Peeking into the Stingers: A Comprehensive SWATH-MS Study of the European Hornet Vespa crabro (Linnaeus, 1758) (Hymenoptera: Vespidae) Venom Sac Extracts.

This study aimed to investigate the venom sac extracts (VSEs) of the European hornet (EH) Vespa crabro (Linnaeus, 1758) (Hymenoptera: Vespidae), focusing on the differences between stinging females, gynes (G), and workers (W), at the protein level. Using a quantitative "Sequential Window Acquisition of all Theoretical Fragment Ion Mass Spectra" (SWATH-MS) analysis, we identified and quantified a total of 240 proteins. Notably, within the group, 45.8% (n = 110) showed significant differential expression between VSE-G and VSE-W. In this set, 57.3% (n = 63) were upregulated and 42.7% (n = 47) downregulated in the G. Additionally, the two-hundred quantified proteins from the class Insecta belong to sixteen different species, six of them to the Hymenoptera/Apidae lineage, comprising seven proteins with known potential allergenicity. Thus, phospholipase A1 (Vesp v 1), phospholipase A1 verutoxin 2b (VT-2b), hyaluronidase A (Vesp v 2A), hyaluronidase B (Vesp v 2B), and venom allergen 5 (Vesp v 5) were significantly downregulated in the G, and vitellogenin (Vesp v 6) was upregulated. Overall, 46% of the VSE proteins showed differential expression, with a majority being upregulated in G. Data are available via ProteomeXchange with identifier PXD047955. These findings shed light on the proteomic differences in VSE between EH castes, potentially contributing to our understanding of their behavior and offering insights for allergy research.

Frank's Sign and Cardiovascular Risk: An Observational Descriptive Study.

PURPOSE: This study was undertaken to analyze the relationship between the diagonal earlobe crease and the main indices of cardiovascular risk, considering the crease's anatomical variations. METHODS: The study group consisted of 1050 adults residing in Spain. Participants underwent the following determinations: age, sex, body mass index, smoking habit, blood pressure, glycemia, glycated hemoglobin, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and cardiovascular events. Cardiovascular risk was calculated applying the Framingham-Anderson equation, the Systematic Coronary Risk Evaluation equation, and the Atherosclerotic Cardiovascular Disease Risk Score calculator. Both earlobes were examined, recording diagonal earlobe crease presence, length and depth, and presence of accessory creases. Results were analyzed by using chi-square test, Student's t test, analysis of variance, and Mann-Whitney or Kruskal-Wallis tests. To extract the functions of cardiovascular risk, a script in R was created (https://cran.r-project.org/). RESULTS: The estimated cardiovascular mortality risk was significantly higher in individuals who presented diagonal earlobe crease (P < .001). The number of individuals with moderate, high, or very high cardiovascular risk increased significantly as the presence of the crease increased (23.8% had no crease, 35.6% had unilateral creases, and 58% had bilateral creases; P < .001). The mean cardiovascular risk estimated was significantly higher for individuals with longest and deepest diagonal earlobe crease (P < .001 and P < .001, respectively), and with accessory creases (P < .001). CONCLUSIONS: The diagonal earlobe crease is independently associated with higher cardiovascular risk scores, especially when the crease is complete, bilateral, deep, and has accessory creases.

Structural Similarities, in Relation with the Cross-Reactivity, of Hymenoptera Allergenic Dipeptidyl Peptidases IV-An Overall Comparison Including a New Dipeptidyl Peptidase IV Sequence from Vespa velutina.

(1) Background: Dipeptidyl Peptidases IV (DPPIVs), present in many organisms, are minor components in the venoms of Hymenoptera, where they have been identified as cross-reactive allergenic molecules. Considering that the structure of homologous DPPIVs is well characterized, we aimed to explain which regions have higher similarity among these proteins and present a comparison among them, including a new Vespa velutina DPPIV sequence. Moreover, two cases of sensitization to DPPIVs in wasp- and honeybee-sensitized patients are presented. (2) Methods: Proteomic analyses have been performed on the venom of the Asian hornet Vespa velutina to demonstrate the sequence of its DPPIV (allergen named Vesp v 3, with sequence accession number P0DRB8, and with the proteomic data available via ProteomeXchange with the identifier PXD046030). A comparison performed through their alignments and analysis of the three-dimensional structure showed a region with higher similarity among Hymenoptera DPPIVs. Additionally, ImmunoCAP™ determinations (including specific inhibition experiments), as well as IgE immunoblotting, are performed to demonstrate the allergenicity of Api m 5 and Ves v 3. (3) Results and Conclusions: The data presented demonstrate that the similarities among Hymenoptera DPPIVs are most likely localized at the C-terminal region of these enzymes. In addition, a higher similarity of the Vespa/Vespula DPPIVs is shown. The clinical cases analyzed demonstrated the allergenicity of Api m 5 and Ves v 3 in the sera of the allergic patients, as well as the presence of this minor component in the preparations used in venom immunotherapy.

