Publications by authors named "Norbert Tripolt"

25 Publications

  • Page 1 of 1

EndoBarrier™ Implantation Rapidly Improves Insulin Sensitivity in Obese Individuals with Type 2 Diabetes Mellitus.

Biomolecules 2021 Apr 14;11(4). Epub 2021 Apr 14.

Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria.

The EndoBarrier™ medical device is a duodenal-jejunal bypass liner designed to mimic the effects of gastric bypass surgery to induce weight loss and glycaemic improvement. In this study, 10 participants with type 2 diabetes mellitus (T2DM), a mean body mass index (BMI) of 43.3 ± 5.0 (kg/m) and a mean glycated haemoglobin A1c (HbA1c) of 60.6 ± 8.6 mmol/mol were examined at baseline (before implantation of EndoBarrier™), 4 weeks after implantation, at 36 weeks (right before explantation) and 24 weeks after the removal of the device to explore the short and long-term effects on glucose metabolism. Besides a significant reduction in body weight and fat mass, EndoBarrier™ treatment significantly improved insulin sensitivity during Botnia clamp investigations after four weeks of implantation. The beneficial effects decreased over time but remained significant 24 weeks after removal of the device.
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http://dx.doi.org/10.3390/biom11040574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070956PMC
April 2021

Can sodium glucose cotransporter 2 (SGLT-2) inhibitors be beneficial in patients with acute myocardial infarction?

Kardiol Pol 2021 Apr 20. Epub 2021 Apr 20.

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin, dapagliflozin, and canagliflozin have shown impressive beneficial effects in patients with type-2 diabetes mellitus in mandatory cardiovascular outcome trials. Retrospective data analysis revealed signals that pointed towards positive effects independent of the antidiabetic effects. This could be confirmed for empagliflozin and dapagliflozin in circumstances of chronic heart failure with reduced ejection fraction alone, where rates for hospitalization for heart failure and cumulative major adverse cardiovascular events were reduced in a similar extend in patients with and without diabetes mellitus in corresponding outcome trials. Cardiac remodelling following myocardial infarction leads to heart failure with reduced ejection fraction in many patients and aggravates morbidity and mortality. Clinical data of SGLT2i treatment after acute myocardial infarction is sparse. This review focuses on available experimental data on the effects of SGLT2i used before, during, and after myocardial infarction as well as already published and currently ongoing clinical trials.
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http://dx.doi.org/10.33963/KP.15969DOI Listing
April 2021

Performance of the Intermittently Scanned Continuous Glucose Monitoring (isCGM) System during a High Oral Glucose Challenge in Adults with Type 1 Diabetes-A Prospective Secondary Outcome Analysis.

Biosensors (Basel) 2021 Jan 15;11(1). Epub 2021 Jan 15.

Cardiovascular Diabetology Research Group, Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

To assess intermittently scanned continuous glucose monitoring (isCGM) performance for different rates of change in plasma glucose (RCPG) during glycemic challenges in type 1 diabetes (T1D). Nineteen people with T1D (7 females; age 35 ± 11 years; HbA 7.3 ± 0.6% (56 ± 7 mmol/mol)) performing two glycemic challenges (OGTT) were included. During OGTTs, plasma glucose was compared against sensor glucose for timepoints 0 min (pre-OGTT), +15 min, +30 min, +60 min, +120 min, +180 min, and +240 min by means of median absolute (relative) difference (MARD and MAD) and Clarke Error Grid (CEG), then was stratified for RCPG and glycemic ranges. Overall, MARD was 8.3% (4.0-14.8) during hypoglycemia level 1 18.8% (15.8-22.0), euglycemia 9.5% (4.3-15.1), hyperglycemia level 1 9.4% (4.0-17.2), and hyperglycemia level 2 7.1% (3.3-11.9). The MARD was associated with the RCPG ( < 0.0001), detailing significant differences in comparison of low, moderate, high, and very high RCPG ( = 0.014). Overall, CEG resulted in 88% (212 values) of comparison points in zone A, 12% (29 values) in zone B, and 0.4% (1 value) in zone D. The isCGM system was accurate during OGTTs. Its performance was dependent on the RCPG and showed an overestimation of the actual reference glucose during hypoglycemia.
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http://dx.doi.org/10.3390/bios11010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830732PMC
January 2021

Rapid glucose rise reduces heart rate variability in adults with type 1 diabetes: A prospective secondary outcome analysis.

Diabetes Obes Metab 2020 Dec 7. Epub 2020 Dec 7.

