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1.
Biosensors (Basel) ; 14(9)2024 Sep 21.
Article in English | MEDLINE | ID: mdl-39329826

ABSTRACT

Adolescence remains a crucial age associated with diabetes distress in individuals living with type 1 diabetes (T1D). The Austrian organization "Diabär" regularly hosts a one-week adventure camp for adolescents (12-18 years) living with T1D. The camp focuses on "fun activities" without a structured educational protocol in order to minimize diabetes distress and increase diabetes management skills. In contrast to educational camps, training is kept to a minimum. However, attendees analyze the glycemic data of the previous day with their medical supervisor once daily during the camp. All subjects used a standardized real-time continuous glucose monitoring (CGM) system (DexcomG7) throughout the whole study. Glycemic metrics were prospectively analyzed during three periods: week 1 = home phase, week 2 = adventure camp, and week 3 = after the camp. Safety (time below range 1 [TBR1], 69-54 mg/dL, and time below range 2 [TBR2], <54 mg/dL) and efficacy (time in range [TIR], 70-180 mg/dL) were assessed by comparing the CGM data during weeks 1-3. The CGM data of 14 participants were analyzed. The TIR was higher during the camp week versus week 1 (70.4 ± 11.1% vs. 53.1 ± 20.2%; p = 0.001). The TBR1 significantly increased during camp compared to week 1 (2.5 ±1.7% vs. 1.3 ± 1.2%; p = 0.009), whereas the TBR2 did not differ. No serious adverse events occurred. This adventure camp without a main focus on education showed feasibility and safety in adolescents with T1D.


Subject(s)
Blood Glucose , Diabetes Mellitus, Type 1 , Glycemic Control , Humans , Diabetes Mellitus, Type 1/drug therapy , Adolescent , Male , Female , Child , Blood Glucose Self-Monitoring
2.
Nat Cell Biol ; 26(9): 1571-1584, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39117797

ABSTRACT

Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine-hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity.


Subject(s)
Autophagy , Caenorhabditis elegans , Caloric Restriction , Fasting , Longevity , Spermidine , Autophagy/drug effects , Longevity/drug effects , Spermidine/metabolism , Spermidine/pharmacology , Animals , Humans , Caenorhabditis elegans/metabolism , Peptide Initiation Factors/metabolism , Peptide Initiation Factors/genetics , Eukaryotic Translation Initiation Factor 5A , Drosophila melanogaster/metabolism , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae/genetics , Mice , Male , Mice, Inbred C57BL
3.
J Proteome Res ; 23(8): 3496-3514, 2024 Aug 02.
Article in English | MEDLINE | ID: mdl-38986055

ABSTRACT

Dupilumab is a monoclonal antibody approved for the treatment of atopic dermatitis (AD); however, its effects on molecular, cellular, and immunological levels remain to be elucidated. In this study, blood and dermal interstitial fluid (ISF) from nonlesional (NL) and lesional (L) skin were collected from eight patients with moderate to severe AD, before (visit 2-v2) and at the end of a 16-week treatment with dupilumab (visit 10-v10). Clinical treatment effect was demonstrated by significantly decreased AD severity scores at the end of treatment. At v10 versus v2, the percentages of CD4+ interleukin-producing cells showed a decreasing trend in ISF L and NL, unbound IL-4 levels in plasma were increased, IL-5 levels in ISF L reduced, and levels of factors involved in anti-inflammatory pathways and re-epithelization increased. At v2, ISF L showed that AD lesions might have altered amino acid pathways and lipid signaling compared to ISF NL. At v10, ISF L exhibited raised levels of long- and very-long-chain fatty acids and lipids compared to v2. Furthermore, dupilumab administration caused reduced expression of miR-155-5p and miR-378a-3p in ISF L. In conclusion, results from the present study provided novel knowledge by linking local immune and metabolic alterations to AD pathogenesis and treatment response.


