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Introduction: We aimed to characterise and compare individuals diagnosed with type 1 diabetes (T1D), latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D), in a real-world setting., Methods: Anthropometric and clinical data from 36 959 people with diabetes diagnosed at age 30-70 years enrolled in the prospective diabetes patients follow-up (DPV) registry from 1995 to 2022 were analysed cross-sectionally at diagnosis and follow-up (≥6 months after diagnosis). LADA was defined as clinical diagnosis of T2D, positivity of ≥1 islet autoantibody and an insulin-free interval of ≥6 months upon diabetes diagnosis., Results: At diagnosis, age, body mass index, waist circumference, C-peptide and HbA1c in people with LADA (n = 747) fell in between individuals with T1D (n = 940) and T2D (n = 35 272) (all p-values < 0.01). At follow-up, after adjusting for age, sex and diabetes duration, the prevalence of dyslipidemia and hypertension was the highest in people with LADA (90.6%, 77.7%) compared to people with T2D (81.8%, 60.4%) and T1D (75.7%, 39.7%) (p < 0.01). The prevalence of diabetic kidney disease (DKD) was higher in LADA (44.2%), than in T1D (19.9%) (p < 0.01). The prevalence of peripheral neuropathy was higher in individuals with LADA (55.1%) than in T2D (43.9%) and T1D (42.1%) (p < 0.05). Coverage of treatment for hypertension and dyslipidemia were 22.4% and 15.0% in T1D, 63.0% and 36.6% in LADA and 29.4% and 18.2% in T2D., Conclusion: People with LADA had a higher prevalence of cardiovascular risk factors (dyslipidemia, hypertension) and cardiovascular complications (DKD and peripheral neuropathy), suggesting that people with LADA are at need for improved recognition and care., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The subjective experiences of individuals living with diabetes is commonly assessed with patient-reported outcomes (PROs; eg, depression symptoms, wellbeing, health-related quality of life [HRQOL], and diabetes-related distress). Cluster analyses have identified novel diabetes subtypes differing in phenotypic and metabolic characteristics. We aimed to investigate associations between these subtypes and PROs and whether subtype predicted PROs 5 years later., Methods: Baseline (<12 months after a diabetes diagnosis) and 5-year follow-up data were collected from German Diabetes Study (GDS) participants. Multiple regressions were applied to analyse associations between diabetes subtypes and depression symptoms (Center for Epidemiologic Studies Depression Scale), wellbeing (WHO-5), HRQOL (SF-36), and diabetes-related distress (Problem Areas in Diabetes Scale)., Findings: Cluster analyses at baseline (n=1391) identified participants with severe autoimmune diabetes (SAID, 417 [30%]), severe insulin-deficient diabetes (SIDD, 33 [2%]), severe insulin-resistant diabetes (SIRD, 150 [11%]), mild obesity-related diabetes (MOD, 354 [25%]), and mild age-related diabetes (MARD, 437 [31%]). At baseline, multiple regression analyses showed that participants with SIRD had higher depression symptoms than participants with MARD and lower physical HRQOL than all other subtypes. Participants with SAID reported higher depression symptoms and lower mental HRQOL than participants with MARD, higher physical HRQOL than participants with MARD and MOD, and higher diabetes-related distress than most other subtypes. At the 5-year follow-up, clustering predicted no statistically significant changes in PROs after adjustment for multiple testing, whereas descriptive analyses demonstrated that individuals with SIRD were more likely to experience clinically relevant depression symptoms (16% vs 6%) and low wellbeing (31% vs 14%), respectively, than individuals with MARD., Interpretation: Diabetes subtypes already differ in PROs at diabetes diagnosis. Our analyses had limited predictive power during follow-up. However, our findings suggest that clustering could predict future changes in depression symptoms., Funding: The GDS was initiated and financed by the German Diabetes Center, which is funded by the German Federal Ministry of Health, the Ministry of Culture and Science of the state of North Rhine-Westphalia, and by the German Federal Ministry of Education and Research to the German Center for Diabetes Research., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests The research of MR and CH is also supported by grants from the European Community (HORIZON-HLTH-2022-STAYHLTH-02–01: Panel A) to the INTERCEPT-T2D consortium. The research of MR is further supported by the German Science Foundation (DFG; CRC/SFB 1116/2 B12; RTG/GRK 2576 vivid, Project 3 and 493659010 Future4CSPMM), the Schmutzler Stiftung and the programme “Profilbildung 2020”, an initiative of the Ministry of Culture and Science of the State of Northrhine Westphalia, Boehringer Ingelheim, and Novo Nordisk. MR also reports honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Kenes Group, Madrigal, and MSD, consulting fees for Echosens, Novo Nordisk, and Target RWE, and participation for advisory boards from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. The research of CH is also supported by the DFG. RW reports honoraria for lectures, presentations, or speaker's bureaus from Eli Lilly, Boehringer Ingelheim, Novo Nordisk, and Sanofi Aventis; travel support from NovoNordisk; and honoraria for advisory boards from Eli Lilly and Akcea Therapeutics. The research of AFHP is supported by the following grants: EU AI-DAPT (No. 101135826); EFSD/Boehringer Ingelheim European Research Programme (No. 98103); BMFW-Forschungskreis der Ernährungsindustrie (No. 21701). He also reports honoraria from Novo Nordisk, Berlin-Chemie, Sanofi, SCIARC, Berufsverband Deutscher Internistinnen und Internisten Wiesbaden, Lilly, AstraZeneca, Abbott, Nestlé, and FOMF. MB declares receiving honoraria for lectures or as a consultant from the following companies: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. The research of HM is supported by a grant from EFSD/Novo Nordisk Foundation (grant number NNF22SA0079478) and the German Diabetes Association (DDG). SM has received travel expenses support and honoraria for speaking and consulting activities from Biomarin, Lilly Germany, Novo Nordisk, and Sanofi. She also states that her husband is an employee at Novo Nordisk. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Daily dietary intake of macronutrients and energy is closely associated with long-term metabolic health outcomes, but whether 24-h nutritional intervention under isocaloric conditions leads to changes in metabolism remains unclear. Moreover, the short-term effect of diets with different macronutrient composition on hedonic appetite regulation is less clear., Methods: This study examined the impact of an acute high-fat (F+) and high-carbohydrate (C+) diet on glucose metabolism and hedonic regulation of food intake in young healthy men under controlled conditions. Using a cross-over design, 19 male participants received a one-day isocaloric diet with different macronutrient composition (F+ = 11% carbohydrates, 74% fat; C+ = 79% carbohydrates, 6% fat) compared to a control diet (CON = 55% carbohydrates, 30% fat). Protein content was set at 15% of energy in all diets. The feeling of hunger, as well as "liking" and "wanting" for foods, was assessed through visual analog scales, and blood samples for glucose, insulin, and cortisol levels were assessed repeatedly during the experimental day. An intravenous glucose tolerance test was conducted the next morning., Results: Postprandial glucose and insulin levels were lowest in F+ over the 24 h. Except for dinner, the CON diet showed the highest mean values in glucose. F+ diet improved insulin resistance, lowering Homeostatis Model Assessment Insulin Resistance (HOMA-IR) values. Changes in hedonic regulation of food intake were not observed during the intervention between the diets, except for higher feelings of satiety under the CON diet., Conclusion: An acute, isocaloric, high-fat diet improved insulin resistance even in healthy individuals but did not affect hedonic food intake regulation. Macronutrient composition modulate glucose metabolism even under short-term (24-h) and isocaloric diets, which should be considered for personalized preventive dietary treatments., Competing Interests: SMM was employed by Novo Nordisk Pharma GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pointke, Strenge, Piotrowski, Matteikat, Meyhöfer, Meyhöfer, Chamorro and Wilms.)

Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε-3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes., (© 2024. The Author(s).)

Introduction: The prevalence of overweight and obesity has increased dramatically. At the same time, lack of sleep has become a part of the modern lifestyle, as well as shift and night work. As a result, chronodisruption, i. e. a change in physiological processes that are controlled by the internal clock, becomes commonplace. Epidemiological data show that too short but also too long sleep are associated with an increased risk of obesity, also seen for night shift work. Overweight and obesity are associated with metabolic syndrome and data likewise report an increased risk by both short and long sleep. It has not yet been conclusively clarified how chronodisruption influences the metabolic risks. Clinical experimental studies report on neuroendocrine and circadian mechanisms and it has been shown that lack of sleep increases the hunger-promoting hormone ghrelin as well as subjective feelings of hunger and increases leptin levels. Lack of sleep also increases hedonic hunger and food-related reward signals. Through preventive measures, chronodisruption and thus, the risk of obesity can be counteracted. The extent to which smartwatches and fitness trackers, which according to the manufacturer can measure and analyze sleep, provide an objective picture of sleep has not been sufficiently investigated. However, smartwatches and fitness trackers can - probably - increase awareness of sleep in the modern society., Competing Interests: Die Autorinnen haben keine Interessenkonflikte im Zusammenhang mit diesem Artikel deklariert., (© 2024 Aerzteverlag medinfo AG.)

Competing Interests: JA received honoraria for scientific collaboration, speakers bureau, and advisory boads from Amgen, Astra Zeneca, Boehringer Ingelheim, Bayer, Lilly, Novartis, Novo Nordisk, rhythm pharmaceuticals. AL declares the following conflicts of interest: Travel expenses: Lilly Germany and Novo Nordisk; research support: Astra Zeneca; advisory board activities: Novo Nordisk. SM declares having received travel support from NovoNordisk, Lilly and Biomarin. SMM declares the following conflicts of interest: advisory boards and lecture for: Amarin, Astra Zeneca, Bayer, Boehringer Ingelheim, Daichii-Sankyo, esanum, Ipsen, Lilly, Novartis, Novo Nordisk, Sandoz, Sanofi. Institutional research funding: Daichi-Sankyo, Lilly, Novo Nordisk, Takeda. MM declares receiving travel expenses and lecture fees form Novo Nordisk. LS has no conflicts of interest. MB has received lecture and consulting fees from Amgen, Astra Zeneca, Boehringer-Ingelheim, Daiichi-Sankyo, Lilly, Novartis, Novo Nordisk and Sanofi.

