Effect of Repeated Bolus and Continuous Glucose Infusion on DNA Damage and Oxidative Stress Biomarkers in Healthy Male Volunteers.

Glucose variability (GV), which describes fluctuations in blood glucose levels within the day, is a phenomenon that is increasingly becoming the target of scientific attention when it comes to increased risk of coronary heart disease. Effects of GV may contribute to the development of metabolic syndrome and type 2 diabetes. Hyperglycemia can lead to oxidative stress resulting in molecular damage due to accumulation of reactive oxygen species (ROS). To discover more about the immediate effects of GV, continuous vs. bolus intravenous glucose administration was applied to 10 healthy men aged 21-30 years over a time frame of 48 h. Whole blood and plasma were analyzed for DNA damage using a comet assay with 3 different treatments (lysis buffer, H2O2, and the lesion-specific enzyme formamidopyrimidine DNA glycosylase (FPG)) as well as for the oxidative stress markers protein carbonyls (PC), unconjugated bilirubin (UCB), and ferric reducing antioxidant power (FRAP). A significant time effect was found in the three DNA damage treatments as well as in PC and UCB possibly due to circadian changes on oxidative stress, but no intervention group effect was observed for any of the markers. In conclusion, bolus vs. continuous glucose administration had no significant acute effect on DNA damage and markers of oxidative stress in healthy men.

Glucose and lipopolysaccharide differentially regulate fibroblast growth factor 21 in healthy male human volunteers - A prospective cross-over trial.

Fibroblast growth factor 21 (FGF21) affects the regulation of metabolism. Additionally, anti-inflammatory properties are attributed to FGF21, and studies in animals and humans show conflicting results. This study aimed to investigate how FGF21 is affected by glucose and lipopolysaccharide (LPS) in humans. Therefore, FGF21 was measured eight times at different time points within 48 h in this prospective cross-over trial after glucose and LPS on two different study days. The study included ten healthy, non-smoking male subjects aged 18-40. Repeated measures analysis of variance and paired t-test as post hoc analysis were applied. The administration of glucose and LPS resulted in a significant difference in regulating FGF21 (p < 0.001). After glucose administration, FGF21 declined sharply at 360 min, with a subsequent steep increase that exceeded baseline levels. LPS induced a drop in FGF21 after 180 min, while the baseline concentrations were not reached. After 180 min and 24 h, a statistically significant difference was demonstrated after adjusting the Bonferroni-Holm method. So, our results support the hypothesis that glucose and LPS differentially affect the human expression of FGF21 over 48 h.

Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial.

BACKGROUND: Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects. METHODS: The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18-40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models. RESULTS: Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP. CONCLUSIONS: Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway. TRIAL REGISTRATION: This study is based on a study registered at ClinicalTrials.gov, NCT03392701 . Registered 21 December 2017.

Performance of the recommended ESC/EASD cardiovascular risk stratification model in comparison to SCORE and NT-proBNP as a single biomarker for risk prediction in type 2 diabetes mellitus.

BACKGROUND: Recently, the European Society of Cardiology (ESC) and European Association for the Society of Diabetes (EASD) introduced a new cardiovascular disease (CVD) risk stratification model to aid further treatment decisions in individuals with diabetes. Our study aimed to investigate the prognostic performance of the ESC/EASD risk model in comparison to the Systematic COronary Risk Evaluation (SCORE) risk model and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in an unselected cohort of type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: A total of 1690 T2DM patients with a 10-year follow up for fatal CVD and all-cause death and a 5-year follow up for CVD and all-cause hospitalizations were analyzed. According to ESC/EASD risk criteria 25 (1.5%) patients were classified as moderate, 252 (14.9%) high, 1125 (66.6%) very high risk and 288 (17.0%) were not classifiable. Both NT-proBNP and SCORE risk model were associated with 10-year CVD and all-cause death and 5-year CVD and all-cause hospitalizations while the ESC/EASD model was only associated with 10-year all-cause death and 5-year all-cause hospitalizations. NT-proBNP and SCORE showed significantly higher C-indices than the ESC/EASD risk model for CVD death [0.80 vs. 0.53, p < 0.001; 0.64 vs. 0.53, p = 0.001] and all-cause death [0.73, 0.66 vs. 0.52, p < 0.001 for both]. The performance of SCORE improved in a subgroup without CVD aged 40-64 years compared to the unselected cohort, while NT-proBNP performance was robust across all groups. CONCLUSION: The new introduced ESC/EASD risk stratification model performed limited compared to SCORE and single NT-proBNP assessment for predicting 10-year CVD and all-cause fatal events in individuals with T2DM.