Subject(s)
Antibodies, Monoclonal, Humanized , Dermatitis, Atopic , Extracellular Fluid , Humans , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Extracellular Fluid/drug effects , Extracellular Fluid/metabolism , Male , Female , Adult , Inflammation Mediators/metabolism , Metabolome/drug effects , Interleukin-4/metabolism , MicroRNAs/metabolism , MicroRNAs/genetics , Skin/metabolism , Skin/drug effects , Skin/blood supply , Middle Aged , Interleukin-5
4.
Endocr Pract ; 30(9): 863-869, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38880349

ABSTRACT

OBJECTIVE: A new generation of basal insulin analogs enabling once-weekly administration is currently under development. Weekly basal insulins have the potential to overcome limitations exhibited by current daily basal insulins. The pharmacokinetic and glucodynamic characteristics differ significantly between weekly and daily basal insulins and will require paradigm shifts in how basal insulins are dosed. METHODS: An overview of pharmacokinetic and glucodynamic principles of basal insulins is presented. Specifically, the pharmacokinetic and glucodynamic properties of daily basal insulins and how these differ for the new weekly basal insulins are discussed. Finally, models and simulations are used to describe the impact of weekly insulin properties on dosing. RESULTS: Two approaches have been used to extend the half-lives of these insulins, creating fusion proteins with reduced clearance and reduced receptor-mediated degradation of the insulin. The resulting prolonged exposure-response profiles affect dosing and the impact of dosing errors. Specifically, the impact of loading doses, missed doses, and double doses, and the effect on glycemic variability of a once weekly basal insulin option are demonstrated using pharmacokinetic/glucodynamic models and simulations. CONCLUSIONS: The transition from daily to weekly basal insulin dosing requires an understanding of the implications of the prolonged exposure-response profiles to effectively and confidently incorporate these weekly basal insulins into clinical practice. By reviewing the application of pharmacokinetic and glucodynamic principles to daily basal insulin analogs, the differences with weekly basal insulins, and the impact of these properties on dosing, this review intends to explain the principles behind weekly basal insulin dosing.


Subject(s)
Blood Glucose , Hypoglycemic Agents , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/administration & dosage , Blood Glucose/analysis , Blood Glucose/drug effects , Drug Administration Schedule , Insulin/administration & dosage , Insulin/pharmacokinetics , Insulin/analogs & derivatives , Insulin, Long-Acting/pharmacokinetics , Insulin, Long-Acting/administration & dosage , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/blood
6.
PLoS One ; 19(2): e0297491, 2024.
Article in English | MEDLINE | ID: mdl-38412194

ABSTRACT

BACKGROUND: In hospital medication errors are common. Our aim was to investigate risks of the analogue and digitally-supported medication process and any potential solutions. METHODS: A mixed methods study including a structured literature search and online questionnaires based on the Delphi method was conducted. First, all risks were structured into main and sub-risks and second, risks were grouped into risk clusters. Third, healthcare experts assessed risk clusters regarding their likelihood of occurrence their possible impact on patient safety. Experts were also asked to estimate the potential for digital solutions and solutions that strengthen the competence of healthcare professionals. RESULTS: Overall, 160 main risks and 542 sub-risks were identified. Main risks were grouped into 43 risk clusters. 33 healthcare experts (56% female, 50% with >20 years professional-experience) ranked the likelihood of occurrence and the impact on patient safety in the top 15 risk clusters regarding the process steps: admission (n = 4), prescribing (n = 3), verifying (n = 1), preparing/dispensing (n = 3), administering (n = 1), discharge (n = 1), healthcare professional competence (n = 1), and patient adherence (n = 1). 28 healthcare experts (64% female, 43% with >20 years professional-experience) mostly suggested awareness building and training, strengthened networking, and involvement of pharmacists at point-of-care as likely solutions to strengthen healthcare professional competence. For digital solutions they primarily suggested a digital medication list, digital warning systems, barcode-technology, and digital support in integrated care. CONCLUSIONS: The medication process holds a multitude of potential risks, in both the analogue and the digital medication process. Different solutions to strengthen healthcare professional competence and in the area of digitalization were identified that could help increase patient safety and minimize possible errors.


Subject(s)
Medication Errors , Patient Safety , Humans , Female , Male , Medication Errors/prevention & control , Hospitals , Health Personnel , Pharmacists
8.
J Clin Med ; 12(24)2023 Dec 06.
Article in English | MEDLINE | ID: mdl-38137600