Objectives: Recent studies have suggested a link between type 1 diabetes mellitus (T1D) and metabolic dysfunction associated steatotic liver disease (MASLD) in children and adolescent, but longitudinal evidence is lacking. This study aimed to investigate the potential association between poorly controlled T1D and elevated alanine aminotransferase (ALT), serving as a proxy for MASLD in children and adolescents over time., Methods: The study included 32,325 children aged 2-17 years with T1D from Germany, Austria, and Switzerland who had undergone at least one assessment of liver enzyme levels recorded in the Diabetes-Patienten- Verlaufsdokumentation registry. Multivariable logistic and Cox regression models were calculated to show possible associations between T1D and elevated ALT values (>26 U/L in males, >22 U/L in females) as a proxy for MASLD., Results: Children with poorly controlled T1D (HbA1c > 11%) exhibited increased odds of elevated ALT values, after adjustment for age, sex, diabetes duration and overweight (odds ratio [OR] 2.54; 95% confidence interval [CI], 2.10-3.10; p < 0.01). This finding is substantiated by a longitudinal analysis, which reveals that inadequately controlled T1D was associated with a higher hazard ratio (HR) of elevated ALT values compared to children with controlled T1D over an observation period extending up to 5.5 (HR: 1.54; 95% CI, 1.19-2.01; p < 0.01)., Conclusion: In conclusion, the current study strongly links poorly controlled T1D in children and adolescents to MASLD irrespective of overweight. This association is not only present cross-sectionally but also increases over time. The study underscores the critical role of effective diabetes management in reducing the risk of MASLD in this population., (© 2024 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Hypoglycemia is a particular problem in people with diabetes while it can also occur in other clinical circumstances. Hypoglycemia unawareness describes a condition in which autonomic and neuroglycopenic symptoms of hypoglycemia decrease and hence are hardly perceivable. A failure to recognize hypoglycemia in time can lead to unconsciousness, seizure, and even death. The risk factors include intensive glycemic control, prior episodes of severe hypoglycemia, long duration of diabetes, alcohol consumption, exercise, renal failure, and sepsis. The pathophysiological mechanisms are manifold, but mainly concern altered brain glucose sensing, cerebral adaptations, and an impaired hormonal counterregulation with an attenuated release of glucagon, epinephrine, growth hormone, and other hormones, as well as impaired autonomous and neuroglycopenic symptoms. Physiologically, this counterregulatory response causes blood glucose levels to rise. The impaired hormonal counterregulatory response to recurrent hypoglycemia can lead to a vicious cycle of frequent and poorly recognized hypoglycemic episodes. There is a shift in glycemic threshold to trigger hormonal counterregulation, resulting in hypoglycemia-associated autonomic failure and leading to the clinical syndrome of hypoglycemia unawareness. This clinical syndrome represents a particularly great challenge in diabetes treatment and, thus, prevention of hypoglycemia is crucial in diabetes management. This mini-review provides an overview of hypoglycemia and the associated severe complication of impaired hypoglycemia awareness and its symptoms, pathophysiology, risk factors, consequences, as well as therapeutic strategies.

Background: Heterogeneity in type 2 diabetes can be represented by a tree-like graph structure by use of reversed graph-embedded dimensionality reduction. We aimed to examine whether this approach can be used to stratify key pathophysiological components and diabetes-related complications during longitudinal follow-up of individuals with recent-onset type 2 diabetes., Methods: For this cohort analysis, 927 participants aged 18-69 years from the German Diabetes Study (GDS) with recent-onset type 2 diabetes were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualised for age and sex. Insulin sensitivity was assessed by a hyperinsulinaemic-euglycaemic clamp, insulin secretion was assessed by intravenous glucose tolerance test, hepatic lipid content was assessed by 1 H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 were assessed by ELISA, and peripheral and autonomic neuropathy were assessed by functional and clinical measures. Participants were followed up for up to 16 years. We also investigated heart failure and all-cause mortality in 794 individuals with type 2 diabetes undergoing invasive coronary diagnostics from the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort., Findings: There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·0001) and insulin secretion (p dim1 <0·0001, p dim2 =0·00097) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest hepatic lipid content (n=205, p dim1 <0·0001, p dim2 =0·037), pro-inflammatory biomarkers (IL-6: n=348, p dim1 <0·0001, p dim2 =0·013; IL-18: n=350, p dim1 <0·0001, p dim2 =0·38), and elevated cardiovascular risk (n events =143, p dim1 =0·14, p dim2 <0·00081), whereas individuals positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (n events =85, p dim1 =0·032, p dim2 =0·12) and had the highest risk of diabetic sensorimotor polyneuropathy (n events =184, p dim1 =0·012, p dim2 =0·044) and cardiac autonomic neuropathy (n events =118, p dim1 =0·0094, p dim2 =0·06). In the LURIC cohort, all-cause mortality was highest in the tree branch showing insulin resistance (n events =488, p dim1 =0·12, p dim2 =0·0032). Significant gradients differentiated individuals having heart failure with preserved ejection fraction from those who had heart failure with reduced ejection fraction., Interpretation: These data define the pathophysiological underpinnings of the tree structure, which has the potential to stratify diabetes-related complications on the basis of routinely available variables and thereby expand the toolbox of precision diabetes diagnosis., Funding: German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, European Community, German Research Foundation, and Schmutzler Stiftung., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Obstructive sleep apnea syndrome (OSAS) and obesity go hand in hand in the majority of patients and both are associated with a systemic inflammation, immune disturbance and comorbidities such as cardiovascular disease. However, the unambiguous impact of OSAS and obesity on the individual inflammatory microenvironment and the immunological consequences of human monocytes has not been distinguished yet. Therefore, aim of this study was to investigate the impact of OSAS and obesity related factors on the inflammatory microenvironment by performing flow cytometric whole blood measurements of CD14/CD16 monocyte subsets in normal weight OSAS patients, patients with obesity but without OSAS, and patients with OSAS and obesity, compared to healthy donors. Moreover, explicitly OSAS and obesity related plasma levels of inflammatory mediators adiponectin, leptin, lipocalin and metalloproteinase-9 were determined and the influence of different OSAS and obesity related factors on cytokine secretion and expression of different adhesion molecules by THP-1 monocytes was analysed. Our data revealed a significant redistribution of circulating classical and intermediate monocytes in all three patient cohorts, but differential effects in terms of monocytic adhesion molecules CD11a, CD11b, CD11c, CX3CR1, CD29, CD49d, and plasma cytokine levels. These data were reflected by differential effects of OSAS and obesity related factors leptin, TNFα and hypoxia on THP-1 cytokine secretion patterns and expression of adhesion molecules CD11b and CD49d. In summary, our data revealed differential effects of OSAS and obesity, which underlines the need for a customized therapeutic regimen with respect to the individual weighting of these overlapping diseases., (© 2024. The Author(s).)

