Publications by authors named "Mikkel Christensen"

151 Publications

Glucagon Clearance is Preserved in Type 2 Diabetes.

Diabetes 2021 Oct 21. Epub 2021 Oct 21.

Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.

Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to the hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Each participant underwent a 1-hour glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-hour wash-out period. Plasma levels, the metabolic clearance rate (MCR), half-life (T½) and volume of distribution of glucagon were evaluated and a pharmacokinetic model was constructed. Glucagon MCR and volume of distribution were significantly higher in the type 2 diabetes group compared to the control group, while no significant differences between the groups were found in glucagon T½. Individuals with obesity had neither a significantly decreased MCR, T½, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positively with fasting plasma glucose and negatively with body weight. In conclusion, our results suggest that impaired glucagon clearance is not a fundamental part of the hyperglucagonemia observed in obesity and type 2 diabetes.
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http://dx.doi.org/10.2337/db21-0024DOI Listing
October 2021

High natural PHA production from acetate in Cobetia sp. MC34 and Cobetia marina DSM 4741 and in silico analyses of the genus specific PhaC polymerase variant.

Microb Cell Fact 2021 Dec 20;20(1):225. Epub 2021 Dec 20.

Department of Chemistry, UiT-The Arctic University of Norway, 9037, Tromsø, Norway.

Background: Several members of the bacterial Halomonadacea family are natural producers of polyhydroxyalkanoates (PHA), which are promising materials for use as biodegradable bioplastics. Type-strain species of Cobetia are designated PHA positive, and recent studies have demonstrated relatively high PHA production for a few strains within this genus. Industrially relevant PHA producers may therefore be present among uncharacterized or less explored members. In this study, we characterized PHA production in two marine Cobetia strains. We further analyzed their genomes to elucidate pha genes and metabolic pathways which may facilitate future optimization of PHA production in these strains.

Results: Cobetia sp. MC34 and Cobetia marina DSM 4741 were mesophilic, halotolerant, and produced PHA from four pure substrates. Sodium acetate with- and without co-supplementation of sodium valerate resulted in high PHA production titers, with production of up to 2.5 g poly(3-hydroxybutyrate) (PHB)/L and 2.1 g poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV)/L in Cobetia sp. MC34, while C. marina DSM 4741 produced 2.4 g PHB/L and 3.7 g PHBV/L. Cobetia marina DSM 4741 also showed production of 2.5 g PHB/L from glycerol. The genome of Cobetia sp. MC34 was sequenced and phylogenetic analyses revealed closest relationship to Cobetia amphilecti. PHA biosynthesis genes were located at separate loci similar to the arrangement in other Halomonadacea. Further genome analyses revealed some differences in acetate- and propanoate metabolism genes between the two strains. Interestingly, only a single PHA polymerase gene (phaC) was found in Cobetia sp. MC34, in contrast to two copies (phaC and phaC) in C. marina DSM 4741. In silico analyses based on phaC genes show that the PhaC variant is conserved in Cobetia and contains an extended C-terminus with a high isoelectric point and putative DNA-binding domains.

Conclusions: Cobetia sp. MC34 and C. marina DSM 4741 are natural producers of PHB and PHBV from industrially relevant pure substrates including acetate. However, further scale up, optimization of growth conditions, or use of metabolic engineering is required to obtain industrially relevant PHA production titers. The putative role of the Cobetia PhaC variant in DNA-binding and the potential implications remains to be addressed by in vitro- or in vivo methods.
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http://dx.doi.org/10.1186/s12934-021-01713-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8686332PMC
December 2021

Ensembl Genomes 2022: an expanding genome resource for non-vertebrates.

Nucleic Acids Res 2022 Jan;50(D1):D996-D1003

Cold Spring Harbor Laboratory, 1 Bungtown Rd, Cold Spring Harbor, NY 11724, USA.

Ensembl Genomes (https://www.ensemblgenomes.org) provides access to non-vertebrate genomes and analysis complementing vertebrate resources developed by the Ensembl project (https://www.ensembl.org). The two resources collectively present genome annotation through a consistent set of interfaces spanning the tree of life presenting genome sequence, annotation, variation, transcriptomic data and comparative analysis. Here, we present our largest increase in plant, metazoan and fungal genomes since the project's inception creating one of the world's most comprehensive genomic resources and describe our efforts to reduce genome redundancy in our Bacteria portal. We detail our new efforts in gene annotation, our emerging support for pangenome analysis, our efforts to accelerate data dissemination through the Ensembl Rapid Release resource and our new AlphaFold visualization. Finally, we present details of our future plans including updates on our integration with Ensembl, and how we plan to improve our support for the microbial research community. Software and data are made available without restriction via our website, online tools platform and programmatic interfaces (available under an Apache 2.0 license). Data updates are synchronised with Ensembl's release cycle.
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http://dx.doi.org/10.1093/nar/gkab1007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728113PMC
January 2022

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.

