 287,119 ED visits between 2015 and 2017 of the two EDs of Charité Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow Klinikum were analyzed. Result: EDs were used significantly more frequently on weekends than on weekdays (Mdn = 290 vs. 245 visits/day; p < 0.001). The proportion of less urgent, outpatient emergency visits on weekends was above average. Holiday periods were characterized by at least 6, and at most 176 additional ED visits. In a comparison of different holidays, most ED visits were observed at New Year (+68% above average). In addition, a significant increase in in-hospital mortality on holidays was evident among inpatients admitted to hospital via the ED (3.0 vs. 3.2%; p < 0.001), with New Year's Day being particularly striking (5.4%). Conclusion: These results suggest that, in particular, the resource planning of outpatient emergency treatment capacities on weekends and holidays should be adapted to the increased volume of non-urgent visits in EDs. Nevertheless, treatment capacities for the care of urgent, inpatient emergencies should not be disregarded and further research projects are necessary to investigate the causes of increased mortality during holiday periods.

SARS-CoV-2 screening in patients in need of urgent inpatient treatment in the Emergency Department (ED) by digitally integrated point-of-care PCR: a clinical cohort study.

Patients in need of urgent inpatient treatment were recruited prospectively. A rapid point of care polymerase chain reaction test (POC-PCR; Liat®) for SARS-CoV2 was conducted in the Emergency Department (ED) and a second PCR-test from the same swab was ordered in the central laboratory (PCR). POC-PCR analyzers were digitally integrated in the laboratory information system. Overall, 160 ED patients were included. A valid POC-PCR-test result was available in 96.3% (n = 154) of patients. N = 16 patients tested positive for Severe Acute Respiratory Syndrome-Corona Virus 2 (10.0%). The POC PCR test results were available within 102 minutes (median, interquartile range: 56-211), which was significantly earlier compared to the central laboratory PCR (811 minutes; interquartile range: 533-1289, P < 0.001). The diagnostic accuracy of the POC-PCR test was 100%. The implementation and digital laboratory information system integration was successfully done. Staff satisfaction with the POC process was high. The POC-PCR testing in the ED is feasible and shows a very high diagnostic performance. Trial registration: DRKS00019207.

[The way to routine data from 16 emergency departments for cross-sectoral health services research : Experiences, challenges and solution approaches from the extraction of pseudonymous data for the INDEED project]. / Der Weg zu Routinedaten aus 16 Notaufnahmen für die sektorenübergreifende Versorgungsforschung : Erfahrungen, Herausforderungen und Lösungsansätze aus der Extraktion pseudonymer Daten für das Projekt INDEED.

BACKGROUND: In Germany there is currently no health reporting on cross-sectoral care patterns in the context of an emergency department care treatment. The INDEED project (Utilization and trans-sectoral patterns of care for patients admitted to emergency departments in Germany) collects routine data from 16 emergency departments, which are later merged with outpatient billing data from 2014 to 2017 on an individual level. AIM: The methodological challenges in planning of the internal merging of routine clinical and administrative data from emergency departments in Germany up to the final data extraction are presented together with possible solution approaches. METHODS: Data were selected in an iterative process according to the research questions, medical relevance, and assumed data availability. After a preparatory phase to clarify formalities (including data protection, ethics), review test data and correct if necessary, the encrypted and pseudonymous data extraction was performed. RESULTS: Data from the 16 cooperating emergency departments came mostly from the emergency department and hospital information systems. There was considerable heterogeneity in the data. Not all variables were available in every emergency department because, for example, they were not standardized and digitally available or the extraction effort was judged to be too high. CONCLUSION: Relevant data from emergency departments are stored in different structures and in several IT systems. Thus, the creation of a harmonized data set requires considerable resources on the part of the hospital as well as the data processing unit. This needs to be generously calculated for future projects.

INDEED-Utilization and Cross-Sectoral Patterns of Care for Patients Admitted to Emergency Departments in Germany: Rationale and Study Design.