Reproducibility of continuous glucose monitoring results under real-life conditions in an adult population: a functional data analysis.

Continuous glucose monitoring systems (CGM) are a very useful tool to understand the behaviour of glucose in different situations and populations. Despite the widespread use of CGM systems in both clinical practice and research, our understanding of the reproducibility of CGM data remains limited. The present work examines the reproducibility of the results provided by a CGM system in a random sample of a free-living adult population, from a functional data analysis approach. Functional intraclass correlation coefficients (ICCs) and their 95% confidence intervals (CI) were calculated to assess the reproducibility of CGM results in 581 individuals. 62% were females 581 participants (62% women) mean age 48 years (range 18-87) were included, 12% had previously been diagnosed with diabetes. The inter-day reproducibility of the CGM results was greater for subjects with diabetes (ICC 0.46 [CI 0.39-0.55]) than for normoglycaemic subjects (ICC 0.30 [CI 0.27-0.33]); the value for prediabetic subjects was intermediate (ICC 0.37 [CI 0.31-0.42]). For normoglycaemic subjects, inter-day reproducibility was poorer among the younger (ICC 0.26 [CI 0.21-0.30]) than the older subjects (ICC 0.39 [CI 0.32-0.45]). Inter-day reproducibility was poorest among normoglycaemic subjects, especially younger normoglycaemic subjects, suggesting the need to monitor some patient groups more often than others.

Proteomics of Vespa velutina nigrithorax Venom Sac Queens and Workers: A Quantitative SWATH-MS Analysis.

Health risks caused by stings from Vespa velutina nigrithorax (VV), also known as the yellow-legged Asian hornet, have become a public concern, but little is known about its venom composition. This study presents the proteome profile of the VV's venom sac (VS) based on Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS). The study also performed proteomic quantitative analysis and examined the biological pathways and molecular functions of the proteins in the VS of VV gynes (i.e., future queens [SQ]) and workers [SW]. The total protein content per VS was significantly higher in the SW than in the SQ (274 ± 54 µg/sac vs. 175 ± 22 µg/sac; p = 0.02). We quantified a total of 228 proteins in the VS, belonging to 7 different classes: Insecta (n = 191); Amphibia and Reptilia (n = 20); Bacilli, γ-Proteobacteria and Pisoniviricetes (n = 12); and Arachnida (n = 5). Among the 228 identified proteins, 66 showed significant differential expression between SQ and SW. The potential allergens hyaluronidase A, venom antigen 5 and phospholipase A1 were significantly downregulated in the SQ venom.

Age-Related Changes in Serum N-Glycome in Men and Women-Clusters Associated with Comorbidity.

(1) Aim: To describe, in a general adult population, the serum N-glycome in relation to age in men and women, and investigate the association of N-glycome patterns with age-related comorbidity; (2) Methods: The serum N-glycome was studied by hydrophilic interaction chromatography with ultra-performance liquid chromatography in 1516 randomly selected adults (55.3% women; age range 18-91 years). Covariates included lifestyle factors, metabolic disorders, inflammatory markers, and an index of comorbidity. Principal component analysis was used to define clusters of individuals based on the 46 glycan peaks obtained in chromatograms; (3) Results: The serum N-glycome changed with ageing, with significant differences between men and women, both in individual N-glycan peaks and in groups defined by common features (branching, galactosylation, sialylation, fucosylation, and oligomannose). Through K-means clustering algorithm, the individuals were grouped into a cluster characterized by abundance of simpler N-glycans and a cluster characterized by abundance of higher-order N-glycans. The individuals of the first cluster were older, showed higher concentrations of glucose and glycation markers, higher levels of some inflammatory markers, lower glomerular filtration rate, and greater comorbidity index; (4) Conclusions: The serum N-glycome changes with ageing with sex dimorphism. The N-glycome could be, in line with the inflammaging hypothesis, a marker of unhealthy aging.