Obesity is characterized by excessive body fat accumulation and comorbidities such as diabetes mellitus, cardiovascular disease, and obstructive sleep apnea syndrome (OSAS). Both obesity and OSAS are associated with immune disturbance, alterations of systemic inflammatory mediators, and immune cell recruitment to metabolic tissues. Chemokine CXCL10 is an important regulator of proinflammatory immune responses and is significantly increased in patients with severe obesity. This research project aims to investigate the impact of CXCL10 on human monocytes in patients with obesity. We studied the distribution of the CD14/CD16 monocyte subsets as well as their CX3CR1 expression patterns in whole-blood measurements from 92 patients with obesity and/or OSAS with regard to plasma CXCL10 values and individual clinical parameters. Furthermore, cytokine secretion by THP-1 monocytes in response to CXCL10 was analyzed. Data revealed significantly elevated plasma CXCL10 in patients with obesity with an additive effect of OSAS. CXCL10 was found to drive monocytic secretion of macrophage migration inhibitory factor via receptor protein CX3CR1, which significantly correlated with the individual body mass index. Our data show, for the first time, to our knowledge, that CX3CR1 is involved in alternative CXCL10 signaling in human monocytes in obesity-related inflammation. Obesity is a multifactorial disease, and further investigations regarding the complex interplay between obesity-related inflammatory mediators and systemic immune balances will help to better understand and improve the individual situation of our patients., (Copyright © 2024 The Authors.)

Objective: There is evidence that reduced sleep duration increases hunger, appetite, and food intake, leading to metabolic diseases, such as type 2 diabetes and obesity. However, the impact of sleep timing, irrespective of its duration and on the regulation of hunger and appetite, is less clear. We aimed to evaluate the impact of sleep loss during the late vs. early part of the night on the regulation of hunger, appetite, and desire for food., Methods: Fifteen normal-weight ([mean ± SEM] body-mass index: 23.3 ± 0.4 kg/m 2 ) healthy men were studied in a randomized, balanced, crossover design, including two conditions of sleep loss, i.e., 4 h sleep during the first night-half ('late-night sleep loss'), 4 h sleep during the second night-half ('early-night sleep loss'), and a control condition with 8h sleep ('regular sleep'), respectively. Feelings of hunger and appetite were assessed through visual analogue scales, and plasma ghrelin and leptin were measured from blood samples taken before, during, and after night-time sleep., Results: Ghrelin and feelings of hunger and appetite, as well as the desire for food, were increased after 'late-night sleep loss', but not 'early-night sleep loss', whereas leptin remained unaffected by the timing of sleep loss., Conclusions: Our data indicate that timing of sleep restriction modulates the effects of acute sleep loss on ghrelin and appetite regulation in healthy men. 'Late-night sleep loss' might be a risk factor for metabolic diseases, such as obesity and type 2 diabetes. Thereby, our findings highlight the metabolic relevance of chronobiological sleep timing.

Obesity is a dramatically increasing disease, accompanied with comorbidities such as cardiovascular disease and obstructive sleep apnea syndrome (OSAS). Both obesity and OSAS per se are associated with systemic inflammation. However, the multifactorial impact of obesity, OSAS, and its concomitant diseases on the immunological characteristics of circulating monocytes has not yet been fully resolved. Monocyte subsets of 82 patients with obesity were analyzed in whole blood measurements in terms of the CD14/CD16 cell surface expression patterns and different monocytic adhesion molecules using flow cytometry. Plasma levels of adipokines adiponectin and leptin of all patients were evaluated and correlated with accompanying cellular and clinical values. Whole blood measurements revealed a significant overall redistribution of CD14/CD16 monocyte subsets in patients with obesity. Monocytic adhesion molecules CD11a, CD11b, and CX3CR1 were significantly elevated. The observed alterations significantly correlated with plasma leptin levels and diabetes status as crucial amplifying factors. The additive impact of obesity, diabetes, and OSAS on the immunological balance of peripheral blood monocytes requires a coordinated regimen in terms of therapeutic treatment, respiratory support, and weight loss to improve the systemic immunity in these patients., (Copyright © 2023 The Authors.)