COVID-19 fatality prediction in people with diabetes and prediabetes using a simple score upon hospital admission.

AIM: To assess predictors of in-hospital mortality in people with prediabetes and diabetes hospitalized for COVID-19 infection and to develop a risk score for identifying those at the greatest risk of a fatal outcome. MATERIALS AND METHODS: A combined prospective and retrospective, multicentre, cohort study was conducted at 10 sites in Austria in 247 people with diabetes or newly diagnosed prediabetes who were hospitalized with COVID-19. The primary outcome was in-hospital mortality and the predictor variables upon admission included clinical data, co-morbidities of diabetes or laboratory data. Logistic regression analyses were performed to identify significant predictors and to develop a risk score for in-hospital mortality. RESULTS: The mean age of people hospitalized (n = 238) for COVID-19 was 71.1 ± 12.9 years, 63.6% were males, 75.6% had type 2 diabetes, 4.6% had type 1 diabetes and 19.8% had prediabetes. The mean duration of hospital stay was 18 ± 16 days, 23.9% required ventilation therapy and 24.4% died in the hospital. The mortality rate in people with diabetes was numerically higher (26.7%) compared with those with prediabetes (14.9%) but without statistical significance (P = .128). A score including age, arterial occlusive disease, C-reactive protein, estimated glomerular filtration rate and aspartate aminotransferase levels at admission predicted in-hospital mortality with a C-statistic of 0.889 (95% CI: 0.837-0.941) and calibration of 1.000 (P = .909). CONCLUSIONS: The in-hospital mortality for COVID-19 was high in people with diabetes but not significantly different to the risk in people with prediabetes. A risk score using five routinely available patient variables showed excellent predictive performance for assessing in-hospital mortality.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Is Not Induced in Artificial Human Inflammation and Is Not Correlated with Inflammatory Response.

Lipoproteins, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9), have been shown to play a key role in the innate immune response. However, knowledge about the role and kinetics of PCSK9 in human inflammation is currently insufficient. This study aimed to investigate the interaction between inflammation and lipid metabolism, including the possible role of PCSK9. A single-blinded, placebo-controlled cross-over study using the human endotoxin model was performed. Ten healthy men received lipopolysaccharide (LPS) or placebo on two different study days after overnight fasting. Lipoproteins as well as PCSK9 were measured repetitively over 48 h. PCSK9 plasma concentrations were not induced by LPS infusion, and no correlation between PCSK9 plasma concentrations and the degree of inflammation could be identified. The observed low-density lipoprotein (LDL) response to inflammation was more complex than anticipated, especially in the very early phase after the inflammatory stimulus. Baseline concentrations of LDL, as well as high-density lipoprotein (HDL), correlated negatively with inflammatory response. Our data suggest that the lipoprotein response to inflammation is independent of PCSK9. The proposed elevations of PCSK9 and suspected correlations between PCSK9 levels and inflammatory response are not supported by our data. (This study has been registered at ClinicalTrials.gov under registration no. NCT03392701.).

Unrecognised cardiovascular disease in type 2 diabetes: is it time to act earlier?

Cardiovascular disease (CVD) is the most significant prognostic factor in individuals with type 2 diabetes (T2D). However, a significant number of individuals may develop CVD that does not present with the classic angina-related or heart failure symptoms. In these cases, CVD may seem to be 'silent' or 'asymptomatic', but may be more accurately characterised as unrecognised diabetic cardiac impairment. An initial step to raise awareness of unrecognised CVD in individuals with T2D would be to reach a consensus regarding the terminology used to describe this phenomenon. By standardising the terminologies, and agreeing on the implementation of an efficient screening program, it is anticipated that patients will receive an earlier diagnosis and appropriate and timely treatment. Given the availability of anti-diabetic medications that have been shown to concomitantly reduce CV risk and mortality, it is imperative to improve early identification and initiate treatment as soon as possible in order to enable as many patients with T2D as possible to benefit.

GDF-15 Is Associated with Cancer Incidence in Patients with Type 2 Diabetes.