Time above range for predicting the development of type 2 diabetes.

Aim: To investigate the prognostic value of time range metrics, as measured by continuous glucose monitoring, with respect to the development of type 2 diabetes (T2D). Research design and methods: A total of 499 persons without diabetes from the general population were followed-up for 5 years. Time range metrics were measured at the start and medical records were checked over the period study. Results: Twenty-two subjects (8.3 per 1,000 person-years) developed T2D. After adjusting for age, gender, family history of diabetes, body mass index and glycated hemoglobin concentration, multivariate analysis revealed 'time above range' (TAR, i.e., with a plasma glucose concentration of >140 mg/dL) to be significantly associated with a greater risk (OR = 1.06, CI 1.01-1.11) of developing diabetes (AUC = 0.94, Brier = 0.035). Conclusions: Time above range provides additional information to that offered by glycated hemoglobin to identify patients at a higher risk of developing type 2 diabetes in a population-based study.

Changes in Serum N-Glycome for Risk Drinkers: A Comparison with Standard Markers for Alcohol Abuse in Men and Women.

Background and aim: Glycomic alterations serve as biomarker tools for different diseases. The present study aims to evaluate the diagnostic capability of serum N-glycosylation to identify alcohol risk drinking in comparison with standard markers. Methods: We included 1516 adult individuals (age range 18-91 years; 55.3% women), randomly selected from a general population. A total of 143 (21.0%) men and 50 (5.9%) women were classified as risk drinkers after quantification of daily alcohol consumption and the Alcohol Use Disorders Identification Test (AUDIT). Hydrophilic interaction ultra-performance liquid chromatography (HILIC-UPLC) was used for the quantification of 46 serum N-glycan peaks. Serum gamma-glutamyltransferase (GGT), carbohydrate-deficient transferrin (CDT), and red blood cell mean corpuscular volume (MCV) were measured by standard clinical laboratory methods. Results: Variations in serum N-glycome associated risk drinking were more prominent in men compared to women. A unique combination of N-glycan peaks selected by the selbal algorithm shows good discrimination between risk-drinkers and non-risk drinkers for men and women. Receiver operating characteristics (ROC) curves show accuracy for the diagnosis of risk drinking, which is comparable to that of the golden standards, GGT, MCV and CDT markers for men and women. Additionally, the inclusion of N-glycan peaks improves the diagnostic accuracy of the standard markers, although it remains relatively low, due to low sensitivity. For men, the area under the ROC curve using N-glycome data is 0.75, 0.76, and 0.77 when combined with GGT, MCV, and CDT, respectively. In women, the areas were 0.76, 0.73, and 0.73, respectively. Conclusion: Risk drinking is associated with significant variations in the serum N-glycome, which highlights its potential diagnostic utility.

C-Reactive Protein versus Erythrocyte Sedimentation Rate: Implications Among Patients with No Known Inflammatory Conditions.

BACKGROUND: Measurements of C-reactive protein (CRP) concentration and erythrocyte sedimentation rate (ESR) are frequently ordered jointly in clinical practice. AIM: To investigate the factors associated with discordances between CRP concentration and ESR in adults. METHODS: We conducted a cross-sectional study of 1472 adults with no known inflammatory disorders (44.5% male; median age, 52 years; range, 18-91 years), randomly selected from a municipality in Spain. The participants underwent simultaneous measurements of ESR, serum CRP, and interleukin-6 concentrations. Alcohol consumption, smoking, and physical activity were evaluated by questionnaire. Body mass index (BMI) measurement and metabolic syndrome criteria were available for all participants. RESULTS: Most (n = 1123, 74.9%) of the participants showed normal CRP and ESR values. Sixty-nine (4.6%) participants showed high CRP and ESR values. Seventy-two (4.8%) participants showed a discordant pattern of high ESR and normal CRP values, which was associated with age after adjusting for sex, alcohol consumption, physical activity, BMI, and the presence of metabolic syndrome (odds ratio [OR], 1.052; 95% CI, 1.034-1.071; P < .001). A total of 208 (13.8%) participants showed a discordant pattern of high CRP and normal ESR values, which was associated with BMI after adjusting for covariates (OR, 1.099; 95% CI, 1.064-1.136; P < .001). BMI appeared to be the main determinant of serum CRP concentrations in this population. Serum interleukin-6 concentrations were positively associated with the discordant pattern of high CRP and normal ESR values. CONCLUSION: In this general adult population with no overt inflammatory disease, the discordant pattern of high ESR and normal CRP was associated with greater age, whereas the pattern of high CRP and normal ESR was associated with higher BMI.

