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Abstract Background D-3-hydroxybutyrate (D-3-OHB) is a ketone body that serves as an alternative nutritional fuel but also as an important signaling metabolite. Oral ketone supplements containing D/L-3-OHB are becoming a popular approach to achieve ketosis. Aim To explore the gut-derived effects of ketone supplements. Methods Eight healthy lean male volunteers were investigated on 2 separate occasions: i) Following oral D/L-3-OHB consumption (oral) ii) Following isoketonemic intravenous ketone (D/L-3-OHB) infusion. An acetaminophen test was performed to evaluate gastric emptying and blood samples were obtained consecutively throughout the study period. Results We show that oral consumption of D/L-3-OHB stimulates cholecystokinin release (P = 0.02), elevates insulin (P = 0.03) and C-peptide (P < 0.001) concentrations, and slows gastric emptying (P = 0.01) compared with matched intravenous D/L-3-OHB administration. Measures of appetite and plasma concentrations of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were unaffected by interventions. Conclusion Our findings show that D/L-3-OHB exert incretin effects and indicate luminal sensing in the gut endothelium. This adds to our understanding of ketones as signaling metabolites and displays the important difference between physiological ketosis and oral ketone supplements.

IntroductionThe aim of this study was to investigate serum Neurofilament Light polypeptide (NfL) as a biomarker for diabetic polyneuropathy (DPN) in adolescents with type 1 diabetes (T1D). Secondarily, to investigate vitamin B12 (B12) deficiency as a cause for DPN in adolescents with T1D.Research design and methodsCross-sectional study. Sixty Danish adolescents with T1D (age 15–18 years, diabetes duration >5 years) and 23 age-matched control subjects were included. Based on nerve conduction studies (NCS), intraepidermal nerve fibre density (IENFD) and neurological examination, patients were divided into three groups: (1) T1D without DPN, (2) T1D with subclinical DPN and (3) T1D with confirmed DPN. Blood levels of NfL, B12, B12-binding protein holotranscobalamin (HoloTC) and methylmalonic acid (MMA) were determined.ResultsTwenty-four of the adolescents were without DPN, twenty-one had subclinical DPN and eight had confirmed DPN. NCS was not conducted in three participants and four patients did not have blood samples taken. There were no significant differences in NfL levels or any of the B12 parameters between any of the groups.ConclusionsNfL used in a cross-sectional manner was not found useful to distinguish between the adolescents with DPN and those without. Vitamin B12 deficiency did not contribute to neuropathy in Danish adolescents with T1D.

ObjectivesThe aims of this study were to investigate circulating levels of inflammatory markers in adolescents with type 1 diabetes with and without different types of neuropathies and evaluate the association between inflammatory biomarkers, nerve function and clinical parameters.DesignCross-sectional study.SettingHospitals and Steno Diabetes Center in Denmark.ParticipantsAdolescents with more than 5 years of diabetes duration were investigated for large fibre, small fibre and autonomic neuropathy as a part of the T1DANES study. Blood samples from the participants were analysed for inflammatory biomarkers by Meso Scale Discovery multiplexing technology.Primary and secondary outcome measuresInflammatory biomarkers and results of diagnostic nerve tests.ResultsFifty-six adolescents with type 1 diabetes and 23 healthy controls were included. The adolescents with diabetes had significantly higher interferon-gamma, tumour necrosis factor-alpha (TNF-a), interleukin (IL)-10 and soluble urokinase plasminogen activator receptor (suPAR) compared with healthy controls (p values<0.05). TNF-a was higher in the adolescents with large fibre neuropathy (LFN) (p=0.03) compared with those without LFN in the group with diabetes. A negative correlation was seen between TNF-a and conduction velocity in nervus tibialis (p=0.04), and higher TNF-a and IL-6 were associated with higher gastric motility index (TNF-a, p value=0.03; IL-6, p value=0.02). There were no significant associations between inflammatory markers and expressed symptoms, haemoglobin A1c, diabetes duration or body mass index standard derivation score (p values>0.05). The receiver operating characteristic (ROC) curves for the inflammatory markers suggested them as poor screening methods for all types of neuropathies with an area under the curve between 0.47 and 0.67.ConclusionOur results confirm increased low-grade inflammation in adolescents with type 1 diabetes. TNF-a was higher in adolescents with LFN and correlated negatively with nervus tibialis conduction velocity. The other inflammatory biomarkers fail to support differences in those with and without different types of diabetic neuropathies. However, TNF-a and IL-6 were positively correlated to gastric motility index.