Cardiovascular Diabetology Research Group, Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

To investigate differences in heart rate variability (HRV) during oral glucose tolerance tests (OGTTs) in response to the rate of change in glucose and to different glycaemic ranges in individuals with type 1 diabetes. This was a single-centre, prospective, secondary outcome analysis in 17 individuals with type 1 diabetes (glycated haemoglobin 53 ± 6.3 mmol/L), who underwent two OGTTs (after 12 and 36 hours of fasting) investigating differences in HRV in response to rapid glucose increases/decreases and different glycaemic ranges during OGTT. Based on the rate of change in glucose level, the variables heart rate (P < 0.001), square root of the mean standard difference of successive R-R intervals (P = 0.002), percentage of pairs of R-R intervals with >50 ms difference (P < 0.001) and corrected QT interval (P = 0.04) were significantly altered, with HRV particularly reduced during episodes of rapid glucose rises. Glycaemic ranges during OGTT had no impact on HRV (P < 0.05). Individuals with type 1 diabetes showed no changes in HRV in response to different glycaemic ranges. HRV was dependent on the rate of change in glucose, especially rapid increases in glucose level.
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http://dx.doi.org/10.1111/dom.14287DOI Listing
December 2020

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

Diabetes Obes Metab 2021 02 4;23(2):589-598. Epub 2020 Dec 4.

Department for Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.

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.
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http://dx.doi.org/10.1111/dom.14256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753560PMC
February 2021

Improved glycaemic variability and basal insulin dose reduction during a running competition in recreationally active adults with type 1 diabetes-A single-centre, prospective, controlled observational study.

PLoS One 2020 11;15(9):e0239091. Epub 2020 Sep 11.

Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Introduction: To investigate the glycaemic response, macronutrient intake and insulin management in people with type 1 diabetes (T1D) compared to healthy individuals around a running competition.

Material And Methods: This was a single-centre, prospective, controlled observational study performed in individuals with T1D and healthy people. 24 people (12 T1D) were included in this study (age: T1D 41±12 vs. healthy 38±6 years, females: 3 vs. 6, BMI: 25.53.0 vs. 22.9±2.8 kg/m2). Both groups received an intermittently scanned continuous glucose monitoring (isCGM; FreeStyle Libre 1, Abbott, USA) system to assess glycaemia 24 hours before, during and 24 hours after a running competition. During this period, participants recorded their food intake and insulin administration. Data were analysed via ANOVA and mixed model analyses with post-hoc testing (p≤0.05).

Results: For overall glycaemic ranges in comparison of groups, significant differences were found for time in range (T1D 63±21% vs. healthy 89±13%, p = 0.001), time above range (TAR) 1 (T1D 21±15% vs. healthy 0±0%, p<0.001) and TAR 2 (T1D 8 [0-16%] vs. healthy 0±0%, p<0.001). When glycaemic variability was assessed, people with T1D had a higher glycaemic variability compared to healthy individuals (p<0.0001). Basal insulin dose was significantly reduced when compared against the regular pre-study basal insulin dose (pre-study 22±6 vs. pre-competition day 11±9 (-50±41%), p = 0.02; competition day 15±5 (-32± 1%)).

Conclusion: People with T1D have impaired glucose responses around a running competition compared to healthy individuals. However, basal insulin dose reductions were sufficient to prevent further dysglycaemia.

Clinical Trial Id: drks.de; DRKS00019886.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239091PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485886PMC
November 2020

Efficacy of Carbohydrate Supplementation Compared With Bolus Insulin Dose Reduction Around Exercise in Adults With Type 1 Diabetes: A Retrospective, Controlled Analysis.

Can J Diabetes 2020 Dec 22;44(8):697-700. Epub 2020 Mar 22.

Cardiovascular Diabetology Research Group, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria. Electronic address:

Objectives: Individuals with type 1 diabetes try to manage the risk of exercise-induced hypoglycemia by either pre-exercise/pre-meal bolus insulin dose reductions and/or consuming additional carbohydrates during exercise. Both strategies have proven to be effective in offsetting hypoglycemia, but it remains unclear which one is more beneficial. The aim of this study was to assess the efficacy of carbohydrate supplementation vs bolus insulin dose reduction in prevention of hypoglycemia during moderate-intensity exercise in those with type 1 diabetes.

Methods: This investigation was a retrospective, controlled analysis of 2 independent clinical trials. All participants performed continuous, moderate-intensity cycle ergometer exercise for ∼45 minutes. Two therapy management groups and a control group were compared. Group A was supplemented with 15 to 30 g carbohydrates at a glycemic threshold of 7.0 mmol/L during exercise, group B reduced their individual bolus insulin dose by 50% with their last meal before exercise and group C served as a control.

Results: No hypoglycemic events occurred in group A, whereas 4 events were recorded in groups B (p=0.02) and C (p=0.02).

Conclusions: Carbohydrate supplementation was superior to bolus insulin reduction for prevention of hypoglycemia during exercise in people with type 1 diabetes.
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http://dx.doi.org/10.1016/j.jcjd.2020.03.003DOI Listing
December 2020

Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction-The EMMY trial.

