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Background: Alterations in glucose metabolism that lead to the development of metabolic and cardiovascular disease may begin already in childhood. Objective: This study aims to generate pediatric age and sex‐specific reference values for fasting concentrations of glucose, hemoglobin A1c (HbA1c), insulin, C‐peptide, and homeostasis model assessment: insulin resistance (HOMA‐IR) in Danish/North‐European white children and adolescents from a population‐based cohort and to compare values from children and adolescents with overweight/obesity with this reference. Methods: The population‐ and obesity clinic‐based cohorts consisted of 2451 and 1935 children and adolescents between 6 and 18 years of age. Anthropometric measurements and blood samples were obtained and percentile curves were calculated. Results: In the population‐based cohort, glucose, insulin, and HOMA‐IR values increased before the expected onset of puberty (P < .05). Thereafter, all variables decreased in girls (P < .05) and HbA1c decreased in boys (P < .05). Concentrations of all measured markers of glucose metabolism were higher in the obesity clinic‐based cohort than the population‐based cohort (both sexes P < .001). Specifically, insulin and HOMA‐IR continued to increase to 18 years in the clinic‐based cohort, particularly among boys. Conclusions: Fasting glucose, insulin, and HOMA‐IR change during childhood, making pediatric reference values essential for timely identification of derangements in glucose metabolism. Children and adolescents with obesity exhibit increased concentrations of these biomarkers. [ABSTRACT FROM AUTHOR]

Objective: Whether the definitions of impaired fasting glucose (IFG) from the American Diabetes Association (ADA) and the World Health Organization (WHO) differentially impact estimates of the metabolic profile and IFG‐related comorbidities in Danish children and adolescents is unknown. Methods: Two thousand one hundred and fifty four (979 boys) children and adolescents with overweight or obesity (median age 12 years) and 1824 (728 boys) children with normal weight (median age 12 years) from The Danish Childhood Obesity Biobank were studied. Anthropometrics, blood pressure, puberty, and fasting concentrations of glucose, insulin, glycosylated hemoglobin (HbA1c), and lipids were measured. Results: About 14.1% of participants with overweight or obesity exhibited IFG according to the ADA and 3.5% according to the WHO definition. Among individuals with normal weight, the corresponding prevalences were 4.3% and 0.3%. IFG was associated with a higher systolic blood pressure, higher concentrations of HbA1c, insulin, C‐peptide (P < .0001) and triglycerides (P = .03), and lower HOMA2‐IS and HOMA2‐B (P < .0001) independent of sex, age, puberty, waist‐to‐height ratio, and degree of obesity. Furthermore, IFG was associated with a higher risk for hypertension (OR = 1.66 [95%CI: 1.21; 2.28], P = .002) and dyslipidemia (OR = 1.90 [95%CI: 1.38; 2.56], P < .0001) compared with the group without IFG independent of age, sex, and puberty. Conclusions: The prevalence of IFG, when applying the ADA criterion compared with the WHO criterion, was 4 times higher in individuals with overweight and obesity and 14 times higher in individuals with normal weight in this study sample of children and adolescents. IFG was associated with a higher risk of hypertension and dyslipidemia compared with their normoglycemic peers regardless of the definition applied. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether children and adolescents exhibiting an impaired glucose metabolism are more obese at treatment entry and less likely to reduce their degree of obesity during treatment. Methods: The present study is a longitudinal observational study, including children and adolescents from the Children's Obesity Clinic, Holbæk, Denmark. Anthropometrics, pubertal development, socioeconomic status (SES), and fasting concentrations of plasma glucose, serum insulin, serum C‐peptide, and whole blood glycosylated hemoglobin (HbA1c) were collected at treatment entry and at follow‐up. Proxies of Homeostasis Model Assessment 2‐insulin sensitivity (HOMA2‐IS) and Homeostasis Model Assessment 2‐β‐cell function (HOMA2‐B) were calculated with the Homeostasis Model Assessment 2 program. Results: In total, 569 (333 boys) patients, median 11.5 years of age (range 6‐22 years), and median body mass index (BMI) z‐score 2.94 (range 1.34‐5.54) were included. The mean BMI z‐score reduction was 0.31 (±0.46) after 13 months (range 6‐18) of treatment. At treatment entry, patients with impaired estimates of glucose metabolism were more obese than normoglycemic patients. Baseline concentration of C‐peptide was associated with a lower weight loss during treatment in girls (P = .02). Reduction in the insulin concentrations was associated with reduction in BMI z‐score in both sexes (P < .0001, P = .0005). During treatment, values of glucose, HbA1c, HOMA2‐IS, and HOMA2‐B did not change or impact the treatment outcome, regardless of age, sex, SES, or degree of obesity at treatment entry. Conclusion: The capability to reduce weight during multidisciplinary treatment in children and adolescents with overweight/obesity is not influenced by an impaired glucose metabolism at study entry or during the course of treatment. [ABSTRACT FROM AUTHOR]