Factors associated with serum IgM concentrations: a general adult population study.

BACKGROUND AND AIM: To investigate the influence of common factors on serum immunoglobulin M (IgM) concentrations in adults, and clinical associations with high and low values. METHODS: We measured serum IgM levels using immunonephelometry in a random sample of 1510 individuals (aged 18-91 years, 44.7% male). We obtained data defining metabolic syndrome from all participants, defined atopy by skin prick tests to aeroallergens, and assessed lifestyle factors by questionnaire. RESULTS: Women showed higher IgM concentrations than men; 95 (6.3%, mostly male) individuals showed low (<0.40 g/L) IgM values, and 64 (4.2%, mostly female) showed high (>2.30 g/L) IgM values. Individuals with abnormal IgM concentrations had no history of opportunistic infections nor a different atopy prevalence. Serum IgM concentrations decreased with age, and obesity was negatively associated with IgM concentrations. Alcohol consumption, smoking, physical activity, and metabolic syndrome had no significant influence in the multivariate analyses. CONCLUSIONS: Many adults in the general population show abnormally high or low IgM concentrations with no evidence of immunodeficiency-associated diseases. Sex and age should be considered when defining reference IgM concentrations.

Factors Influencing Total Serum IgE in Adults: The Role of Obesity and Related Metabolic Disorders.

BACKGROUND AND AIM: Few reports have investigated the association between metabolic abnormalities (obesity and related metabolic syndrome) and total serum IgE concentrations. METHODS: This cross-sectional study included a random sample of 1,516 adult individuals (44.7% men, aged 18-91 years, median 52 years) from a single municipality in Spain. Serum IgE was measured in the ADVIA Centaur system. Atopy was defined by the presence of positive skin prick tests to a panel of common aeroallergens in the area. Body mass index and data related to the definition of metabolic syndrome were obtained from all participants. Alcohol consumption, smoking, and regular physical exercise were assessed by a questionnaire. RESULTS: Atopy (present in 21.9% of 1,514 evaluable individuals) was the strongest factor determining serum IgE concentrations. Male sex and heavy alcohol drinking were independently associated with higher IgE concentrations, particularly in the non-atopic individuals. Body mass index was positively associated with IgE concentrations, independent of potential confounders, although the effect was only evident among non-atopic individuals. In that group, median IgE concentrations in normal-weight and obese individuals were 15 and 24 kU/L, respectively (p < 0.001); likewise, obesity was associated with high (>100 kU/L) IgE concentrations after adjusting for potential confounders (odds ratio: 1.79, 95% confidence interval: 1.26-2.56, p = 0.001). The presence of metabolic syndrome and its components, particularly abdominal obesity and hyperglycaemia, was also positively and independently associated with higher IgE concentrations in non-atopic individuals. CONCLUSIONS: Obesity and metabolic syndrome components are associated with high total serum IgE concentrations, particularly in non-atopic individuals.

Diagnostic accuracy of IL1ß in saliva: The development of predictive models for estimating the probability of the occurrence of periodontitis in non-smokers and smokers.

AIM: To obtain salivary interleukin (IL) 1ß-based models to predict the probability of the occurrence of periodontitis, differentiating by smoking habit. MATERIALS/METHODS: A total of 141 participants were recruited, 62 periodontally healthy controls and 79 subjects affected by periodontitis. Fifty of the diseased patients were given non-surgical periodontal treatment and showed significant clinical improvement in 2 months. IL1ß was measured in the salivary samples using the Luminex instrument. Binary logistic regression models were obtained to differentiate untreated periodontitis from periodontal health (first modelling) and untreated periodontitis from treated periodontitis (second modelling), distinguishing between non-smokers and smokers. The area under the curve (AUC) and classification measures were calculated. RESULTS: In the first modelling, IL1ß presented AUC values of 0.830 for non-smokers and 0.689 for smokers (accuracy = 77.6% and 70.7%, respectively). In the second, the predictive models revealed AUC values of 0.671 for non-smokers and 0.708 for smokers (accuracy = 70.0% and 75.0%, respectively). CONCLUSION: Salivary IL1ß has an excellent diagnostic capability when it comes to distinguishing systemically healthy patients with untreated periodontitis from those who are periodontally healthy, although this discriminatory potential is reduced in smokers. The diagnostic capacity of salivary IL1ß remains acceptable for differentiating between untreated and treated periodontitis.