Ghrelin Infusion in Humans Induces Acute Insulin Resistance and Lipolysis Independent of Growth Hormone Signaling Esben Thyssen Vestergaard , Lars Christian Gormsen , Niels Jessen , Sten Lund , Troels Krarup Hansen , Niels Moller and Jens Otto Lunde Jorgensen From Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus, Denmark Corresponding author: Esben Thyssen Vestergaard, etv{at}dadlnet.dk Abstract OBJECTIVE— Ghrelin is a gut-derived peptide and an endogenous ligand for the growth hormone (GH) secretagogue receptor. Exogenous ghrelin stimulates the release of GH (potently) and adrenocorticotropic hormone (ACTH) (moderately). Ghrelin is also orexigenic, but its impact on substrate metabolism is controversial. We aimed to study direct effects of ghrelin on substrate metabolism and insulin sensitivity in human subjects. RESEARCH DESIGN AND METHODS— Six healthy men underwent ghrelin (5 pmol · kg −1 · min −1 ) and saline infusions in a double-blind, cross-over study to study GH signaling proteins in muscle. To circumvent effects of endogenous GH and ACTH, we performed a similar study in eight hypopituitary adults but replaced with GH and hydrocortisone. The methods included a hyperinsulinemic-euglycemic clamp, muscle biopsies, microdialysis, and indirect calorimetry. RESULTS— In healthy subjects, ghrelin-induced GH secretion translated into acute GH receptor signaling in muscle. In the absence of GH and cortisol secretion, ghrelin acutely decreased peripheral, but not hepatic, insulin sensitivity together with stimulation of lipolysis. These effects occurred without detectable suppression of AMP-activated protein kinase phosphorylation (an alleged second messenger for ghrelin) in skeletal muscle. CONCLUSIONS— Ghrelin infusion acutely induces lipolysis and insulin resistance independently of GH and cortisol. We hypothesize that the metabolic effects of ghrelin provide a means to partition glucose to glucose-dependent tissues during conditions of energy shortage. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 5 September 2008. Clinical trial reg. nos. NCT00116025 and NCT00139945, clinicaltrials.gov. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 26, 2008. Received January 8, 2008. DIABETES

Aim: This study is aimed at assesing the impact of neuropathy on well‐being and health‐related quality of life (HRQoL) in adolescents with Type 1 diabetes (T1D). Methods: In a cross‐sectional study, 60 adolescents with T1D (15–18 years, diabetes duration > 5 years) were enrolled. Clinical and biochemical data were collected, and well‐being and HRQoL were assessed using the WHO‐5 well‐being index and DISABKIDS questionnaires, including diabetes‐specific modules. Diagnostic tests for large fiber neuropathy (LFN), small fiber neuropathy (SFN), and autonomic neuropathy were performed as part of the T1DANES study. The participants were divided into groups depending on the presence or absence of specific forms of neuropathy. Those with autonomic neuropathy were further divided depending on reported autonomic symptoms (Composite Autonomic Symptom Scale 31 (COMPASS‐31) score ≥ 24 or < 24). Additionally, the data was compared to 23 healthy control subjects. Results: The median diabetes duration was 8.5 years (range 5–17), and the HbA1c was 60 mmol/mol (7.6%) (range 41–93 [5.9%–10.6%]). Adolescents who had abnormal autonomic function test(s) and a COMPASS‐31 score ≥ 24 exhibited lower WHO‐5 well‐being index compared to the following groups: those with abnormal autonomic test(s) and fewer autonomic symptoms (COMPASS‐31 < 24), the remaining adolescents with T1D, and the control subjects ( p values < 0.05). There was no significant difference in the total score of DISABKIDS between the groups; however, the subdomain social inclusion was lowest in the group with COMPASS‐31 ≥ 24. Gastric motility index ( p = 0.04) and uroflow acceleration ( p = 0.02) were positively associated with the total score of DISABKIDS. Females reported lower well‐being and HRQoL than males ( p values < 0.05); in total, 28% had a WHO‐5 well‐being index < 50. Conclusion: In conclusion, adolescents with diabetic autonomic neuropathy who also reported autonomic symptoms had lower well‐being and impaired social inclusion. Adolescents with symptoms of neuropathy and females appear to be at higher risk of lower well‐being, and using standardized screening tools helps to identify the subjects at risk.