Objective: We investigated the relationship between hs-CRP, a marker of low-grade inflammation, alone or in combination with C-peptide, a marker of hyperinsulinemia/insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D)., Research Design and Methods: In patients with recent-onset T2D, we measured serum hs-CRP (n = 7,301) and C-peptide (n = 5,765) in the prospective Danish Centre for Strategic Research in Type 2 Diabetes cohort study. Patients with no prior CVE (n = 6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n = 7,301) were followed for all-cause mortality. We computed adjusted hazard ratios (aHRs) by Cox regression and tested for the interaction between hs-CRP and C-peptide., Results: During follow-up (median 4.8 years), high (>3 mg/L) versus low (<1 mg/L) hs-CRP was associated with increased CVE risk (aHR 1.45 [95% CI 1.07-1.96]) and with even greater risk of all-cause mortality (2.47 [1.88-3.25]). Compared with patients with low hs-CRP (≤3 mg/L) and low C-peptide (<1,470 pmol/L), those with high levels of both biomarkers had the highest CVE (1.61 [1.10-2.34]) and all-cause mortality risk (2.36 [1.73-3.21]). Among patients with high C-peptide, risk of CVEs did not differ by low or high hs-CRP, whereas risk of all-cause mortality did., Conclusions: The finding of high hs-CRP as a stronger prognostic biomarker of all-cause mortality than of CVEs may facilitate improved early detection and prevention of deadly diseases besides CVEs. Conversely, elevated C-peptide as a strong CVE biomarker supports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention., (© 2023 by the American Diabetes Association.)

Study Question: What is the prevalence of reactive hypoglycemia (RH) in polycystic ovary syndrome (PCOS) versus age- and body mass index (BMI)-matched healthy controls.Summary Answer: The prevalence of RH was increased in PCOS versus controls.What Is Known Already: Previous studies suggested an increased prevalence of RH in PCOS.Study Design, Size, Duration: Cross-sectional study of 88 women with PCOS and 34 healthy age- and BMI-matched controls.Participants/materials, Setting, Methods: Eighty-eight women with PCOS and 34 age- and BMI-matched controls were included. The study was conducted at Odense University Hospital, Denmark. Participants underwent 5 h oral glucose tolerance test (5 h OGTT). Indices of insulin resistance, β-cell function, and area under the curve (AUC) for glucose, insulin and C-peptide were calculated. Insulin clearance was estimated as 5 h AUC C-peptide/insulin. RH was defined as blood glucose ≤3.3 mmol/l during 5 h OGTT.Main Results and the Role Of Chance: RH occurred in 15/88 (17%) women with PCOS versus 0/34 controls ( ITALIC! P = 0.01). Nine out of 15 women with RH were obese and 6 were lean ( ITALIC! P = 0.42). Obese patients with RH had significantly higher 5 h AUCs insulin and C-peptide compared with lean patients with RH ( ITALIC! P = 0.02 and 0.04, respectively). Obese patients with RH had significantly lower 5 h AUC C-peptide/insulin versus obese patients without RH ( ITALIC! P = 0.02). In lean patients with RH, 5 h AUCs insulin and C-peptide were similar to lean controls.Limitations, Reasons For Caution: The 5 h OGTT was used to diagnose RH and may be a limitation of the study. Although the 5 h OGTT is the most widely accepted method, no gold standard exists in terms of diagnosing RH. The 5 h OGTT was suggested to over-estimate the incidence of RH compared with meal test.Wider Implications Of the Findings: The study supports previous suggestions of increased prevalence of RH in women with PCOS compared with controls.Study Funding/competing Interests: This study was funded by Jacob Madsen's and Olga Madsen's Foundation, Institute of Clinical Research, Odense University Hospital, Kolding Hospital, AP Møller's Foundation, Bernhard and Marie Kleins Foundation, The Novo Nordisk Foundation, and The Danish Medical Association. The authors declare no conflict of interest.Trial Registration Number: The trial was registered at www.clinicaltrials.gov (registration numbers NCT00451568 (patients) and NCT01995773 (controls)). [ABSTRACT FROM AUTHOR]