ABSTRACT

Diabetes mellitus (DM) is a prominent risk factor for malignant and non-malignant pancreatic diseases. Furthermore, the presence of DM predicts an unfavourable outcome in people with pancreatic cancer. This retrospective observational study investigated 370 patients who underwent pancreatic resection surgery for various indications (84.3% in malignant indication) in a single surgery centre in Graz, Austria. The preoperative and postoperative diabetes statuses were evaluated according to surgery method and disease entity and predictors for diabetes development after surgery, as well as outcomes (survival and cancer recurrence) according to diabetes status, were analysed. In the entire cohort, the postoperative diabetes (postopDM) incidence was 29%. PostopDM occurred significantly more frequently in malignoma patients than in those with benign diseases (31.3% vs. 16.7%; p = 0.040, OR = 2.28). In the malignoma population, BMI, longer surgery duration, and prolonged ICU and hospital stay were significant predictors of diabetes development. The 1- and 2-year follow-ups showed a significantly increased mortality of people with postopDM in comparison to people without diabetes (HR 1-year = 2.02, p = 0.014 and HR 2-years = 1.56, p = 0.034). Local cancer recurrence was not influenced by the diabetes status. Postoperative new-onset diabetes seems to be associated with higher mortality of patients with pancreatic malignoma undergoing pancreatobiliary surgery.

9.
Intensive Care Med ; 49(11): 1317-1326, 2023 11.
Article in English | MEDLINE | ID: mdl-37870597

ABSTRACT

PURPOSE: Intensive care unit (ICU) hospitalization is challenging for the family members of the patients. Most family members report some level of anxiety and depression, sometimes even resulting in post-traumatic stress disorder (PTSD). An association has been reported between lack of information and PTSD. This study had three aims: to quantify the psychological burden of family members of critically ill patients, to explore whether a website with specific information could reduce PTSD symptoms, and to ascertain whether a website with information about intensive care would be used. METHOD: A multicenter double-blind, randomized, placebo-controlled trial was carried out in Austria and Switzerland. RESULTS: In total, 89 members of families of critically ill patients (mean age 47.3 ± 12.9 years, female n = 59, 66.3%) were included in the study. 46 relatives were allocated to the intervention website and 43 to the control website. Baseline Impact of Event Scale (IES) score was 27.5 ± 12.7. Overall, 50% showed clinically relevant PTSD symptoms at baseline. Mean IES score for the primary endpoint (~ 30 days after inclusion, T1) was 24 ± 15.8 (intervention 23.9 ± 17.9 vs. control 24.1 ± 13.5, p = 0.892). Hospital Anxiety and Depression Scale (HADS - Deutsch (D)) score at T1 was 12.2 ± 6.1 (min. 3, max. 31) and did not differ between groups. Use of the website differed between the groups (intervention min. 1, max. 14 vs. min. 1, max. 3; total 1386 "clicks" on the website, intervention 1021 vs. control 365). Recruitment was prematurely stopped in February 2020 due to coronavirus disease 2019 (COVID-19). CONCLUSION: Family members of critically ill patients often have significant PTSD symptoms and online information on critical illness did not result in reduced PTSD symptoms.


Subject(s)
Stress Disorders, Post-Traumatic , Adult , Female , Humans , Male , Middle Aged , Anxiety/psychology , Critical Care/psychology , Critical Illness/therapy , Critical Illness/psychology , Depression/psychology , Intensive Care Units , Stress Disorders, Post-Traumatic/prevention & control , Stress Disorders, Post-Traumatic/psychology , Double-Blind Method
10.
Diabetes Obes Metab ; 25(12): 3716-3723, 2023 12.
Article in English | MEDLINE | ID: mdl-37694740

ABSTRACT

AIMS: To characterize the pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in type 2 diabetes (T2D). MATERIALS AND METHODS: In an open-label trial, 46 individuals with T2D (18-75 years; body mass index 18.0-38.0 kg/m2 ; glycated haemoglobin ≤75 mmol/mol [≤9%]; basal insulin-treated) received subcutaneous once-weekly icodec for ≥8 weeks at individualized doses, aiming at a pre-breakfast plasma glucose concentration of 4.4 to 7.0 mmol/L (80-126 mg/dL) on the last three mornings of each weekly dosing interval. Frequent blood sampling to assess total serum icodec concentration (ie, albumin-bound and unbound) occurred from first icodec dose until 35 days after last dose. Icodec trough concentrations following initiation of once-weekly dosing were predicted by pharmacokinetic modelling. During the final 3 weeks of icodec treatment, while at steady state, the icodec glucose-lowering effect was assessed in three glucose clamps (target 7.5 mmol/L [135 mg/dL]): 0 to 36, 40 to 64 and 144 to 168 h post-dose, thus covering the initial, middle and last part of the 1-week dosing interval. Glucose-lowering effect during a complete dosing interval was predicted by pharmacokinetic-pharmacodynamic modelling. RESULTS: Model-predicted icodec steady state was attained after 3 to 4 weeks. At steady state, model-predicted daily proportions of glucose-lowering effect on days 1 to 7 of the 1-week dosing interval were 14.1%, 16.1%, 15.8%, 15.0%, 14.0%, 13.0% and 12.0%, respectively. Icodec duration of action was at least 1 week in all participants. Once-weekly icodec was overall safe and well tolerated in the current trial. CONCLUSIONS: The pharmacokinetic and pharmacodynamic characteristics of icodec in individuals with T2D support its potential as a once-weekly basal insulin.