Am Heart J 2020 03 12;221:39-47. Epub 2019 Dec 12.

Medical University of Graz, Department of Internal Medicine, Division of Endocrinology and Diabetology, Graz, Austria.

Background: Sodium glucose cotransporter 2 (SGLT2) inhibitors are established antidiabetic drugs with proven cardiovascular benefit. Although growing evidence suggests beneficial effects on myocardial remodeling, fluid balance and cardiac function, the impact of empagliflozin initiated early after acute myocardial infarction (AMI) has not been investigated yet. Therefore, the impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction (EMMY) trial was designed to investigate the efficacy and safety of empagliflozin in diabetic and non-diabetic patients after severe AMI.

Methods: Within a multicenter, randomized, double-blind, placebo-controlled, phase 3b trial we will enroll patients with AMI and characteristics suggestive of severe myocardial necrosis are randomized in a 1:1 ratio to empagliflozin (10 mg once daily) or matching placebo. The primary endpoint is the impact of empagliflozin on changes in NT-proBNP within 6 months after AMI. Secondary endpoints include changes in echocardiographic parameters, levels of ketone body concentrations, HbA1c levels and body weight, respectively. Hospitalization rate due to heart failure or other causes, the duration of hospital stay and all-cause mortality will be assessed as exploratory secondary endpoints.

Discussion: The EMMY trial will test empagliflozin in patients with AMI regardless of their diabetic status. The EMMY trial may therefore underpin the concept of SGLT2 inhibition to improve cardiac remodeling, pre-and afterload reduction and cardiac metabolism regardless of its antidiabetic effects. Results will provide the rationale for the conduct of a cardiovascular outcome trial to test the effect of empagliflozin in patients with AMI.
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http://dx.doi.org/10.1016/j.ahj.2019.12.004DOI Listing
March 2020

Effects of a multispecies synbiotic on glucose metabolism, lipid marker, gut microbiome composition, gut permeability, and quality of life in diabesity: a randomized, double-blind, placebo-controlled pilot study.

Eur J Nutr 2020 Oct 15;59(7):2969-2983. Epub 2019 Nov 15.

Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.

Purpose: Diabesity, the combination of obesity and type 2 diabetes, is an ever-growing global health burden. Diabesity-associated dysbiosis of the intestinal microbiome has gained attention as a potential driver of disease and, therefore, a possible therapeutic target by means of pro- or prebiotic supplementation. This study tested the effects of a multispecies synbiotic (i.e. a combination of probiotics and prebiotics) on glucose metabolism, gut microbiota, gut permeability, neutrophil function and quality of life in treatment-experienced diabesity patients.

Methods: A randomized, double-blind, placebo-controlled pilot study with 26 diabesity patients was conducted in which patients received a daily dose of a multispecies probiotic and a prebiotic (or a placebo) for 6 months.

Results: There were no changes in glucose metabolism or mixed meal tolerance test responses throughout the study. The analysis of secondary outcomes revealed beneficial effects on hip circumference [- 1 (95% CI - 4; 3) vs +3 (- 1; 8) cm, synbiotics vs. placebo, respectively, p = 0.04], serum zonulin [- 0.04 (- 0.2; 0.1) vs +0.3 (- 0.05; 0.6) ng/ml, p = 0.004)] and the physical role item of the SF36 quality of life assessment [+ 5.4 (- 1.7; 12.5) vs - 5.0 (- 10.1; 0.2) points, p = 0.02] after 3 months of intervention, and lipoprotein (a) [- 2.1 (- 5.7; 1.6) vs +3.4 (- 0.9; 7.9) mg/dl, p = 0.02] after 6 months. There were no significant differences in alpha or beta diversity of the microbiome between groups or time points.

Conclusions: Glucose metabolism as the primary outcome was unchanged during the intervention with a multispecies synbiotic in patients with diabesity. Nevertheless, synbiotics improved some symptoms and biomarkers of type 2 diabetes and aspects of quality of life suggesting a potential role as adjuvant tool in the management of diabesity.
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http://dx.doi.org/10.1007/s00394-019-02135-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501130PMC
October 2020

Hypoglycaemia leads to a delayed increase in platelet and coagulation activation markers in people with type 2 diabetes treated with metformin only: Results from a stepwise hypoglycaemic clamp study.

Diabetes Obes Metab 2020 02 3;22(2):212-221. Epub 2019 Nov 3.

Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria.

Aims: To investigate the effect of hypoglycaemia on platelet and coagulation activation in people with type 2 diabetes.

Materials And Methods: This monocentric, open, single-arm, mechanistic trial included 14 people with established type 2 diabetes (four women, 10 men, age 55 ± 7 years, glycated haemoglobin concentration 51 ± 7 mmol/mol) receiving metformin monotherapy. A stepwise hyperinsulinaemic-hypoglycaemic clamp experiment (3.5 and 2.5 mmol/L, for 30 minutes respectively) was performed, aiming to investigate platelet and coagulation activity during predefined plateaus of hypoglycaemia, as well as 1 day and 7 days later.