Aim To examine prescribing practices and predictors of glucose-lowering therapy within the first year following diagnosis of Type 2 diabetes mellitus in a clinical care setting. Methods We followed people enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort from outpatient hospital clinics and general practices throughout Denmark in 2010-2013. We used Poisson regression to compute age- and gender-adjusted risk ratios (RRs). Results Among 1158 new Type 2 diabetes mellitus patients, 302 (26%) did not receive glucose-lowering therapy within the first year, 723 (62%) received monotherapy [685 (95%) with metformin], and 133 (12%) received more than one drug. Predictors of receiving any vs. no therapy and combination vs. monotherapy were: age < 40 years [RR: 1.29 (95% CI: 1.16-1.44) and 3.60 (95% CI: 2.36-5.50)]; high Charlson Comorbidity Index [RRs: 1.20 (95% CI: 1.05-1.38) and 2.08 (95% CI: 1.16-3.72)]; central obesity [RRs: 1.23 (95% CI: 1.04-1.44) and 1.93 (95% CI: 0.76-4.94)]; fasting blood glucose of ≥ 7.5 mmol/l [RRs: 1.25 (95% CI: 1.10-1.42) and 1.94 (95% CI: 1.02-3.71)]; and HbA1c = 59 mmol/mol (≥ 7.5%) [RR: 1.26 (95% CI: 1.20-1.32) and 2.86 (95% CI: 1.97-4.14)]. Weight gain = 30 kg since age 20, lack of physical exercise and C-peptide of < 300 pmol/l also predicted therapy. Conclusions Comorbidity, young age, central obesity and poor baseline glycaemic control are important predictors of therapy one year after Type 2 diabetes mellitus debut. [ABSTRACT FROM AUTHOR]

The gut microbiota has been implicated in obesity and its progression towards metabolic disease. Dietary interventions that target the gut microbiota have been suggested to improve metabolic health. The aim of the present study was to investigate the effect of interventions with Lactobacillus paracasei F19 or flaxseed mucilage on the gut microbiota and metabolic risk markers in obesity. A total of fifty-eight obese postmenopausal women were randomised to a single-blinded, parallel-group intervention of 6-week duration, with a daily intake of either L. paracasei F19 (9·4 × 1010 colony-forming units), flaxseed mucilage (10 g) or placebo. Quantitative metagenomic analysis of faecal DNA was performed to identify the changes in the gut microbiota. Diet-induced changes in metabolic markers were explored using adjusted linear regression models. The intake of flaxseed mucilage over 6 weeks led to a reduction in serum C-peptide and insulin release during an oral glucose tolerance test (P< 0·05) and improved insulin sensitivity measured by Matsuda index (P< 0·05). Comparison of gut microbiota composition at baseline and after 6 weeks of intervention with flaxseed mucilage showed alterations in abundance of thirty-three metagenomic species (P< 0·01), including decreased relative abundance of eight Faecalibacterium species. These changes in the microbiota could not explain the effect of flaxseed mucilage on insulin sensitivity. The intake of L. paracasei F19 did not modulate metabolic markers compared with placebo. In conclusion, flaxseed mucilage improves insulin sensitivity and alters the gut microbiota; however, the improvement in insulin sensitivity was not mediated by the observed changes in relative abundance of bacterial species. [ABSTRACT FROM PUBLISHER]