Subject(s)
Diabetes Mellitus, Type 2 , Humans , Blood Glucose , Double-Blind Method , Hypoglycemic Agents , Insulin, Long-Acting , Adolescent , Young Adult , Adult , Middle Aged , Aged
11.
Nutrients ; 15(9)2023 Apr 25.
Article in English | MEDLINE | ID: mdl-37432211

ABSTRACT

Background: C-peptide is produced in equimolar amounts with insulin from pancreatic beta cells, and thus is a fundamental biomarker for beta cell function. A non-invasive urinary C-peptide-to-creatinine ratio (UCPCR) has attracted attention as a biomarker for metabolic conditions. However, the UCPCR as an indicative risk predictor for prediabetes is still being investigated. Methods: We aimed to characterize UCPCRs in healthy people using American Diabetes Association (ADA) criteria and to evaluate their metabolic outcomes over time. A total of 1022 participants of the Biomarkers in Personalized Medicine cohort (BioPersMed) were screened for this study. Totals of 317 healthy with normal glucose metabolism, 87 prediabetic, and 43 diabetic subjects were included. Results: Prediabetic participants had a significantly higher UCPCR median value than healthy participants (p < 0.05). Dysglycaemia of healthy baseline participants was measured twice over 4.5 ± 0.9 years; 25% and 30% were detected with prediabetes during follow-ups, predicted by UCPCR both for the first (p < 0.05) and the second visit (p < 0.05), respectively. This is in good agreement with the negative predictive UCPCR value of 60.2% based on logistic regression. UCPCR levels were equal in both sexes. Conclusion: UCPCR measurements provide an indicative approach for metabolic risk, representing a potential use for prevention and monitoring of impaired glucose metabolism.


Subject(s)
Prediabetic State , Female , Male , Humans , Adult , Prediabetic State/diagnosis , C-Peptide , Creatinine , Cohort Studies , Glucose
12.
J Clin Med ; 12(13)2023 Jul 04.
Article in English | MEDLINE | ID: mdl-37445513

ABSTRACT

Serum concentrations of anti-Müllerian hormone (AMH) have been found to decrease with increasing body mass index (BMI) in many studies. It is not yet clear whether this stems from an adverse effect of adiposity on AMH production, or from dilution due to the greater blood volume that accompanies a larger body size. To investigate a possible hemodilution effect, we explored the relationships between serum AMH levels and different parameters of body composition using linear regression models in a cohort of adult males. Body weight, lean mass (LM), and body surface area (BSA) were found to be better predictors of AMH than measures of adiposity, such as BMI or fat mass. Since both LM and BSA correlate with plasma volume better than adipose tissue, we conclude that hemodilution of AMH does occur in adult males and should be considered for normalization in future studies.