Introduction: The crowding of emergency departments (ED) has been a growing problem for years, putting the care of critically ill patients increasingly at risk. The INDEED project's overall aim is to get a better understanding of ED utilization and to evaluate corresponding primary health care use patterns before and after an ED visit while driving forward processes and methods of cross-sectoral data merging. We aim to identify adequate utilization of EDs and potentially avoidable patient contacts as well as subgroups and clusters of patients with similar care profiles. Methods: INDEED is a joint endeavor bringing together research institutions and hospitals with EDs in Germany. It is headed by the Charité-Universitätsmedizin Berlin, collaborating with Otto von Guericke University Magdeburg, Technische Universität Berlin, the Central Research Institute of Ambulatory/Outpatient Health Care in Germany (Zi), and the AOK Research Institute as part of the Federal Association of AOK, as well as experts in the technological, legal, and regulatory aspects of medical research (TMF). The Institute for Information Technology (OFFIS) was involved as the trusted third party of the project. INDEED is a retrospective study of approximately 400,000 adult patients with statutory health insurance who visited the ED of one of 16 participating hospitals in 2016. The routine hospital data contain information about treatment in the ED and, if applicable, about the subsequent hospital stay. After merging the patients' hospital data from 2016 with their outpatient billing data from 2 years before to 1 year after the ED visit (years 2014-2017), a harmonized dataset will be generated for data analyses. Due to the complex data protection challenges involved, first results will be available in 2021. Discussion: INDEED will provide knowledge on extracting and harmonizing large scale data from varying routine ED and hospital information systems in Germany. Merging these data with the corresponding outpatient care data of patients offers the opportunity to characterize the patient's treatment in outpatient care before and after ED use. With this knowledge, appropriate interventions may be developed to ensure adequate patient care and to avoid adverse events such as ED crowding.

Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin.

Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N = 848) and KORA (N = 1628) from Germany and PPP-Botnia (N = 335) from Finland (total N = 2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N = 967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N = 833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23-PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P = 5.75 × 10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P = 1.51 × 10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion.

Renal function is independently associated with circulating betatrophin.

OBJECTIVE: Betatrophin has been identified as a marker linking liver with beta cell function and lipid metabolism in murine models. Until now, the regulation of circulating betatrophin in humans is not entirely clear. We here analyzed the relation of betatrophin levels to phenotypes of the metabolic syndrome and speculated that renal function might influence circulating betatrophin levels and explain age-dependent changes of betatrophin. SUBJECTS: We analyzed blood samples from 535 individuals participating in the Metabolic Syndrome Berlin Potsdam study. RESULTS: In a crude analysis we found a positive correlation between betatrophin levels and HbA1c (r = 0.24; p < 0.001), fasting glucose (r = 0.20; p < 0.001) and triglycerides (r = 0.12; p = 0.007). Furthermore betatrophin was positively correlated with age (r = 0.47; p <0.001), systolic blood pressure (r = 0.17; p < 0.001), intima media thickness (r = 0.26; p < 0.001) and negatively correlated with CKD-EPI eGFR (r = -0.33; p < 0.001) as an estimate of renal function. Notably, eGFR remained highly associated with betatrophin after adjustment for age, waist circumference, gender, HbA1c and lipid parameters in a multivariate linear regression model (ß = -0.197, p< 0.001). CONCLUSIONS: Our data suggest that circulating levels of betatrophin depend on age, gender, waist circumference, total/HDL cholesterol ratio and renal function. Especially the association to eGFR highlights the importance for future studies to address renal function as possible influence on betatrophin regulation and consider eGFR as potential confounder when analyzing the role of betatrophin in humans.

Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5).