Results: While platelet activation assessed by light transmittance aggregometry did not significantly increase after the hypoglycaemic clamp procedure, the more sensitive flow cytometry-based measurement of platelet surface activation markers showed hypoglycaemia-induced activation 24 hours (PAC1 CD62P , PAC1 CD63P and PAC1 CD62P CD63 ; P < .01) and 7 days after the hypoglycaemic clamp (P < .001 for PAC1 CD63 ; P < .01 for PAC1 CD62P and PAC1 CD62P CD63 ) in comparison to baseline. Coagulation markers, such as fibrinogen, D-dimer, plasminogen activator inhibitor-1, von Willebrand factor activity and factor VIII, were also significantly increased, an effect that was most pronounced 24 hours after the hypoglycaemic clamp.

Conclusion: A single event of insulin-induced hypoglycaemia led to an increase in markers of platelet activation and coagulation in people with early stages of type 2 diabetes on metformin therapy. However, the activation occurred with a delay and was evident 24 hours and 7 days after the actual hypoglycaemic episode.
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http://dx.doi.org/10.1111/dom.13889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972619PMC
February 2020

Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.

Cell Metab 2019 09 27;30(3):462-476.e6. Epub 2019 Aug 27.

Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria; Center for Biomarker Research in Medicine (CBmed), Graz, Austria; HEALTH Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz, Austria.

Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.
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http://dx.doi.org/10.1016/j.cmet.2019.07.016DOI Listing
September 2019

The future is now: SGLT2 inhibitors and type 1 diabetes - What about exercise?

Diabetes Res Clin Pract 2019 09 1;155:107806. Epub 2019 Aug 1.

Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1016/j.diabres.2019.107806DOI Listing
September 2019

Impact of Duodeno-Jejunal Bypass Liner (EndoBarrierTM) Implantation on Insulin Sensitivity in Patients with Type 2 Diabetes Mellitus (T2DM): A Study Protocol for a Pilot Trial.

Diabetes Ther 2019 Feb 11;10(1):299-309. Epub 2018 Dec 11.

Divisions of Endocrinology and Diabetology, Division of Gastroenterology and Hepatology, Medizinische Universitat Graz, Graz, Austria.

Introduction: A 60-cm endoscopically implantable duodenal-jejunal bypass liner (Endobarrier™, GI Dynamics, Lexington, MA, USA) has been introduced as a therapeutic option to support weight loss for a selected group of obese subjects with type 2 diabetes mellitus (T2DM). The sleeve prevents contact between chyme and the intestinal mucosa of the upper gastrointestinal tract. The primary aim of this study is to elucidate the changes in insulin sensitivity and beta-cell function after EndoBarrier™ implantation in obese patients with T2DM; changes in gut permeability and gut microbiome are also to be examined.

Methods: This is an open, single-center, prospective trial in which ten obese subjects with T2DM and suboptimal glycemic control (glycosylated hemoglobin A1 (HbA1c) level > 48 mmol/mol) are investigated with regards to EndoBarrier™ implantation. The Endobarrier™ is implanted shortly after baseline and left in situ for a period of 36 weeks. Dual-energy X-ray absorptiometry measurement, assessment of beta-cell function and insulin sensitivity as measured by a Botnia clamp procedure, and a mixed-meal tolerance test are performed prior to implantation and at 4, 36, and 64 weeks after implantation. The composition of the gut microbiota is characterized from stool using 454 pyrosequencing of 16S rRNA genes. Gut permeability is assessed by a differential sugar absorption method.

Planned Outcome: This study will give mechanistic insights in particulr into changes of insulin sensitivity, beta-cell function or microbiome changes over time in subjects implanted with an Endobarrier device.

Trial Registration: NCT02769728, Registered 12 May 2016. Current Protocol Date/Version: 04 September 2017/Version 1.9.
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http://dx.doi.org/10.1007/s13300-018-0540-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349299PMC
February 2019

Feasibility and safety of using an automated decision support system for insulin therapy in the treatment of steroid-induced hyperglycemia in patients with acute graft-versus-host disease: A randomized trial.

J Diabetes Investig 2019 Mar 1;10(2):339-342. Epub 2018 Oct 1.

Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria.