13.
Diabetologia ; 66(8): 1413-1430, 2023 08.
Article in English | MEDLINE | ID: mdl-37308751

ABSTRACT

AIMS/HYPOTHESIS: This study compared the frequency of hypoglycaemia, time to hypoglycaemia and recovery from hypoglycaemia after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100. Furthermore, the symptomatic and counterregulatory responses to hypoglycaemia were compared between icodec and glargine U100 treatment. METHODS: In a randomised, single-centre (Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria), open-label, two-period crossover trial, individuals with type 2 diabetes (age 18-72 years, BMI 18.5-37.9 kg/m2, HbA1c ≤75 mmol/mol [≤9.0%]) treated with basal insulin with or without oral glucose-lowering drugs received once-weekly icodec (for 6 weeks) and once-daily glargine U100 (for 11 days). Total weekly doses were equimolar based on individual titration of daily glargine U100 during the run-in period (target fasting plasma glucose [PG]: 4.4-7.2 mmol/l). Randomisation was carried out by assigning a randomisation number to each participant in ascending order, which encoded to one of two treatment sequences via a randomisation list prepared prior to the start of the trial. At steady state, double and triple doses of icodec and glargine U100 were administered followed by hypoglycaemia induction: first, euglycaemia was maintained at 5.5 mmol/l by variable i.v. infusion of glucose; glucose infusion was then terminated, allowing PG to decrease to no less than 2.5 mmol/l (target PGnadir). The PGnadir was maintained for 15 min. Euglycaemia was restored by constant i.v. glucose (5.5 mg kg-1 min-1). Hypoglycaemic symptoms score (HSS), counterregulatory hormones, vital signs and cognitive function were assessed at predefined PG levels towards the PGnadir. RESULTS: Hypoglycaemia induction was initiated in 43 and 42 participants after double dose of icodec and glargine U100, respectively, and in 38 and 40 participants after triple doses, respectively. Clinically significant hypoglycaemia, defined as PGnadir <3.0 mmol/l, occurred in comparable proportions of individuals treated with icodec vs glargine U100 after double (17 [39.5%] vs 15 [35.7%]; p=0.63) and triple (20 [52.6%] vs 28 [70.0%]; p=0.14) doses. No statistically significant treatment differences were observed in the time to decline from PG values of 5.5 mmol/l to 3.0 mmol/l (2.9-4.5 h after double dose and 2.2-2.4 h after triple dose of the insulin products). The proportion of participants with PGnadir ≤2.5 mmol/l was comparable between treatments after double dose (2 [4.7%] for icodec vs 3 [7.1%] for glargine U100; p=0.63) but higher for glargine U100 after triple dose (1 [2.6%] vs 10 [25.0%]; p=0.03). Recovery from hypoglycaemia by constant i.v. glucose infusion took <30 min for all treatments. Analyses of the physiological response to hypoglycaemia only included data from participants with PGnadir <3.0 mmol/l and/or the presence of hypoglycaemic symptoms; in total 20 (46.5%) and 19 (45.2%) individuals were included after a double dose of icodec and glargine U100, respectively, and 20 (52.6%) and 29 (72.5%) individuals were included after a triple dose of icodec and glargine U100, respectively. All counterregulatory hormones (glucagon, adrenaline [epinephrine], noradrenaline [norepinephrine], cortisol and growth hormone) increased during hypoglycaemia induction with both insulin products at both doses. Following triple doses, the hormone response was greater with icodec vs glargine U100 for adrenaline at PG3.0 mmol/l (treatment ratio 2.54 [95% CI 1.69, 3.82]; p<0.001), and cortisol at PG3.0 mmol/l (treatment ratio 1.64 [95% CI 1.13, 2.38]; p=0.01) and PGnadir (treatment ratio 1.80 [95% CI 1.09, 2.97]; p=0.02). There were no statistically significant treatment differences in the HSS, vital signs and cognitive function. CONCLUSIONS/INTERPRETATION: Double or triple doses of once-weekly icodec lead to a similar risk of hypoglycaemia compared with double or triple doses of once-daily glargine U100. During hypoglycaemia, comparable symptomatic and moderately greater endocrine responses are elicited by icodec vs glargine U100. TRIAL REGISTRATION: ClinicalTrials.gov NCT03945656. FUNDING: This study was funded by Novo Nordisk A/S.


Subject(s)
Diabetes Mellitus, Type 2 , Hypoglycemia , Humans , Adolescent , Young Adult , Adult , Middle Aged , Aged , Insulin Glargine/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Cross-Over Studies , Hydrocortisone , Hypoglycemia/chemically induced , Hypoglycemia/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Glucose , Epinephrine , Blood Glucose/analysis
14.
medRxiv ; 2023 Nov 29.
Article in English | MEDLINE | ID: mdl-37292870