Reducing the expression of the Indy (I'm Not Dead Yet) gene in lower organisms extends life span by mechanisms resembling caloric restriction. Similarly, deletion of the mammalian homolog, mIndy (Slc13a5), encoding for a plasma membrane tricarboxylate transporter, protects from aging- and diet-induced adiposity and insulin resistance in mice. The organ specific contribution to this phenotype is unknown. We examined the impact of selective inducible hepatic knockdown of mIndy on whole body lipid and glucose metabolism using 2'-O-methoxyethyl chimeric anti-sense oligonucleotides (ASOs) in high-fat fed rats. 4-week treatment with 2'-O-methoxyethyl chimeric ASO reduced mIndy mRNA expression by 91% (P=0.001) compared to control ASO. Besides similar body weights between both groups, mIndy-ASO treatment lead to a 74% reduction in fasting plasma insulin concentrations as well as a 35% reduction in plasma triglycerides. Moreover, hepatic triglyceride content was significantly reduced by the knockdown of mIndy, likely mediating a trend to decreased basal rates of endogenous glucose production as well as an increased suppression of hepatic glucose production by 25% during a hyperinsulinemic-euglycemic clamp. Together, these data suggest that inducible liver-selective reduction of mIndy in rats is able to ameliorate hepatic steatosis and insulin resistance, conditions occurring with high calorie diets and during aging.

Knockdown of Indy/CeNac2 extends Caenorhabditis elegans life span by inducing AMPK/aak-2.

Reducing the expression of the Indy (Acronym for 'I'm Not Dead, Yet') gene in lower organisms promotes longevity and leads to a phenotype that resembles various aspects of caloric restriction. In C. elegans, the available data on life span extension is controversial. Therefore, the aim of this study was to determine the role of the C. elegans INDY homolog CeNAC2 in life span regulation and to delineate possible molecular mechanisms. siRNA against Indy/CeNAC2 was used to reduce expression of Indy/CeNAC2. Mean life span was assessed in four independent experiments, as well as whole body fat content and AMPK activation. Moreover, the effect of Indy/CeNAC2 knockdown in C. elegans with inactivating variants of AMPK (TG38) was studied. Knockdown of Indy/CeNAC2 increased life span by 22±3 % compared to control siRNA treated C. elegans, together with a decrease in whole body fat content by ~50%. Indy/CeNAC2 reduction also increased the activation of the intracellular energy sensor AMPK/aak2. In worms without functional AMPK/aak2, life span was not extended when Indy/CeNAC2 was reduced. Inhibition of glycolysis with deoxyglucose, an intervention known to increase AMPK/aak2 activity and life span, did not promote longevity when Indy/CeNAC2 was knocked down. Together, these data indicate that reducing the expression of Indy/CeNAC2 increases life span in C. elegans, an effect mediated at least in part by AMPK/aak2.

Chemerin and prediction of Diabetes mellitus type 2.

OBJECTIVE: Insulin resistance and subclinical inflammation are characteristics in the development of type 2 diabetes mellitus (T2DM). The adipokine chemerin has been associated with both factors. The aim of this study was to analyse whether chemerin predicts T2DM. DESIGN: Blood samples of 440 participants of the Metabolic-Syndrome Berlin-Potsdam (MesyBepo) follow-up study without diabetes at baseline were available for chemerin measurement. Mean follow-up of participants was 5·3 years. Glucose metabolism was analysed using oral glucose tolerance test including insulin measurements. Chemerin was measured using a commercially available ELISA. RESULTS: Thirty-five individuals developed T2DM during follow-up. Chemerin predicted incident T2DM (Chemerin 1. Tertile: reference, 2. Tertile: OR 2·33 [0·68-7·95]; Chemerin 3. Tertile: OR 3·42 [1·01-11·58] after adjustment for age, sex, BMI, follow-up time, HbA1c, HOMA-IR and WHR). In a secondary analysis, chemerin also predicted worsening of fasting glucose and HbA1c (adjusted for age, sex, BMI, time of follow-up, WHR, HDL cholesterol and triglycerides). CONCLUSIONS: Our data suggest that chemerin is a weak predictor of T2DM.

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.

Patients with established type 2 diabetes display both ß-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

THOC5: a novel gene involved in HDL-cholesterol metabolism.