BACKGROUND: Diabetes has been linked epidemiologically to increased cancer incidence and mortality. Growth differentiation factor 15 (GDF-15) is increased in patients with diabetes and has recently been linked to the occurrence of cancer. We investigated whether circulating GDF-15 concentrations can predict the incidence of malignant diseases in a diabetic patient cohort already facing increased risk for cancer. METHODS: We prospectively enrolled a total of 919 patients with type 2 diabetes and no history of malignant disease, who were clinically followed up for 60 months. GDF-15, N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline; an additional 4 cardiovascular biomarkers were determined for a subpopulation (n = 259). Study end point was defined as the first diagnosis of any type of cancer during the follow-up period. RESULTS: During a median follow-up of 60 months, 66 patients (7.2%) were diagnosed with cancer. Baseline circulating GDF-15 concentrations were higher in patients that developed cancer over the follow-up period when compared to cancer-free patients. Increased GDF-15 concentrations were significantly associated with cancer incidence [crude hazard ratio (HR) per 1-IQR (interquartile range) increase 2.13, 95% CI 1.53-2.97, P < 0.001]. This effect persisted after multivariate adjustment with an adjusted HR of 1.86 (95% CI 1.22-2.84; P = 0.004). Among the 4 additionally tested cardiovascular markers in the subpopulation, only troponin T and C-terminal proendothelin-1 showed a significant association with future cancer incidence with unadjusted HRs of 1.71 (95% CI 1.28-2.28, P < 0.001) and 1.68 (95% CI 1.02-2.76, P = 0.042), respectively. CONCLUSIONS: Increased circulating concentrations of GDF-15 are associated with increased cancer incidence in patients with type 2 diabetes.

Lactation and appetite-regulating hormones: increased maternal plasma peptide YY concentrations 3-6 months postpartum.

Breast-feeding is associated with maternal hormonal and metabolic changes ensuring adequate milk production. In this study, we investigate the impact of breast-feeding on the profile of changes in maternal appetite-regulating hormones 3-6 months postpartum. Study participants were age- and BMI-matched lactating mothers (n 10), non-lactating mothers (n 9) and women without any history of pregnancy or breast-feeding in the previous 12 months (control group, n 10). During study sessions, young mothers breast-fed or bottle-fed their babies, and maternal blood samples were collected at five time points during 90 min: before, during and after feeding the babies. Outcome parameters were plasma concentrations of ghrelin, peptide YY (PYY), leptin, adiponectin, prolactin, cortisol, insulin, glucose and lipid values. At baseline, circulating PYY concentrations were significantly increased in lactating mothers (100·3 (se 6·7) pg/ml) v. non-lactating mothers (73·6 (se 4·9) pg/ml, P=0·008) and v. the control group (70·2 (se 9) pg/ml, P=0·021). We found no differences in ghrelin, leptin and adiponectin values. Baseline prolactin concentrations were over 4-fold higher in lactating mothers (P<0·001). Lactating women had reduced TAG levels and LDL-cholesterol:HDL-cholesterol ratio, but increased waist circumference, when compared with non-lactating women. Breast-feeding sessions further elevated circulating prolactin (P<0·001), but induced no acute effects on appetite-regulating hormones. In summary, one single breast-feeding session did not acutely modulate circulating appetite-regulating hormones, but increased baseline PYY concentrations are associated with prolonged lactation. PYY might play a role in the coordination of energy balance during lactation, increasing fat mobilisation from maternal depots and ensuring adequate milk production for the demands of the growing infant.

Association of endostatin with mortality in patients with chronic heart failure.

BACKGROUND: Experimental data imply that in decompensated heart failure (HF), the anti-angiogenic factor endostatin is increased. This study aimed to investigate whether the angiogenesis inhibitor endostatin is related to the risk of all-cause mortality in a prospective cohort study of chronic HF patients. METHODS: In this prospective observational cohort study, endostatin serum concentrations were determined in patients with chronic HF. Mortality data were recorded during a median follow-up of 31 months. RESULTS: One fifty one patients were included. The overall mortality rate was 20%. Baseline endostatin concentrations > 245 ng/mL were associated with higher risk of all-cause mortality [HR 8·7 (95% CI 2·5-30·0); P = 0·001] in the multivariate analysis as compared to endostatin concentrations ≤ 245 ng/mL. When both endostatin and NT-proBNP were above the calculated cut-off of 245 ng/mL and 2386 pg/mL, respectively, the prognostic utility of both biomarkers increased [HR 40·8 (95% CI 4·7-354·6); P = 0·001] compared with values lower than the cut-offs. CONCLUSIONS: Serum endostatin concentrations are independently associated with all-cause mortality. Furthermore, combination of endostatin and NT-proBNP discriminates patients at high risk.