ABSTRACT

Background: Pulmonary hypertension (PH) poses a significant health threat with high morbidity and mortality, necessitating improved diagnostic tools for enhanced management. Current biomarkers for PH lack functionality and comprehensive diagnostic and prognostic capabilities. Therefore, there is a critical need to develop biomarkers that address these gaps in PH diagnostics and prognosis. Methods: To address this need, we employed a comprehensive metabolomics analysis in 233 blood based samples coupled with machine learning analysis. For functional insights, human pulmonary arteries (PA) of idiopathic pulmonary arterial hypertension (PAH) lungs were investigated and the effect of extrinsic FFAs on human PA endothelial and smooth muscle cells was tested in vitro. Results: PA of idiopathic PAH lungs showed lipid accumulation and altered expression of lipid homeostasis-related genes. In PA smooth muscle cells, extrinsic FFAs caused excessive proliferation and endothelial barrier dysfunction in PA endothelial cells, both hallmarks of PAH.In the training cohort of 74 PH patients, 30 disease controls without PH, and 65 healthy controls, diagnostic and prognostic markers were identified and subsequently validated in an independent cohort. Exploratory analysis showed a highly impacted metabolome in PH patients and machine learning confirmed a high diagnostic potential. Fully explainable specific free fatty acid (FFA)/lipid-ratios were derived, providing exceptional diagnostic accuracy with an area under the curve (AUC) of 0.89 in the training and 0.90 in the validation cohort, outperforming machine learning results. These ratios were also prognostic and complemented established clinical prognostic PAH scores (FPHR4p and COMPERA2.0), significantly increasing their hazard ratios (HR) from 2.5 and 3.4 to 4.2 and 6.1, respectively. Conclusion: In conclusion, our research confirms the significance of lipidomic alterations in PH, introducing innovative diagnostic and prognostic biomarkers. These findings may have the potential to reshape PH management strategies.

15.
J Neurosci Methods ; 393: 109893, 2023 06 01.
Article in English | MEDLINE | ID: mdl-37217139

ABSTRACT

BACKGROUND: Orthotopic xenograft studies promote the development of targeted/personalized therapies to improve the still poor life expectancy of glioblastoma patients. NEW METHOD: We implemented an atraumatic access to glioblastoma with cerebral Open Flow Microperfusion (cOFM) by implantation of xenograft cells in rat brain with intact blood brain barrier (BBB) and subsequent development of a xenograft glioblastoma at the interface between the cOFM probe and surrounding brain tissue. Human glioma U87MG cells were implanted at a well-defined position into immunodeficient Rowett nude rat´s brain via cOFM (cOFM group) and syringe (control group). Characteristics of the mature tumors from both groups were assessed. RESULTS: For the first time xenograft cells were successfully introduced into rat brain with intact BBB using cOFM, and the tumor tissue developing around the cOFM probe was unaffected by the presence of the probe. Thereby an atraumatic access to the tumor was created. The success rate of glioblastoma development in the cOFM group was high (>70%). The mature cOFM-induced tumors (20-23 days after cell-implantation) resembled the syringe-induced ones and showed typical features of human glioblastoma. COMPARISON WITH EXISTING METHOD: Examining xenograft tumor microenvironment with currently available methods inevitably causes trauma that could affect the reliability of obtained data. CONCLUSION: This novel atraumatic access to human glioblastoma in rat brain provides the possibility to collect interstitial fluid from functional tumor tissue in vivo without trauma generation. Thereby, reliable data can be generated promoting drug research, biomarker identification, and enabling investigation of the BBB of an intact tumor.


Subject(s)
Brain Neoplasms , Glioblastoma , Animals , Humans , Rats , Glioblastoma/pathology , Heterografts , Reproducibility of Results , Brain/pathology , Blood-Brain Barrier , Disease Models, Animal , Brain Neoplasms/pathology , Cell Line, Tumor , Tumor Microenvironment
16.
Diabetes ; 72(9): 1251-1261, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37257067

ABSTRACT

The mechanisms accounting for the functional changes of α- and ß-cells over the course of type 1 diabetes (T1D) development are largely unknown. Permitted by our established technology of high spatiotemporal resolution imaging of cytosolic Ca2+ ([Ca2+]c) dynamics on fresh pancreas tissue slices, we tracked the [Ca2+]c dynamic changes, as the assessment of function, in islet α- and ß-cells of female nonobese diabetic (NOD) mice during the development of spontaneous diabetes. We showed that, during the phases of islet inflammation, 8 mmol/L glucose-induced synchronized short [Ca2+]c events in ß-cells were diminished, whereas long [Ca2+]c events were gradually more triggerable at substimulatory 4 and 6 mmol/L glucose. In the islet destruction phase, the synchronized short [Ca2+]c events in a subset of ß-cells resumed at high glucose condition, while the long [Ca2+]c events were significantly elevated already at substimulatory glucose concentrations. In the α-cells, the glucose sensitivity of the [Ca2+]c events persisted throughout the course of T1D development. At the late islet destruction phase, the α-cell [Ca2+]c events exhibited patterns of synchronicity. Our work has uncovered windows of functional recovery in ß-cells and potential α-cells functional synchronization in NOD mice over the course of T1D development. ARTICLE HIGHLIGHTS: In NOD mice ß-cells, 8 mmol/L glucose-induced synchronized short [Ca2+]c events diminish in the early phases of islet inflammation, and long Ca2+ events became more sensitive to substimulatory 4 and 6 mmol/L glucose. In the late islet destruction phase, the synchronized short [Ca2+]c events in a subset of ß-cells resumed at 8 mmol/L glucose, while the long Ca2+ events were significantly elevated at substimulatory glucose concentrations. In the α-cells, the glucose sensitivity of the [Ca2+]c events persisted throughout the course of type 1 diabetes development. α-Cell [Ca2+]c events occasionally synchronize in the islets with severe ß-cell destruction.