Although numerous genes are known to regulate serum lipid traits, identified variants explain only a small proportion of the expected heritability. We intended to identify further genetic variants associated with lipid phenotypes in a self-contained population of Sorbs in Germany. We performed a genome-wide association study (GWAS) on LDL-cholesterol, HDL-cholesterol (HDL-C), and triglyceride (TG) levels in 839 Sorbs. All single-nucleotide polymorphisms with a P value <0.01 were subjected to a meta-analysis, including an independent Swedish cohort (Diabetes Genetics Initiative; n = ∼3,100). Novel association signals with the strongest effects were subjected to replication studies in an additional German cohort (Berlin, n = 2,031). In the initial GWAS in the Sorbs, we identified 14 loci associated with lipid phenotypes reaching P values <10⁻5 and confirmed significant effects for 18 previously reported loci. The combined meta-analysis of the three study cohorts (n(HDL) = 6041; n(LDL) = 5,995; n(TG) = 6,087) revealed a novel association for a variant in THOC5 (rs8135828) with serum HDL-C levels (P = 1.78 × 10⁻7; Z-score = -5.221). Consistently, the variant was also associated with circulating APOA1 levels in Sorbs. The small interfering RNA-mediated mRNA silencing of THOC5 in HepG2 cells resulted in lower mRNA levels of APOA1, SCARB1, and ABCG8 (all P < 0.05). We propose THOC5 to be a novel gene involved in the regulation of serum HDL-C levels.

Fibroblast growth factor 21 predicts the metabolic syndrome and type 2 diabetes in Caucasians.

OBJECTIVE: The incidence of the metabolic syndrome and type 2 diabetes mellitus (T2DM) is rising worldwide. Liver-derived fibroblast growth factor (FGF)-21 affects glucose and lipid metabolism. The aim of this study was to analyze the predictive value of FGF-21 on the incidence of T2DM and the metabolic syndrome. RESEARCH DESIGN AND METHODS: The Metabolic Syndrome Berlin Potsdam (MeSyBePo) recall study includes 440 individuals. Glucose metabolism was analyzed using an oral glucose tolerance test, including insulin measurements. FGF-21 was measured using enzyme-linked immunosorbent assay. Primary study outcome was diabetes and the metabolic syndrome incidence and change of glucose subtraits. RESULTS: During a mean follow-up of 5.30 ± 0.1 years, 54 individuals developed the metabolic syndrome, 35 developed T2DM, and 69 with normal glucose tolerance at baseline progressed to impaired glucose metabolism, defined as impaired fasting glucose, impaired glucose tolerance, or T2DM. FGF-21 predicted incident metabolic syndrome (lnFGF-21 odds ratio [OR] 2.6 [95% CI 1.5 - 4.5]; P = 0.001), T2DM (2.4 [1.2-4.7]; P = 0.01), and progression to impaired glucose metabolism (2.2 [1.3 - 3.6]; P = 0.002) after adjustment for age, sex, BMI, and follow-up time. Additional adjustment for waist-to-hip ratio, systolic blood pressure, HDL cholesterol, triglycerides, and fasting glucose did not substantially modify the predictive value of FGF-21. CONCLUSIONS: FGF-21 is an independent predictor of the metabolic syndrome and T2DM in apparently healthy Caucasians. These results may indicate FGF-21 resistance precedes the onset of the metabolic syndrome and T2DM.

Caloric restriction chronically impairs metabolic programming in mice.

Although obesity rates are rapidly rising, caloric restriction remains one of the few safe therapies. Here we tested the hypothesis that obesity-associated disorders are caused by increased adipose tissue as opposed to excess dietary lipids. Fat mass (FM) of lean C57B6 mice fed a high-fat diet (HFD; FMC mice) was "clamped" to match the FM of mice maintained on a low-fat diet (standard diet [SD] mice). FMC mice displayed improved glucose and insulin tolerance as compared with ad libitum HFD mice (P < 0.001) or SD mice (P < 0.05). These improvements were associated with fewer signs of inflammation, consistent with the less-impaired metabolism. In follow-up studies, diet-induced obese mice were food restricted for 5 weeks to achieve FM levels identical with those of age-matched SD mice. Previously, obese mice exhibited improved glucose and insulin tolerance but showed markedly increased fasting-induced hyperphagia (P < 0.001). When mice were given ad libitum access to the HFD, the hyperphagia of these mice led to accelerated body weight gain as compared with otherwise matched controls without a history of obesity. These results suggest that although caloric restriction on a HFD provides metabolic benefits, maintaining those benefits may require lifelong continuation, at least in individuals with a history of obesity.