Objective: To investigate the impact of metabolic status on choroidal thickness (ChT) in healthy subjects, patients with obesity, and type 2 diabetes., Design and Methods: Fasting blood glucose, insulin, insulin-like growth factor-1 (IGF-1), and ChT measured by optical coherence tomography were assessed in healthy normal-weight (n=17), obese participants (n=20), and obese participants with T2D (n=16)., Results: ChT increased in obese participants and obese participants with T2D as compared to healthy normal-weight participants (P<0.0001). A negative correlation was observed between IGF1 and ChT (r=-0.268, P=0.050) for all cohorts. Furthermore, body mass index (BMI; R 2 =0.209; P=0.002; beta=0.388) and model assessment-estimated insulin resistance (HOMA-IR; R 2 =0.074; P=0.015; beta=0.305) were independent variables of ChT, explaining 20.9 and 7.4% of its variance (both p<0.016), whereas age, sex, and IGF-1 were not significant confounders of ChT (p>0.975)., Conclusion: ChT is associated with metabolic characteristics, i. e., BMI and HOMA-IR. Due to the key role of choroidal function in retinal physiology, future studies are needed to evaluate whether metabolic traits, ChT, and potential metabolic eye complications are mechanistically linked., Competing Interests: S.M., B.W., R.C., A.K., A.J.P., M.S., N.K., A.S.S., E.P., H.J.G., and S.M.M. have nothing to disclose. One sentence summary This study investigated the impact of metabolic status on choroidal thickness in healthy subjects, patients with obesity, and those with type 2 diabetes and found that choroidal thickness is associated with metabolic characteristics, i. e. BMI and HOMA-IR., (Thieme. All rights reserved.)

Background: Across a variety of solid tumors, prognostic implications of nutritional and inflammation-based risk scores have been identified as a complementary resource of risk stratification. Methods: In this retrospective study, we performed a comparative analysis of several established risk scores and ratios, such as the Glasgow Prognostic Score (GPS), in neuroendocrine neoplasms of the gastro−entero−pancreatic (GEP-NEN) system with respect to their prognostic capabilities. Clinicopathological and treatment-related data for 102 GEP-NEN patients administered to the participating institutions between 2011 and 2021 were collected. Scores/ratios significantly associated with overall or progression-free survival (OS, PFS) upon univariate analysis were subsequently included in a Cox-proportional hazard model for the multivariate analysis. Results: The median age was 62 years (range 18−95 years) and the median follow-up period spanned 51 months. Pancreatic or intestinal localization at the initial diagnosis were present in 41 (40.2%) and 44 (43.1%) cases, respectively. In 17 patients (16.7%), the primary manifestation could not be ascertained (NNUP; neuroendocrine neoplasms of unknown primary). Histological grading (HG) revealed 24/102 (23.5%) NET/NEC (poorly differentiated; high grade G3) and 78/102 (76.5%) NET (highly or moderately differentiated; low−high grade G1−G2). In total, 53/102 (51.9%) patients presented with metastatic disease (UICC IV), 11/102 (10.7%) patients presented with multifocal disease, and 56/102 (54.9%) patients underwent a primary surgical or endoscopic approach, whereas 28 (27.5%) patients received systemic cytoreductive treatment. The univariate analysis revealed the GPS and PI (prognostic index), as well as UICC-stage IV, HG, and the Charlson comorbidity index (CCI) to predict both the PFS and OS in GEP-NEN patients. However, the calculation of the survival did not separate GPS subgroups at lower risk (GPS 0 versus GPS 1). Upon the subsequent multivariate analysis, GPS was the only independent predictor of both OS (p < 0.0001; HR = 3.459, 95% CI = 1.263−6.322) and PFS (p < 0.003; HR = 2.119, 95% CI = 0.944−4.265). Conclusion: In line with previous results for other entities, the present study revealed the GPS at baseline to be the only independent predictor of survival across all stages of GEP-NEN, and thus supports its clinical utility for risk stratification in this group of patients.