Abstract Introduction: Several evaluations of lifestyle interventions for childhood obesity exist; however, follow-up beyond 2 years is necessary to validate the effect. The aim of the present study was to investigate long-term weight development following children participating in one of two pragmatic family-centered lifestyle interventions treating childhood obesity. Methods: This real-life observational study included Danish children 4–17 years of age classified as having obesity. Data from 2010 to 2020, from two community-based family-centered lifestyle interventions (designated hereafter as the Aarhus- and the Randers-intervention) were merged with national registers and routine health check-ups, including height and weight. Adjusted mixed effect models were used to model changes in body mass index (BMI) z score. We performed exploratory analyses of the development in BMI z-score within stratified subgroups of children treated in the interventions before investigating potential effect modifications induced by sex, age, family structure, socioeconomic, or immigration status. Results: With a median follow-up of 2.8 years (interquartile range: 1.3; 4.8), 703 children participated in an intervention (445 the Aarhus-intervention; 258 the Randers-intervention) and 2,337 children were not invited to participate (no-intervention). Children in both interventions experienced a comparable reduction in BMI z-scores during the first 6 months compared to the no-intervention group (Aarhus-intervention: −0.12 SD/year and Randers-intervention: −0.25 SD/year). Only children in the Randers-intervention reduced their BMI z-score throughout follow-up (Aarhus-intervention vs. no-intervention: 0.01 SD/year; confidence interval [CI]: −0.01; 0.04; Randers-intervention vs. no-intervention: −0.05 SD/year; CI: −0.08; −0.02). In subgroup comparisons, combining the two interventions, family income below the median (−0.05 SD/year, CI: −0.02; −0.09), immigrant background (0.04 SD/year, CI: 0.00; 0.07), or receiving intervention less than 1 year (0.04 SD/year, CI: 0.00; 0.08) were associated with a yearly increase in BMI z score. In addition, effect modification analyses did not observe any interaction by sex, age, family structure, socioeconomic, or immigration. Conclusions: Although the more dynamic intervention with longer duration obtained and sustained a minor reduction in BMI z score, the clinical impact may only be modest and still not effective enough to induce a long-term beneficial development in BMI in children with obesity.

Background . Beta‐hydroxybuturate ( β ‐OHB) supplements are commonly utilized in sports by both recreational and professional athletes. In a recent study, we observed a drop in testosterone levels following the oral ingestion of racemic sodium‐ β ‐OHB. In this investigation, we aim to determine whether a single oral dose of ketone ester (study I) and prolonged endogenous ketosis (study II) also reduces testosterone levels. Design . This investigation integrated samples from two distinct studies. Study I was a randomized, controlled, crossover trial with ten healthy, young male participants receiving either a weight‐adjusted ketone ester or control (water, CTR) and vice versa following an overnight fast. Repeated blood sampling was used to monitor plasma β ‐OHB and testosterone levels. Study II, another randomized, controlled, crossover trial, included 11 middle‐aged participants (five males). They followed either a ketogenic diet (KD) characterized by low carbohydrates and high fat content or a standard diet (SDD) for three weeks. After each study period, participants underwent examination following an overnight fast, with repeated measures employed to analyze concentrations of plasma β ‐OHB and sex hormone levels. Results . Study I: Testosterone decreased from 23.8 ± 2.4 nmol/l to 22.3 ± 2.5 nmol/l 300 minutes after the ketone ester and increased from 20.9 ± 2.1 nmol/l to 22.2 ± 1.9 300 minutes after CTR. This difference was not significant, p  = 0.06. Study II . Total testosterone was unaffected after the KD compared to the SDD in men (20.2 ± 1.23 nmol/l vs. 18.2 ± 1.23 nmol/l ( p  = 0.1)) and was lower after KD in women (0.87 ± 0.06 vs. 1.1 ± 0.06 nmol/l ( p  < 0.0001)). Sex hormone‐binding globulin (SHBG) increased in men after KD compared with SDD (31.2 ± 2.6 nmol/l vs 25.0 ± 2.6 nmol/l, p  < 0.0001) and women (26.5 ± 3.05 nmol/l vs 24.2 ± 3.05 nmol/l, p  = 0.003). The free androgen index decreased after KD in men (ratio: 0.65 ± 0.05 vs. ratio: 0.74 ± 0.05, p  = 0.04) and in women (ratio: 0.036 ± 0.006 vs. SDD 0.05 ± 0.006, p  = 0.0001). Free estradiol index was also found lower after KD in men (ratio: 3.1 ± 0.8 vs. ratio: 4.8 ± 0.8, p  = 0.0003) and in women (ratio: 1.2 ± 2.2 vs. 9.8 ± 2.2, p  = 0.0001). Conclusion . Our findings indicate that the acute ingestion of ketone ester may not reduce testosterone levels in healthy young males. However, a three‐week exposure to KB from a KD results in an increase in SHBG in men and women with obesity as well as it lowers free testosterone and estradiol for men and women. We thus present evidence of crosstalk between alterations in a metabolite, β ‐OHB, and the regulation of the hypothalamic‐pituitary‐gonadal axis from a KD. The clinical impact of this reduction remains to be investigated. This trial is registered with NCT04156477 ​ and NCT05012748 .