Objective To validate the partial remission ( PR) definition based on insulin dose-adjusted HbA1c ( IDAA1c). Subjects and methods The IDAA1c was developed using data in 251 children from the European Hvidoere cohort. For validation, 129 children from a Danish cohort were followed from the onset of type 1 diabetes ( T1D). Receiver operating characteristic curve ( ROC) analysis was used to evaluate the predictive value of IDAA1c and age on partial C-peptide remission (stimulated C-peptide, SCP > 300 pmol/L). Results PR ( IDAA1c ≤ 9) in the Danish and Hvidoere cohorts occurred in 62 vs. 61% (3 months, p = 0.80), 47 vs. 44% (6 months, p = 0.57), 26 vs. 32% (9 months, p = 0.32) and 19 vs. 18% (12 months, p = 0.69). The effect of age on SCP was significantly higher in the Danish cohort compared with the Hvidoere cohort (p < 0.0001), likely due to higher attained Boost SCP, so the sensitivity and specificity of those in PR by IDAA1c ≤ 9, SCP > 300 pmol/L was 0.85 and 0.62 at 6 months and 0.62 vs. 0.38 at 12 months, respectively. IDAA1c with age significantly improved the ROC analyses and the AUC reached 0.89 ± 0.04 (age) vs. 0.94 ± 0.02 (age + IDAA1c) at 6 months (p < 0.0004) and 0.76 ± 0.04 (age) vs. 0.90 ± 0.03 (age + IDAA1c) at 12 months (p < 0.0001). Conclusions The diagnostic and prognostic power of the IDAA1c measure is kept but due to the higher Boost stimulation in the Danish cohort, the specificity of the formula is lower with the chosen limits for SCP (300 pmol/L) and IDAA1c ≤9, respectively. [ABSTRACT FROM AUTHOR]

Background The zinc transporter 8 ( ZnT8) was recently identified as a common autoantigen in type 1 diabetes ( T1 D) and inclusion of ZnT8 autoantibodies ( ZnT8 Ab) was found to increase the diagnostic specificity of T1 D. Objectives The main aims were to determine whether ZnT8 Ab vary during follow-up 1 year after diagnosis, and to relate the reactivity of three types of ZnT8 Ab to the residual stimulated C-peptide levels during the first year after diagnosis. Subjects A total of 129 newly diagnosed T1 D patients <15 years was followed prospectively 1, 3, 6, and 12 months after diagnosis. Methods Hemoglobin A1c, meal-stimulated C-peptide, ZnT8 Ab, and other pancreatic autoantibodies were measured at each visit. Patients were genotyped for the rs13266634 variant at the SLC 30 A 8 gene and HLA- DQ alleles. Results The levels of all ZnT8 Ab [ ZnT8 Arg (arginine), ZnT8 Trp (tryptophan), ZnT8 Gln (glutamine)] tended to decrease during disease progression. A twofold higher level of ZnT8 Arg and ZnT8 Gln was associated with 4.6%/5.2% (p = 0.02), 5.3%/8.2% (p = 0.02) and 8.9%/9.7% (p = 0.004) higher concentrations of stimulated C-peptide 3, 6, and 12 months after diagnosis. The TT genotype carriers of the SLC 30 A 8 gene had 45.8% (p = 0.01) and 60.1% (p = 0.002) lower stimulated C-peptide 6 and 12 months after diagnosis compared to the CC and the CT genotype carriers in a recessive model. Conclusions The levels of the Arg variant of the ZnT8 autoantibodies are associated with higher levels of stimulated C-peptide after diagnosis of T1 D and during follow-up. Carriers of the TT genotype of the SLC 30 A 8 gene predict lower stimulated C-peptide levels 12 months after diagnosis. [ABSTRACT FROM AUTHOR]