Background: Continuous glucose monitoring (CGM) might have beneficial effects on glycemic control and body mass index (BMI) in adults with type 1 (T1D) or type 2 diabetes (T2D). Methods: The diabetes prospective follow-up registry was used to identify individuals with T1D or T2D ≥18 years starting CGM management in 2015 or later and follow-up information available. Hemoglobin A1c (HbA1c), BMI, and event rates of severe hypoglycemia in the year before CGM start were compared with two follow-up periods: (1) CGM use for 3-6 months and (2) CGM use for >6 months. Repeated measurements linear and negative binomial regressions were used (adjustment for sex, age at diabetes onset, and baseline parameters) and stratified by diabetes type. Results: Mean follow-up time was 1.8 years in T1D ( n  = 2994) and 1.9 years in T2D ( n  = 1440). In T1D, adjusted mean HbA1c decreased significantly from 7.65% (95% confidence interval: 7.62-7.68) at baseline to 7.54% (7.51-7.57) during follow-up. BMI increased slightly (baseline: 25.4 kg/m 2 [25.3-25.5], follow-up >6 months: 25.8 kg/m 2 [25.7-25.9]), whereas event rates of severe hypoglycemia were significantly lower after >6 months with CGM (9.0 events/100 patient-years [PY; 8.0-10.1]) compared with baseline (11.3 events/100 PY [10.4-12.2]) in adults with T1D. In T2D, HbA1c decreased from 7.21% (7.17%-7.25%) to 7.00% (6.95%-7.04%) and BMI did not change after CGM initiation. Conclusion: Our results provide real-world evidence on CGM management in adult individuals with T1D or T2D. We suggest strengthening patients' and physicians' readiness toward diabetes technology in T2D and more openness of health insurance to cover cost based on proven benefits.

Purpose: About 20-25% of patients experience weight regain (WR) or insufficient weight loss (IWL) after bariatric metabolic surgery (BS). Therefore, we aimed to retrospectively assess the effectiveness of adjunct treatment with the GLP-1 receptor agonist semaglutide in non-diabetic patients with WR or IWL after BS., Materials and Methods: Post-bariatric patients without type 2 diabetes (T2D) with WR or IWL (n = 44) were included in the analysis. The primary endpoint was weight loss 3 and 6 months after initiation of adjunct treatment. Secondary endpoints included change in BMI, HbA1c, lipid profile, hs-CRP, and liver enzymes., Results: Patients started semaglutide 64.7 ± 47.6 months (mean ± SD) after BS. At initiation of semaglutide, WR after post-bariatric weight nadir was 12.3 ± 14.4% (mean ± SD). Total weight loss during semaglutide treatment was - 6.0 ± 4.3% (mean ± SD, p < 0.001) after 3 months (3.2 months, IQR 3.0-3.5, n = 38) and - 10.3 ± 5.5% (mean ± SD, p < 0.001) after 6 months (5.8 months, IQR 5.8-6.4, n = 20). At 3 months, categorical weight loss was > 5% in 61% of patients, > 10% in 16% of patients, and > 15% in 2% of patients. Triglycerides (OR = 0.99; p < 0.05), ALT (OR = 0.87; p = 0.05), and AST (OR = 0.89; p < 0.05) at baseline were negatively associated with weight loss of at least 5% at 3 months' follow-up (p < 0.05)., Conclusion: Treatment options to manage post-bariatric excess weight (regain) are scarce. Our results imply a clear benefit of adjunct treatment with semaglutide in post-bariatric patients. However, these results need to be confirmed in a prospective randomized controlled trial to close the gap between lifestyle intervention and revision surgery in patients with IWL or WR after BS., (© 2022. The Author(s).)

Aims/hypothesis: Attenuated counterregulation after recurrent hypoglycaemia is a major complication of diabetes treatment. As there is previous evidence for the relevance of sleep in metabolic control, we assessed the acute contribution of sleep to the counterregulatory adaptation to recurrent hypoglycaemia., Methods: Within a balanced crossover design, 15 healthy, normal-weight male participants aged 18-35 years underwent three hyperinsulinaemic-hypoglycaemic clamps with a glucose nadir of 2.5 mmol/l, under two experimental conditions, sleep and sleep deprivation. Participants were exposed to two hypoglycaemic episodes, followed by a third hypoglycaemic clamp after one night of regular 8 h sleep vs sleep deprivation. The counterregulatory response of relevant hormones (glucagon, growth hormone [GH], ACTH, cortisol, adrenaline [epinephrine] and noradrenaline [norepinephrine]) was measured, and autonomic and neuroglycopenic symptoms were assessed., Results: Sleep deprivation compared with sleep dampened the adaptation to recurrent hypoglycaemia for adrenaline (p=0.004), and this pattern also emerged in an overall analysis including adrenaline, GH and glucagon (p=0.064). After regular sleep, the counterregulatory responses of adrenaline (p=0.005), GH (p=0.029) and glucagon (p=0.009) were attenuated during the 3rd clamp compared with the 1st clamp, but were preserved after sleep deprivation (all p>0.225). Neuroglycopenic and autonomic symptoms during the 3rd clamp compared with the 1st clamp were likewise reduced after sleep (p=0.005 and p=0.019, respectively). In sleep deprivation, neuroglycopenic symptoms increased (p=0.014) and autonomic symptoms were unchanged (p=0.859)., Conclusions/interpretation: The counterregulatory adaptation to recurrent hypoglycaemia is compromised by sleep deprivation between hypoglycaemic episodes, indicating that sleep is essential for the formation of a neurometabolic memory, and may be a potential target of interventions to treat hypoglycaemia unawareness syndrome., (© 2022. The Author(s).)