Factors influencing erythrocyte sedimentation rate in adults: New evidence for an old test.

The erythrocyte sedimentation rate (ESR) is a routine test for inflammation. Few studies have investigated the potential influence of lifestyle factors and common metabolic abnormalities on the ESR. This study investigates the influence of demographic factors, alcohol consumption, smoking, physical activity, obesity, and metabolic syndrome on the ESR in adults.This cross-sectional study covered 1472 individuals (44.5% males; age range, 18-91 years) randomly selected from the population of a Spanish municipality. The ESR was measured using a standardized method. We assessed habitual alcohol consumption in standard drinking units, along with tobacco smoking, regular physical exercise (by questionnaire), body mass index, and variables defining metabolic syndrome. Multivariate analyses were performed, including mean corpuscular volume and hemoglobin concentration in the models.The ESR was higher in females than in males, and increased steadily with age. Median ESR of females was 2-fold higher than that of males, and median ESR of individuals aged >65 years was 2-fold higher than that of individuals in the youngest category (ages 18-35 years). Body mass index, presence of metabolic syndrome, and smoking were independently and positively associated with higher ESR values. Light alcohol drinkers and individuals with high regular physical activity displayed lower ESR values than did alcohol abstainers and individuals with low physical activity, respectively.ESR varies greatly with age and sex, and corresponding reference values are proposed. Lifestyle factors (physical activity, smoking, and alcohol consumption) and common metabolic abnormalities (obesity and related metabolic syndrome) may also influence ESR values.

Prediabetes defined by HbA1c and by fasting glucose: differences in risk factors and prevalence.

AIMS: To investigate, in a sample of nondiabetic adults from a Spanish community, the differences between prediabetes as defined by HbA1c ("H-prediabetes") and by fasting plasma glucose (FPG) ("F-prediabetes") in regard to prevalence and the influence of potential risk factors, adjusting the latter for confounders. METHODS: A total of 1328 nondiabetic participants aged ≥ 18 years were classified as normoglycemic, H-prediabetic [HbA1c 5.7-6.4% (39-47 mmol/mol)] or F-prediabetic (FPG 5.6-6.9 mmol/L). Multivariable analyses were used to compare the impacts of risk factors on the prevalence of H-prediabetes, F-prediabetes and their conjunctive and disjunctive combinations ("HaF-prediabetes" and "HoF-prediabetes," respectively). RESULTS: Some 29.9% of participants were HoF-prediabetic, 21.7% H-prediabetic, 16.3% F-prediabetic and only 8.1% HaF-prediabetic. Whatever the definition of prediabetes, increasing age, fasting insulin and LDL cholesterol were each a risk factor after adjustment for all other variables. Increasing BMI and decreasing mean corpuscular hemoglobin (MCH) were additional risk factors for H-prediabetes; male sex and increasing uric acid for F-prediabetes and increasing BMI for HaF-prediabetes. The participants satisfying the compound condition "hypertension or hyperlipidemia or obesity or hyperuricemia" (59.9% of the whole study group) included 83.1% of all subjects with HoF-prediabetes. CONCLUSIONS: In this population, the most sensitive risk factor for detection of prediabetes was age, followed by fasting insulin, LDL cholesterol, BMI, MCH, male sex and uric acid, with differences depending on the definition of prediabetes. MCH, an indirect measure of erythrocyte survival, significantly influences the prevalence of HbA1c-defined prediabetes. This study suggests that screening of individuals with selected risk factors may identify a high proportion of prediabetic persons.

Protein-Based Salivary Profiles as Novel Biomarkers for Oral Diseases.

The Global Burden of Oral Diseases affects 3.5 billion people worldwide, representing the number of people affected by the burden of untreated dental caries, severe periodontal disease, and edentulism. Thus, much more efforts in terms of diagnostics and treatments must be provided in the fight of these outcomes. In this sense, recently, the study of saliva as biological matrix has been identified as a new landmark initiative in the search of novel and useful biomarkers to prevent and diagnose these conditions. Specifically, saliva is a rich reservoir of different proteins and peptides and accessible due to recent advances in molecular biology and specially in targeted and unbiased proteomics technologies. Nonetheless, emerging barriers are an obstacle to the study of the salivary proteome in an effective way. This review aims at giving an overall perspective of salivary biomarkers identified in several oral diseases by means of molecular biology approaches.