Steroid-induced hyperglycemia (SIHG) has shown to independently increase the risk for mortality in patients with acute graft-versus-host disease, and it is still unclear whether SIHG might be a modifiable risk factor. Therefore, a feasibility trial was carried out aiming to evaluate the performance of a standardized decision support system (GlucoTab [GT]) for insulin therapy in patients with SIHG. A total of 10 hyperglycemic acute graft-versus-host disease patients were included and treated either with GT or standard of care during hospitalization. Follow-up duration was 6 months. Comparing the GT versus standard of care group, 364 versus 1,020 glucose readings were available during a median of 41 days (interquartile range [IQR] 22-89) and 101 days (IQR 55-147) of hospitalization. The median overall glucose levels were 151 mg/dL (123-192) versus 162 mg/dL (IQR 138-193) for GT and standard of care, respectively (P < 0.001); hypoglycemia rates were comparably low. Treatment of SIHG with an algorithm-based system for subcutaneous insulin was feasible and safe.
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http://dx.doi.org/10.1111/jdi.12919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400241PMC
March 2019

Intermittent Fasting (Alternate Day Fasting) in Healthy, Non-obese Adults: Protocol for a Cohort Trial with an Embedded Randomized Controlled Pilot Trial.

Adv Ther 2018 Aug 25;35(8):1265-1283. Epub 2018 Jul 25.

Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background/objectives: Alternate day fasting (ADF) is a subtype of intermittent fasting and is defined as a continuous sequence of a fast day (100% energy restriction, zero calories) and a feed day (ad libitum food consumption), resulting in roughly 36-h fasting periods. Previous studies demonstrated weight reductions and improvements of cardiovascular risk factors with ADF in obese subjects. However, rigorous data on potential endocrine, metabolic and cardiovascular effects, besides weight loss, are lacking. Therefore we aim to investigate the short- and mid- to long-term clinical and molecular effects of ADF in healthy non-obese subjects.

Methods: We will perform a prospective cohort study with an embedded randomized controlled trial (RCT) including 90 healthy subjects. Thirty of them will have performed ADF for at least 6 months (mid-term group). Sixty healthy subjects without a particular diet before enrolment will serve as the control group. These subjects will be 1:1 randomized to either continuing their current diet or performing ADF for 4 weeks. All subjects will undergo study procedures that will be repeated in RCT participants after 4 weeks. These procedures will include assessment of outcome parameters, dual-energy X-ray absorptiometry, measurement of endothelial function, an oral glucose tolerance test, 24-h blood pressure measurement, retinal vessel analysis, echocardiography and physical activity measurement by an accelerometer. Blood, sputum, buccal mucosa and faeces will be collected for laboratory analyses. Participants in the RCT will wear a continuous glucose monitor to verify adherence to the study intervention.

Planned Outcomes: The aim of this project is to investigate the effects of ADF on human physiology and molecular cellular processes. This investigation should gain in-depth mechanistic insights into the concept of ADF and form the basis for larger subsequent cohort recruitment and consecutive intervention studies.

Trial Registration: NCT02673515; registered 24 November 2015. Current protocol date/version: 7 February 2017/version 1.8.
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http://dx.doi.org/10.1007/s12325-018-0746-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096974PMC
August 2018

Effects of linagliptin on endothelial function and postprandial lipids in coronary artery disease patients with early diabetes: a randomized, placebo-controlled, double-blind trial.

Cardiovasc Diabetol 2018 05 17;17(1):71. Epub 2018 May 17.

Cardiovascular Diabetology Research Group, Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.

Background: Early glucose lowering intervention in subjects with type 2 diabetes mellitus was demonstrated to be beneficial in terms of micro- and macrovascular risk reduction. However, most of currently ongoing cardiovascular outcome trials are performed in subjects with manifest atherosclerosis and long-standing diabetes. Therefore, the aim of this study is to investigate the effects of the dipeptidylpeptidase-4 inhibitor linagliptin in subjects with coronary artery disease (CAD) but early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements.

Methods: In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2 h glucose > 200 mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy and an HbA1c < 75 mmol/mol) and established CAD. Participants were randomized to receive either linagliptin (5 mg) once daily orally or placebo for 12 weeks. The primary outcome was the change in flow mediated dilatation (FMD). The secondary objective was to investigate the effect of linagliptin treatment on arginine bioavailability ratios [Global arginine bioavailability ratio (GABR) and arginine to ornithine ratio (AOR)]. Arginine, ornithine and citrulline were measured in serum samples with a conventional usual amino acid analysis technique, involving separation of amino acids by ion exchange chromatography followed by postcolumn continuous reaction with ninhydrin. GABR was calculated by L-arginine divided by the sum of (L-ornithine plus L-citrulline). The AOR was calculated by dividing L-arginine by L-ornithine levels. Group comparisons were calculated by using a two-sample t-test with Satterthwaite adjustment for unequal variances.

Results: We investigated 43 patients (21% female) with a mean age of 63.3 ± 8.2 years. FMD at baseline was 3.5 ± 3.1% in the linagliptin group vs. 4.0 ± 2.9% in the placebo group. The change in mean FMD in the linagliptin group was not significantly different compared to the change in the placebo group (0.43 ± 4.84% vs. - 0.45 ± 3.01%; p = 0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR; p = 0.608 and AOR; p = 0.549).