Subject(s)
Diabetes Mellitus, Type 1 , Islets of Langerhans , Mice , Animals , Female , Mice, Inbred NOD , Calcium , Glucose/pharmacology , Inflammation
17.
Wien Klin Wochenschr ; 135(Suppl 1): 32-44, 2023 Jan.
Article in German | MEDLINE | ID: mdl-37101023

ABSTRACT

Hyperglycemia significantly contributes to complications in patients with diabetes mellitus. While lifestyle interventions remain cornerstones of disease prevention and treatment, most patients with type 2 diabetes will eventually require pharmacotherapy for glycemic control. The definition of individual targets regarding optimal therapeutic efficacy and safety as well as cardiovascular effects is of great importance. In this guideline we present the most current evidence-based best clinical practice data for healthcare professionals.


Subject(s)
Diabetes Mellitus, Type 2 , Hyperglycemia , Humans , Hypoglycemic Agents/therapeutic use , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Hyperglycemia/drug therapy , Blood Glucose
18.
Wien Klin Wochenschr ; 135(Suppl 1): 242-255, 2023 Jan.
Article in German | MEDLINE | ID: mdl-37101046

ABSTRACT

This position statement presents the recommendations of the Austrian Diabetes Association for diabetes management of adult patients during inpatient stay. It is based on the current evidence with respect to blood glucose targets, insulin therapy and treatment with oral/injectable antidiabetic drugs during inpatient hospitalization. Additionally, special circumstances such as intravenous insulin therapy, concomitant therapy with glucocorticoids and use of diabetes technology during hospitalization are discussed.


Subject(s)
Diabetes Mellitus, Type 2 , Diabetes Mellitus , Humans , Diabetes Mellitus/diagnosis , Diabetes Mellitus/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Blood Glucose , Hospitals , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy
19.
Nutrients ; 15(3)2023 Jan 18.
Article in English | MEDLINE | ID: mdl-36771218

ABSTRACT

Metabolic regulation of glucose can be altered by fasting periods. We examined glucose metabolism and metabolomics profiles after 12 h and 36 h fasting in non-obese and obese participants and people with type 2 diabetes using oral glucose tolerance (OGTT) and intravenous glucose tolerance testing (IVGTT). Insulin sensitivity was estimated by established indices and mass spectrometric metabolomics was performed on fasting serum samples. Participants had a mean age of 43 ± 16 years (62% women). Fasting levels of glucose, insulin and C-peptide were significantly lower in all cohorts after 36 h compared to 12 h fasting (p < 0.05). In non-obese participants, glucose levels were significantly higher after 36 h compared to 12 h fasting at 120 min of OGTT (109 ± 31 mg/dL vs. 79 ± 18 mg/dL; p = 0.001) but insulin levels were lower after 36 h of fasting at 30 min of OGTT (41.2 ± 34.1 mU/L after 36 h vs. 56.1 ± 29.7 mU/L; p < 0.05). In contrast, no significant differences were observed in obese participants or people with diabetes. Insulin sensitivity improved in all cohorts after 36 h fasting. In line, metabolomics revealed subtle baseline differences and an attenuated metabolic response to fasting in obese participants and people with diabetes. Our data demonstrate an improved insulin sensitivity after 36 h of fasting with higher glucose variations and reduced early insulin response in non-obese people only.


Subject(s)
Diabetes Mellitus, Type 2 , Insulin Resistance , Humans , Female , Adult , Middle Aged , Male , Obesity , Insulin/metabolism , Glucose/metabolism , Fasting , Blood Glucose/metabolism
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