Immunogenicity Parameters of Cancer Patients Receiving the mRNA Vaccine BNT162b2 While Obtaining Radiotherapy: A Longitudinal Cohort Evaluation.

BACKGROUND: Cancer patients are highly prone to infectious diseases. While undergoing antineoplastic treatment, the risk of severe symptoms upon infection increases, necessitating efficient protective measures, such as vaccination. For patients receiving radiotherapy, there is no specific information about humoral immunity. During the COVID-19 pandemic, serial antibody measurements were therefore offered to cancer patients, following SARS-CoV-2 vaccination while obtaining radiotherapy. METHODS: Out of 74 enrolled patients, 46 met the inclusion criteria. Two cohorts were allocated, depending on an association with chemotherapy or pure radiotherapy. An additional healthy control cohort of 16 healthcare workers was enrolled. All participants followed a two-fold BNT162b2 vaccine schedule. SARS-CoV-2 binding antibodies were measured serially in a 7-day cycle for 35 days and over the long-term, using the Elecsys® Anti-SARS-CoV-2 immunoassay. RESULTS: Cancer patients under pure radiotherapy have a comparable humoral vaccination response and long-term persistency of antibodies to healthy controls. Patients receiving additional chemotherapy show a significantly delayed immune response and decreased antibody titers. The vaccine was well tolerated in all cohorts. CONCLUSIONS: Pure radiotherapy in cancer patients does not interfere with the vaccine-induced humoral immune response or other immunogenetic aspects, whereas previous or simultaneous chemotherapy does. Findings are of particular relevance for future epidemic or pandemic scenarios.

[Diabetes education and counseling in adult patients with diabetes (Update 2023)]. / Diabetesschulung und -beratung bei Erwachsenen mit Diabetes (Update 2023).

Diabetes education and self-management play a critical role in diabetes care. Patient empowerment aims to actively influence the course of the disease by self-monitoring and subsequent treatment modification as well as the ability of patients to integrate diabetes into their daily life and to appropriately adapt diabetes to their life style situation. Diabetes education has to be made accessible for all persons with the disease. In order to be able to provide a structured and validated education program, adequate personnel as well as space, organizational and financial prerequisites are required. Besides an increase in knowledge about the disease it has been shown that a structured diabetes education is able to improve diabetes outcome as measured by parameters, such as blood glucose, HbA1c, lipids, blood pressure and body weight in follow-up evaluations. Modern education programs emphasize the ability of patients to integrate diabetes into everyday life, stress physical activity besides healthy eating as important components of life style therapy and use interactive methods in order to increase the acceptance of personal responsibility. Specific situations (e.g. impaired hypoglycemia awareness, illness, travel), the occurrence of diabetic complications and the use of technical devices such as glucose sensor systems and insulin pumps require additional educational measures supported by adequate electronic tools (diabetes apps and diabetes web portals). New data demonstrate the effect of telemedicine and internet-based services for diabetes prevention and management.

[Treatment of acute diabetic metabolic crises in adults (Update 2023) : Hyperglycemic hyperosmolar state and ketoacidotic metabolic disorder]. / Therapie der akuten diabetischen Stoffwechselentgleisungen bei Erwachsenen (Update 2023) : Hyperglykämisch-hyperosmolare und ketoazidotische Stoffwechselentgleisung.

Diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state (HHS) represent potentially life-threatening situations in adults. Therefore, rapid comprehensive diagnostic and therapeutic measures with close monitoring of vital and laboratory parameters are required. The treatment of DKA and HHS is essentially the same and replacement of the mostly substantial fluid deficit with several liters of a physiological crystalloid solution is the first and most important step. Serum potassium concentrations need to be carefully monitored to guide its substitution. Regular insulin or rapid acting insulin analogues can be initially administered as an i.v. bolus followed by continuous infusion. Insulin should be switched to subcutaneous injections only after correction of the acidosis and stable glucose concentrations within an acceptable range.

[Position statement: surgery and diabetes mellitus (Update 2023)]. / Positionspapier: Operation und Diabetes mellitus (Update 2023).

This position statement reflects the perspective of the Austrian Diabetes Association concerning the perioperative management of people with diabetes mellitus based on the available scientific evidence. The paper covers necessary preoperative examinations from an internal/diabetological point of view as well as the perioperative metabolic control by means of oral antihyperglycemic and/or insulin therapy.