Conclusion: Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or the arginine bioavailability ratios. Trial registration ClinicalTrials.gov, NCT02350478 ( https://clinicaltrials.gov/ct2/show/NCT02350478 ).
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http://dx.doi.org/10.1186/s12933-018-0716-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958406PMC
May 2018

Combined serum free light chain levels are associated with carotid atherosclerosis in type 2 diabetes mellitus.

Diab Vasc Dis Res 2018 03 30;15(2):162-164. Epub 2017 Nov 30.

1 Division of Endocrinology and Diabetology, Cardiovascular Diabetology Research Group, Medical University of Graz, Graz, Austria.

Background: Patients with type 2 diabetes mellitus face an increased risk of cardiovascular events compared to non-diabetic counterparts. Chronic inflammation and activation of the immune system, including B-lymphocyte maturation is believed to play a role in atherosclerosis. Recent investigations suggest combined serum free light chains as a potential biomarker for cardiovascular events. The aim of this analysis was to investigate the association of combined serum free light chain with carotid atherosclerosis in subjects with type 2 diabetes mellitus.

Methods: We performed a cross-sectional analysis of data from a prospective single centre 2-year study of 97 patients with type 2 diabetes mellitus and insufficiently controlled cardiovascular risk factors. Complete data on combined serum free light chain, high-sensitivity C-reactive protein were available for 75 subjects.

Results: We analysed data of 26 female and 49 male subjects, aged 59 ± 8 years. Their mean body mass index was 31.6 ± 4.4 kg/m, and the median B-score was 2 (interquartile range: 0-3). Significant positive correlations between combined serum free light chain and the B-score ( r = 0.38; p = 0.001) as well as combined serum free light chain and high-sensitivity C-reactive protein ( r = 0.35; p = 0.002) were observed. The adjusted odds ratio for a half standard deviation increase in combined serum free light chain was 1.48 (95% confidence interval: 1.05-2.05) in an ordinal regression model for carotid B-score.

Conclusion: In our study, combined serum free light chain was associated with carotid atherosclerosis in subjects with type 2 diabetes mellitus.
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http://dx.doi.org/10.1177/1479164117743939DOI Listing
March 2018

The effects of linagliptin on endothelial function and global arginine bioavailability ratio in coronary artery disease patients with early diabetes: study protocol for a randomized controlled trial.

Trials 2016 10 13;17(1):495. Epub 2016 Oct 13.

Department of Internal Medicine, Division of Endocrinology and Diabetology, Cardiovascular Diabetology Research Group, Medical University of Graz, Graz, Austria.

Background: Patients with type 2 diabetes (T2DM) are at increased risk for macrovascular events as well as for microvascular complications. There is evidence that in patients with coronary artery disease (CAD), about 35 % suffer from manifest T2DM. Early glucose-lowering intervention in subjects with T2DM has been demonstrated to be beneficial in terms of cardiovascular risk reduction. But thus far, no data are available regarding investigating the impact of linagliptin treatment in patients with early diabetes on cardiovascular endpoints or surrogate parameters. Therefore, the aim of this study is to investigate the effects of linagliptin in CAD patients with early T2DM on various cardiovascular surrogate measurements including mechanical and biochemical endothelial function assessments.

Methods/design: Forty-two subjects with early diabetes and CAD are included in this investigator-driven, randomized, placebo-controlled, double-blind, phase IV, single-center study. Participants will be randomized to receive either linagliptin (5 mg) administered once daily per os or placebo for 12 weeks. Before and after the intervention, evaluation of endothelial function (flow-mediated dilatation and biochemical biomarkers) and a Meal Tolerance Test are performed.

Discussion: Cardiovascular surrogate parameters, such as endothelial function, are able to provide insights into the potential mechanisms of the cardiovascular effects of antihyperglycemic agents. Currently ongoing trials do not specifically focus on early diabetes as a target of intervention and we therefore believe that our study will contribute to a better understanding of the cardiovascular effects of dipeptidylpeptidase-4 (DPP-4) inhibitors in early diabetes.

Trial Registration: NCT02350478 . Registered 26 January 2015. Protocol date/version 24 October 2014/version 2.4 EudraCT number: 2013-000330-35.
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http://dx.doi.org/10.1186/s13063-016-1627-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062940PMC
October 2016

Lactobacillus casei Shirota Supplementation Does Not Restore Gut Microbiota Composition and Gut Barrier in Metabolic Syndrome: A Randomized Pilot Study.

PLoS One 2015 28;10(10):e0141399. Epub 2015 Oct 28.

Medical University of Graz, Division of Endocrinology and Metabolism, Graz, Austria; Centre for Biomarker Research in Medicine (CBmed), Graz, Austria.