The globally increasing prevalence of obesity represents a key medical and socioeconomic challenge. Due to related comorbidities and complications such as arterial hypertension, diabetes mellitus, fatty liver disease, and arteriosclerosis, obesity leads to a significant statistical reduction in lifespan. Currently, bariatric surgery is the most effective approach to manage body weight and comorbidities while lifestyle intervention as basic obesity therapy and medical treatment often do not lead to sufficient and sustainable weight loss. However, recent medical approaches show now promising effects on weight control and might close the gap towards bariatric surgical procedures. For instance, semaglutide has been approved by EMA in January 2022 for medical treatment of obesity concomitant to basic lifestyle therapy in adults with a BMI of ≥ 30 kg/m 2 or ≥ 27 kg/m 2 and weight-related comorbidity. Apart from weight control, improvement in cardiometabolic risk factors can be achieved with this treatment. Moreover, other drugs, mostly based on incretin mono- or multiagonism, are currently developed and may open further effective treatment options for obesity and its complications in the near future.On a health political level, first steps for the development of a structured treatment program (DMP) for obesity are in progress to enable early guideline-based and structured treatment of obesity, and to prevent the obesity associated complications., Competing Interests: Dr. Svenja Meyhöfer, Dr. Anne Lautenbach und Dr. Georg Serfling erhalten Reisekostenunterstützung von NovoNordisk und Lilly., (Thieme. All rights reserved.)

The ' time-of-day' modifies the metabolic response to meals, but less data exist on the diurnal variations in the hedonic drive to eat. In the present paper, we evaluate the effects of meal timing and macronutrient composition on metabolic responses and the homeostatic vs. hedonic regulation of appetite. In study 1, 84 young, healthy adults completed an online computer-based task assessing the homeostatic and hedonic drive to eat in the morning and evening. In study 2, 24 healthy, young men received 2 identical (850 kcal each) meals in the morning (8:45 h) and evening (18:00 h), of 2 experimental conditions: (i) regular carbohydrate (CH) meals (regular-CH), and (ii) high carbohydrate (high-CH) meals, containing 50 and 80% of energy from CHs, respectively. Serial blood samples were obtained, and the postprandial feelings of hunger, satiety, wanting and liking were assessed. Study 1 revealed a higher hedonic drive to eat in the evening compared to the morning. Study 2 confirmed this diurnal pattern of hedonic appetite regulation and, moreover, showed increased glucose and insulin responses to the evening meal. Postprandial ghrelin and leptin as well as feelings of hunger and satiety were not different between the mealtimes nor between the macronutrient conditions. In line with this, the homeostatic drive to eat was neither affected by the mealtime nor macronutrient composition. Increased the hedonic drive to eat in the evening may represent a vulnerability to palatable food and, thus, energy overconsumption. Together with lower evening glucose tolerance, these findings reflect an adverse metabolic constellation at the end of the day, especially after the ingestion of CH-rich foods.

Competing Interests: Jens Aberle states fees for lecturing and consulting activities for Astra Zeneca, Boehringer Ingelheim, Lilly Germany and Novo Nordisk. Anne Lautenbach states the following conflicts of interest: Travel support: Eli Lilly and Novo Nordisk; Research support: Astra Zeneca; Advisory Board activity: Novo Nordisk. Matthias Blüher received honorariums for lecturing and consulting work from Amgen, Astra Zeneca, Boehringer-Ingelheim, Daiichi-Sankyo, Lilly, Novartis, Novo Nordisk and Sanofi. Lars Selig, Svenja Meyhöfer and Sebastian M. Schmid have no conflicts of interest.

Objective: We evaluated the effect of acute mild light exposure at night on sleep architecture and glucose homeostasis., Patients/methods: Twenty healthy normal-weight men took part in two conditions of a randomized, controlled, balanced cross-over experimental study: i) two-consecutive nights with 8-h of sleep under dLAN (<5 lux) or ii) total darkness (CON). Sleep was evaluated by polysomnography. In the morning following 'night2', glucose homeostasis was assessed by an intravenous glucose tolerance test (ivGTT) with consecutive measures of glucose, insulin, and c-peptide. Plasma cortisol was measured at night before sleep, after morning awakening, and during mid-afternoon hours., Results: There was no significant difference in total sleep time, sleep efficiency, and sleep latency between conditions (all p > 0.66). However, NREM sleep stage N3 latency was prolonged after dLAN (p = 0.02) and NREM sleep stage 2 was decreased after two nights with dLAN (p = 0.04). During the first sleep hour, power in slow-oscillations, slow-waves, and delta bands diminished after dLAN (all p < 0.04). Glucose, insulin, and c-peptide were not altered by dLAN (all p > 0.14). Cortisol was reduced in the afternoon after 'night1' and in the morning after 'night2' (both p < 0.03)., Conclusions: dLAN slightly disturbed sleep architecture and quality without impairment of glucose homeostasis. Longer exposure to chronic dLAN might be needed to unmask its hypothesized metabolic consequences., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of interests We declare no competing interests.