Background Childhood obesity is associated with impaired Quality-of-Life (QoL), increased stigmatization and higher risk of development of depression compared to their peers. This report describes the long-term development in QoL for cohort of children with obesity after a sustainable weight reduction. Methods This pragmatic descriptive intervention study enrolled 120 children with obesity, age 5–17 years, in a multifactorial lifestyle intervention. The intervention was an across sectors collaboration between a department of pediatrics and community health care workers. QoL was assessed yearly throughout the intervention and evaluated by a 6-item Visual Analogue Scale (VAS). For analyzing changes in VAS, as function BMI-SDS, regression models were used, while ANOVA and Wilcoxon test were applied for normal and not-normal distributed data. 95% confidence interval not containing 0 and p-value < 0.05 was considered statistically significant. Results After 26.4 months (13.9 SD) an overall decrease in bullying (0.6 vs. 0.0 median) and motivation (10.0 vs. 9.6) was observed. QoL increased in children with a BMI-SDS reduction (0.65 (2.49 SD)) opposite children with no-change or increasing BMI-SDS who reported reduced QoL (-0.36 (1.55 SD) and -0.96 (2.27 SD)). A significant inverse relationship was observed for Joy of Life, QoL and body perception as a function of BMI-SDS per year. Conclusion Weight reduction causes improvement in QoL for children with obesity and an inverse relationship for QoL and changing BMI-SDS / year was establish.

IntroductionChildren and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last months to years. Preserving β-cell function can reduce T1D complications and improve glycaemic control. Influenza vaccination has pleiotropic effects and administration of the vaccine during the early phases of T1D may offer β-cell protection. This study aims to assess the effect of influenza vaccination on preserving β-cell function in children and adolescents with recent-onset T1D.Methods and analysisThe INfluenza VaccInation To mitigate typE 1 Diabetes trial is a randomised, double-blind, placebo-controlled, multicentre trial in paediatric patients with recent-onset T1D aged 7–17 years. 100 participants will be randomised in a 1:1 ratio to receive either a standard inactivated quadrivalent influenza vaccine or a placebo within 14 days of diagnosis. The primary outcome is a difference in mean change (from baseline to 12 months) in C-peptide level between groups during a 2-hour mixed-meal tolerance test. Secondary outcomes include mean change (from baseline to 6 months) in C-peptide levels, haemoglobin A1c, ambulatory glucose profiles and insulin requirements. Exploratory outcomes are diabetes-related autoantibodies, inflammatory markers and serum haemagglutinin inhibition antibody titres against the influenza viruses. The current treatment for T1D is largely symptomatic, relying on insulin administration. There is a pressing need for novel pharmacological approaches aimed at modulating the immune system to preserve residual β-cell function. Existing immunotherapies are cost-prohibitive and associated with multiple side effects, whereas influenza vaccination is inexpensive and generally well tolerated. A positive outcome of this study holds potential for immediate implementation into standard care for children and adolescents with recent-onset T1D and may guide future research on immune modulation in T1D.Ethics and disseminationEthical approval was obtained from Danish Health Authorities prior to participant enrollment. The trial results will be submitted to a peer-reviewed journal.Trial registration numberClinicalTrials.gov NCT05585983 and EudraCT Number 2022-500906-17-01.