Unlabelled: Metabolic syndrome is associated with disturbances in gut microbiota composition. We aimed to investigate the effect of Lactobacillus casei Shirota (LcS) on gut microbiota composition, gut barrier integrity, intestinal inflammation and serum bile acid profile in metabolic syndrome. In a single-centre, prospective, randomised controlled pilot study, 28 subjects with metabolic syndrome received either LcS for 12 weeks (n = 13) or no LcS (n = 15). Data were compared to healthy controls (n = 16). Gut microbiota composition was characterised from stool using 454 pyrosequencing of 16S rRNA genes. Serum bile acids were quantified by tandem mass spectrometry. Zonulin and calprotectin were measured in serum and stool by ELISA. Bacteroidetes/Firmicutes ratio was significantly higher in healthy controls compared to metabolic syndrome but was not influenced by LcS. LcS supplementation led to enrichment of Parabacteroides. Zonulin and calprotectin were increased in metabolic syndrome stool samples but not influenced by LcS supplementation. Serum bile acids were similar to controls and not influenced by LcS supplementation. Metabolic syndrome is associated with a higher Bacteroidetes/Firmicutes ratio and gut barrier dysfunction but LcS was not able to change this. LcS administration was associated with subtle microbiota changes at genus level.

Trial Registration: ClinicalTrials.gov NCT01182844.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141399PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625062PMC
June 2016

Effect of Lactobacillus casei Shirota supplementation on trimethylamine-N-oxide levels in patients with metabolic syndrome: An open-label, randomized study.

Atherosclerosis 2015 Sep 8;242(1):141-4. Epub 2015 Jul 8.

Medical University of Graz, Department of Internal Medicine, Division of Endocrinology and Metabolism, Cardiovascular Diabetology Research Group, Graz, Austria; Centre for Biomarker Research in Medicine (CBmed), Graz, Austria. Electronic address:

Background: Recent studies in animal models have shown a link between ingestion of dietary phosphatidylcholine (PC), choline, l-carnitine and cardiovascular risk. Intestinal microbiota-dependent metabolism of PC and l-carnitine is involved in formation of trimethylamine (TMA), which is further metabolized to the proatherogenic compound trimethylamine-N-oxide (TMAO). It has been suggested that changes in gut microbiota by supplementation of probiotic drinks might alter TMAO levels. Hence, the aim of this analysis was to investigate the impact of Lactobacillus casei Shirota (LcS) on formation of TMAO in subjects with metabolic syndrome.

Methods: In a single-center, prospective, randomized-controlled study 30 subjects with metabolic syndrome were randomized to receive either 3 times daily 6.5 × 10(9) CFU (colony-forming units) LcS (probiotic group) or not (standard therapy group) for 12 weeks. TMAO plasma levels were quantified by means of liquid chromatography and tandem mass spectrometry.

Results: Thirteen patients in the probiotic group and 15 in the standard therapy group finished the study. Mean age was 52 ± 11 and 55 ± 9 years, respectively. TMAO levels decreased during the intervention period in both groups (from 4.66 ± 2.66 μM to 4.31 ± 2.04 μM in the probiotic group and from 4.64 ± 2.75 μM to 4.40 ± 2.14 μM in the control group). Changes in TMAO between subjects receiving LcS (-0.25 ± 2.39 μM) and controls (-0.34 ± 2.23 μM) were not significantly different (p = 0.510).

Conclusion: In conclusion, intake of LcS for 12 weeks did not affect levels of TMAO in patients with metabolic syndrome.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.05.005DOI Listing
September 2015

Sonographic assessment of interstitial lung disease in patients with rheumatoid arthritis, systemic sclerosis and systemic lupus erythematosus.

Clin Exp Rheumatol 2015 Jul-Aug;33(4 Suppl 91):S87-91. Epub 2015 Jan 29.

Division of Rheumatology, Medical University of Graz, Graz, Austria.

Objectives: The usefulness of transthoracic ultrasound in the evaluation of lung diseases has been highlighted in the past decades. The aim of our study is to determine the diagnostic value of lung ultrasound in the detection of interstitial pulmonary fibrosis in patients with a rheumatic disease. Furthermore, we studied the possible correlation between the underlying disease and the frequency of pathological ultrasound findings.

Methods: A sample of 45 consecutive patients with RA (n=25), SSc (n=14) and SLE (n=6) and 40 healthy volunteers were enrolled into the study. Every study patient underwent both, lung sonography and HRCT. The following ultrasound findings were documented in each study patient: B- lines, subpleural nodes and irregularities of the pleura. HRCT was analysed by an experienced radiologist blind to sonography findings.