Diabetes mellitus is a chronic metabolic disease associated with multiple long-term complications. Besides macro- and microvascular complications, patient's well-being can be severely impaired by complications affecting the nervous system. About 50 % of patients with diabetes suffer from polyneuropathy. Moreover, the risk of developing cognitive impairment and dementia is also increased in older people with diabetes. Insufficient glycemic control, young age at diagnosis of diabetes are discussed as risk factors for developing diabetes complications. The early identification and prevention of factors predicting diabetes complications that affect the nervous system are still challenging and in need for further research., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Key Points: The Anrep effect represents the alteration of left ventricular (LV) contractility to acutely enhanced afterload in a few seconds, thereby preserving stroke volume (SV) at constant preload. As a result of the missing preload stretch in our model, the Anrep effect differs from the slow force response and has a different mechanism. The Anrep effect demonstrated two different phases. First, the sudden increased afterload was momentary equilibrated by the enhanced LV contractility as a result of higher power strokes of strongly-bound myosin cross-bridges. Second, the slightly delayed recovery of SV is perhaps dependent on Ca 2+ /calmodulin-dependent protein kinase II activation caused by oxidation and myofilament phosphorylation (cardiac myosin-binding protein-C, myosin light chain 2), maximizing the recruitment of available strongly-bound myosin cross-bridges. Short-lived oxidative stress might present a new facet of subcellular signalling with respect to cardiovascular regulation. Relevance for human physiology was demonstrated by echocardiography disclosing the Anrep effect in humans during handgrip exercise., Abstract: The present study investigated whether oxidative stress and Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activity are involved in triggering the Anrep effect. LV pressure-volume (PV) analyses of isolated, preload controlled working hearts were performed at two afterload levels (60 and 100 mmHg) in C57BL/6N wild-type (WT) and CaMKII-double knockout mice (DKO CaMKII ). In snap-frozen WT hearts, force-pCa relationship, H 2 O 2 generation, CaMKII oxidation and phosphorylation of myofilament and Ca 2+ handling proteins were assessed. Acutely raised afterload showed significantly increased wall stress, H 2 O 2 generation and LV contractility in the PV diagram with an initial decrease and recovery of stroke volume, whereas end-diastolic pressure and volume, as well as heart rate, remained constant. Afterload induced increase in LV contractility was blunted in DKO CaMKII -hearts. Force development of single WT cardiomyocytes was greater with elevated afterload at submaximal Ca 2+ concentration and associated with increases in CaMKII oxidation and phosphorylation of cardiac-myosin binding protein-C, myosin light chain and Ca 2+ handling proteins. CaMKII activity is involved in the regulation of the Anrep effect and associates with stimulation of oxidative stress, presumably starting a cascade of CaMKII oxidation with downstream phosphorylation of myofilament and Ca 2+ handling proteins. These mechanisms improve LV inotropy and preserve stroke volume within few seconds., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

The aim of this study was to evaluate the newly developed non-invasive blood glucose system NIRLUS® (Near-Infra Red Light Ultra Sound; NIRLUS Engineering AG, Lübeck, Germany) under standardized conditions. Seventeen healthy men of normal weight (body mass index 22.4 ± 1.4 kg/m 2 ), aged 18 to 45 years, were enrolled in this study. During an intravenous glucose tolerance test, blood glucose profiles were measured simultaneously using the NIRLUS system and a "gold standard" laboratory reference system. Correlation analysis revealed a strong association between NIRLUS and reference values (r = 0.934; P < 0.001). Subsequent Bland-Altman analysis showed a symmetric distribution (r = 0.047; P = 0.395), and 95.5% of the NIRLUS-reference pairs were within the difference (d) of d ± 2 SD. The median deviation of all paired NIRLUS-reference values was 0.5 mmol/L and the mean percent deviation was 11.5%. Error grid analysis showed that 93.6% of NIRLUS-reference pairs are located in the area A, and 6.4% in the area B. No data were allocated in the areas C to E. This proof-of-concept study demonstrates the reproducibility of accurate blood glucose measures obtained by NIRLUS as compared to a gold standard laboratory reference system. The technology of NIRLUS is an important step forward in the development of non-invasive glucose monitoring., (© 2019 John Wiley & Sons Ltd.)

Background: Aldosterone is involved in almost all parts of the cardiovascular system. Hyperaldosteronism causes arterial hypertension and might predispose to stroke, atrial fibrillation, and heart failure., Case Summary: A 60-year-old obese woman with long-standing hypertension, hypokalaemia, and shortness of breath was admitted to our hospital. Hypertension was caused by primary hyperaldosteronism due to an adenoma of the adrenal gland. Detailed transthoracic echocardiography revealed diastolic dysfunction, disturbed ventricular-arterial interaction, and atrial compliance resulting in heart failure with preserved ejection fraction (HFPEF). Three months of aldosterone antagonist treatment improved ventricular-arterial coupling, while left ventricular diastolic and atrial dysfunction remained unchanged., Discussion: Presumably, hyperaldosteronism is the reason for HFPEF in this case. Standard criteria to diagnose HFPEF include clinical symptoms of heart failure and an ejection fraction (EF) >50% as well as echocardiographically or invasively assessed elevated filling pressures. Single beat pressure-volume analysis gives insights on the pathophysiology of increased filling pressures, showing in our case diastolic dysfunction as well as disturbed ventricular-arterial interaction. Three months of aldosterone antagonist treatment reduced blood pressure with concomitant improvement of ventricular-arterial interaction, thereby reducing stroke work while stroke volume remained nearly unchanged. Diastolic dysfunction and increased atrial stiffness were unaltered., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)