Continuous glucose monitoring is more sensitive than HbA1c and fasting glucose in detecting dysglycaemia in a Spanish population without diabetes.

AIMS: To investigate whether continuous glucose monitoring (CGM) reveals patterns of glycaemic behaviour, the detection of which might improve early diagnosis of dysglycaemia. METHODS: A total 1521 complete days of valid CGM data were recorded under real-life conditions from a healthy sample of a Spanish community, as were matching FPG and HbA1C data. No participant was pregnant, had a history of kidney or liver disease, or was taking drugs known to affect glycaemia. RESULTS: CGM and fingerstick measurements showed a mean relative absolute difference of 6.9 ±â€¯2.2%. All subjects were normoglycaemic according to FPG and HbA1C except 21% who were prediabetic. The normoglycaemic subjects had a 24-hour mean blood glucose concentration (MBG) of 5.7 ±â€¯0.4 mmol/L, spending a median of 97% of their time within the target range (3.9-7.8 mmol/L). 73% of them experienced episodes with blood glucose levels above the threshold for impaired glucose tolerance, and 5% levels above the threshold for diabetes. These normoglycaemic participants with episodes of high glycaemia had glycaemic variabilities similar to those of prediabetic subjects with episodes of similar intensity or combined duration. CONCLUSIONS: CGM is a better indicator of possible early dysglycaemia than either FPG or HbA1c.

Fetal Exposure to High Maternal Thyroid Hormone Levels Causes Central Resistance to Thyroid Hormone in Adult Humans and Mice.

Context: Fetuses exposed to the high thyroid hormone (TH) levels of mothers with resistance to thyroid hormone beta (RTH-ß), due to mutations in the THRB gene, have low birth weight and suppressed TSH. Objective: Determine if such exposure to high TH levels in embryonic life has a long-term effect into adulthood. Design: Observations in humans with a parallel design on animals to obtain a preliminary information regarding mechanism. Setting: University research centers. Patients or other participants: Humans and mice with no RTH-ß exposed during intrauterine life to high TH levels from mothers who were euthyroid due to RTH-ß. Controls were humans and mice of the same genotype but born to fathers with RTH-ß and mothers without RTH-ß and thus, with normal serum TH levels. Interventions: TSH responses to stimulation with thyrotropin-releasing hormone (TRH) during adult life in humans and male mice before and after treatment with triiodothyronine (T3). We also measured gene expression in anterior pituitaries, hypothalami, and cerebral cortices of mice. Results: Adult humans and mice without RTH-ß, exposed to high maternal TH in utero, showed persistent central resistance to TH, as evidenced by reduced responses of serum TSH to TRH when treated with T3. In mice, anterior pituitary TSH-ß and deiodinase 3 (D3) mRNAs, but not hypothalamic and cerebral cortex D3, were increased. Conclusions: Adult humans and mice without RTH-ß exposed in utero to high maternal TH levels have persistent central resistance to TH. This is likely mediated by the increased expression of D3 in the anterior pituitary, enhancing local T3 degradation.

Glycemic Variability and Its Association With Demographics and Lifestyles in a General Adult Population.

OBJECTIVE: The objective was to investigate glycemic variability indices in relation to demographic factors and common environmental lifestyles in a general adult population. METHODS: The A Estrada Glycation and Inflammation Study is a cross-sectional study covering 1516 participants selected by sampling of the population aged 18 years and over. A subsample of 622 individuals participated in the Glycation project, which included continuous glucose monitoring procedures. Five glycemic variability indices were analyzed, that is, SD, MAGE, MAG, CONGA1, and MODD. RESULTS: Participants had a mean age of 48 years, 62% were females, and 12% had been previously diagnosed with diabetes. In the population without diabetes, index distributions were not normal but skewed to the right. Distributional regression models that adjusted for age, gender, BMI, alcohol intake, smoking status, and physical activity confirmed that all indices were positively and independently associated with fasting glucose levels and negatively with heavy drinking. SD, MAGE, and CONGA1 were positively associated with aging, and MAG was negatively associated with BMI. None of the GVI studied were influenced by physical activity. Age-group-specific reference values are given for the indices. CONCLUSIONS: This study yielded age-specific reference values for glucose variability indices in a general adult population. Significant increases were observed with aging. Heavy drinking of more than 140 g/week was associated with significant decreases in variability indices. No differences were found between males and females. These normative ranges provide a guide for clinical care, and may offer an alternative treatment target among persons with diabetes.