Results: Twenty-eight percent of the RA cohort, 64% of the SSc patients and four out of 6 SLE patients showed ILD on HRCT. Pathological ultrasound patterns were significant more frequent in the ILD group than in the non-ILD group (comet tail artifacts/B-pattern: 100% vs. 12%, p<0.001; subpleural nodes: 55 % vs. 17%, p=0.006; thickenings of the pleural line: 95% vs. 12.5%, p<0.001). Subpleural nodes were present in 100% of the RA patients vs. 22% the SSc patients (p=0.003) and 50% of the SLE patients (p=0.049) with ILD. An irregular pleural line>3 mm was documented in 100% of SSC and SLE patients with ILD, vs. 86% of ILD patients suffering from RA (p=ns).

Conclusions: Transthoracic ultrasound of the lung might be a sensitive non-invasive tool to observe early stage interstitial lung disease in rheumatic diseases.
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October 2015

Multiple risk factor intervention reduces carotid atherosclerosis in patients with type 2 diabetes.

Cardiovasc Diabetol 2014 May 23;13:95. Epub 2014 May 23.

Department for Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria.

Background: Patients with rapid progression of carotid intima media thickness (CIMT) were shown to have a higher future risk for cardiovascular events.The aim of this study was to investigate the impact of multiple risk factor intervention on CIMT progression and to establish whether new cardiovascular surrogate measurements would allow prediction of CIMT changes.

Materials And Methods: In this prospective, open, 2-years study, we included 97 patients with type 2 diabetes and at least two insufficiently treated cardiovascular risk factors, i.e. HbA1c > 7.5% (58 mmol/mol); LDL-cholesterol >3.1 mmol/l or blood pressure >140/90 mmHg. Treatment was intensified according to current guidelines over 3 months with the aim to maintain intensification over 2 years.The primary outcome was the change in CIMT after 2 years. We also assessed markers of mechanical and biochemical endothelial function and endothelial progenitor cells before and after 3 months of treatment intensification. For testing differences between before and after multifactorial treatment measurements we used either the paired student's t-test or the Wilcoxon signed-rank test, depending on the distribution of the data. Additional, explorative statistical data analysis was done on CIMT progression building a linear multivariate regression model.

Results: Blood glucose, lipids and blood pressure significantly improved during the first 3 months of intensified treatment, which was sustained over the 2-year study duration. Mean CIMT significantly decreased from baseline to 2 year (0.883 ± 0.120 mm vs. 0.860 ± 0.130 mm; p = 0.021). None of the investigated surrogate measures, however, was able to predict changes in IMT early after treatment intensification.

Conclusions: Intensification of risk factor intervention in type 2 diabetes results in CIMT regression over a period of 2 years. None of the biomarkers used including endothelial function parameters or endothelial progenitor cells turned out to be useful to predict CIMT changes.

Trial Registration: Clinical Trial Registration - Unique identifier: NCT00660790.
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http://dx.doi.org/10.1186/1475-2840-13-95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041351PMC
May 2014

A retrospective analysis of securing autologous split-thickness skin grafts with negative pressure wound therapy in paediatric burn patients.

Burns 2014 Sep 15;40(6):1116-20. Epub 2014 Jan 15.

Children's Burn Unit, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.

Background And Aim: Deep dermal and full-thickness burn wounds are excised and grafted with split-thickness skin grafts. Especially in less compliant patients such as young children, conventional fixing methods can often be ineffective due to high mobility rates in this age group. The aim of this retrospective single-centre study was to give an overview of our experience in the fixation of autologous split-thickness skin grafts (ASTSGs) on burn wounds by negative pressure wound therapy (NPWT) in paediatric patients.

Methods: A retrospective analysis describing 53 paediatric patients with burns or burn-related injuries who were treated as 60 individual cases were conducted. All patients received ASTSGs secured by NPWT.

Results: Of the individual cases, 60 cases with a mean age of 8±6 years (the youngest was 3 months, the eldest was 24 years old) were treated in a single procedure with ASTSG and NPWT. Total burn surface area (TBSA) was, median (med) 4.5% (3.0-12.0%). The TBSA of deep dermal thickness to full-thickness (IIb-III°) burns was med 4.0% (2.0-6.0%). The TBSA treated with ASTSG and NPWT was med 3.5% (2.0-6.0%). Take rate was, med 96% (90-99%) with a total range of 70-100%. The only significant correlation that could be found was between the grafted TBSA and the take rate. The smaller the grafted TBSA the better the take rate resulted, as expected. In three cases, major complications were noted.

Conclusion: To sum up our experience, the NPWT system has developed itself to be a constant, well-implemented and useful tool in securing ASTSGs to the wound bed. The main advantage of the technique is a much higher mobility of the patient compared to conventional fixation methods. The high compliance rate of an often challenging group of patients such as children recompenses possible higher costs compared to conventional fixation methods.
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http://dx.doi.org/10.1016/j.burns.2013.12.007DOI Listing
September 2014