[Diabetes mellitus and road traffic-a position paper of the Austrian Diabetes Association (update 2023)]. / Diabetes mellitus und Straßenverkehr ­ ein Positionspapier der Österreichischen Diabetesgesellschaft (Update 2023).

Public safety (prevention of accidents) is the primary objective in assessing fitness to drive a motor vehicle. However, general access to mobility should not be restricted if there is no particular risk to public safety. For people with diabetes mellitus, the Führerscheingesetz (Driving Licence Legislation) and the Führerscheingesetz-Gesundheitsverordnung (Driving Licence Legislation Health enactment) regulate important aspects of driving safety in connection with acute and chronic complications of the disease. Critical complications that may be relevant to road safety include severe hypoglycemia, pronounced hyperglycemia and hypoglycemia perception disorder as well as severe retinopathy and neuropathy, endstage renal disease and certain cardiovascular manifestations. If there is a suspicion of the presence of one of these complications, a detailed evaluation is required.In addition, the individual antihyperglycemic medication should be checked for existing potential for hypoglycemia. Sulfonylureas, glinides and insulin belong to this group and are therefore associated with the requirement of a 5-year limitation of the driver's license. Other antihyperglycemic drugs without potential for hypoglycemia such as Metformin, SGLT­2 inhibitors (Sodium-dependent-glucose-transporter­2 inhibitors, gliflozins), DPP-4-inhibitors (Dipeptidyl-Peptidase inhibitors, gliptins), and GLP­1 analogues (GLP­1 rezeptor agonists) are not associated with such a time limitation.The relevant laws which regulate driving safety give room for interpretation, so that specific topics on driving safety for people with diabetes mellitus are elaborated from a medical and traffic-relevant point of view. This position paper is intended to support people involved in this challenging matter.

[Geriatric aspects for the management of diabetes mellitus (Update 2023)]. / Geriatrische Aspekte bei Diabetes mellitus (Update 2023).

There is a high prevalence of diabetes mellitus in the elderly population of industrial countries. The present article provides recommendations for the screening, prevention and treatment of elderly diabetic patients according to current scientific evidence.

[Obesity and type 2 diabetes (Update 2023)]. / Adipositas und Typ-2-Diabetes (Update 2023).

The body mass index (BMI) is a very crude measure of body fatness in individuals. Even normal weight persons can have too much body fat in cases of a lack of muscle mass (sarcopenia), which is why additional measurements of waist circumference and body fatness, e.g. bioimpedance analysis (BIA), are recommended. Lifestyle management including nutrition modification and increase in physical activity are important measures for the prevention and treatment of diabetes. Regarding the treatment of type 2 diabetes, body weight is increasingly used as a secondary target parameter. The choice of anti-diabetic treatment and additional concomitant therapies is increasingly influenced by body weight. The importance of modern GLP­1 agonists and dual GLP­1 GIP agonists increases since these drugs target obesity and type 2 diabetes. Bariatric surgery is at present indicated with a BMI > 35 kg/m2 with concomitant risk factors, such as diabetes and can lead at least to partial diabetes remission but has to be incorporated into an appropriate lifelong care concept.

[Lipids-Diagnosis and therapy in diabetes mellitus (Update 2023)]. / Lipide: Diagnostik und Therapie bei Diabetes mellitus (Update 2023).

Hyper- and dyslipidemia contribute to cardiovascular morbidity and mortality in diabetic patients. Pharmacological therapy to lower LDL cholesterol has convincingly shown to reduce cardiovascular risk in diabetic patients. The present article represents the recommendations of the Austrian Diabetes Association for the use of lipid-lowering drugs in diabetic patients according to current scientific evidence.

[Diabetes mellitus, coronary artery disease and heart disease (Update 2023)]. / Diabetes mellitus, koronare Herzkrankheit und Herzinsuffizienz (Update 2023).

Diabetes mellitus, cardiovascular disease and heart failure are interacting dynamically. Patients being diagnosed with cardiovascular disease should be screened for diabetes mellitus. Enhanced cardiovascular risk stratification based on biomarkers, symptoms and classical risk factors should be performed in patients with preexisting diabetes mellitus. In patients with previously diagnosed arterosclerotic cardiovascular disease an agent proven to reduce major adverse cardiovascular events or cardiovascular mortality is recommended.