Elife 2021 11 17;10. Epub 2021 Nov 17.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.

Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.
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http://dx.doi.org/10.7554/eLife.72919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654374PMC
November 2021

VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center.

Nucleic Acids Res 2022 Jan;50(D1):D898-D911

Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) represents the 2019 merger of VectorBase with the EuPathDB projects. As a Bioinformatics Resource Center funded by the National Institutes of Health, with additional support from the Welllcome Trust, VEuPathDB supports >500 organisms comprising invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Designed to empower researchers with access to Omics data and bioinformatic analyses, VEuPathDB projects integrate >1700 pre-analysed datasets (and associated metadata) with advanced search capabilities, visualizations, and analysis tools in a graphic interface. Diverse data types are analysed with standardized workflows including an in-house OrthoMCL algorithm for predicting orthology. Comparisons are easily made across datasets, data types and organisms in this unique data mining platform. A new site-wide search facilitates access for both experienced and novice users. Upgraded infrastructure and workflows support numerous updates to the web interface, tools, searches and strategies, and Galaxy workspace where users can privately analyse their own data. Forthcoming upgrades include cloud-ready application architecture, expanded support for the Galaxy workspace, tools for interrogating host-pathogen interactions, and improved interactions with affiliated databases (ClinEpiDB, MicrobiomeDB) and other scientific resources, and increased interoperability with the Bacterial & Viral BRC.
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http://dx.doi.org/10.1093/nar/gkab929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728164PMC
January 2022

Glucagon Clearance is Preserved in Type 2 Diabetes.

Diabetes 2021 Oct 26. Epub 2021 Oct 26.

Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark,

Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to the hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Each participant underwent a 1-hour glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-hour wash-out period. Plasma levels, the metabolic clearance rate (MCR), half-life (T) and volume of distribution of glucagon were evaluated and a pharmacokinetic model was constructed. Glucagon MCR and volume of distribution were significantly higher in the type 2 diabetes group compared to the control group, while no significant differences between the groups were found in glucagon T Individuals with obesity had neither a significantly decreased MCR, T, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positively with fasting plasma glucose and negatively with body weight. In conclusion, our results suggest that impaired glucagon clearance is not a fundamental part of the hyperglucagonemia observed in obesity and type 2 diabetes.
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http://dx.doi.org/10.2337/db21-0024DOI Listing
October 2021

Glucose-dependent insulinotropic polypeptide induces lipolysis during stable basal insulin substitution and hyperglycaemia in men with type 1 diabetes: A randomized, double-blind, placebo-controlled, crossover clinical trial.

Diabetes Obes Metab 2022 Jan 20;24(1):142-147. Epub 2021 Sep 20.

Centre for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.

Glucose-dependent insulinotropic polypeptide (GIP) plays an important role in the glucose and lipid metabolism. We investigated the effects of exogenous GIP on lipid metabolism during time of stable insulin levels. Ten male patients with type 1 diabetes without endogenous insulin secretion (C-peptide-negative, mean [±SD] age 26 ± 4years, body mass index 24 [±2] kg/m , glycated haemoglobin 56 [±8] mmol/mol or 7.3 [±0.8]%) were studied in a randomized, double-blind, placebo-controlled, crossover study with continuous intravenous infusions of GIP (4 pmol/kg/min) or placebo (saline), during two separate 90-minute hyperglycaemic (12 mmol/L) clamps with basal insulin substitution (0.1-0.2 mU/kg/min). Plasma glycerol concentrations increased from baseline during GIP infusion and decreased during placebo infusion (baseline-subtracted area under the curve [bsAUC] 703 ± 407 vs. -262 ± 240 μmol/L × min, respectively; P < 0.001). Free fatty acids (FFAs) increased during GIP infusions (bsAUC 5505 ± 2170 μEq/L × min) and remained unchanged during placebo infusion (bsAUC -74 ± 2363 μEq/L × min), resulting in a significant difference between GIP and placebo infusions (P < 0.001). Plasma concentrations of glucose, insulin, glucagon-like peptide-1 and glucagon were similar during GIP and placebo infusions. GIP increased plasma glycerol and FFAs in patients with type 1 diabetes during hyperglycaemia and stable basal insulin levels. This supports a direct lipolytic effect of GIP at high glucose and low levels of plasma insulin.
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http://dx.doi.org/10.1111/dom.14545DOI Listing
January 2022

The effect of 6-day subcutaneous glucose-dependent insulinotropic polypeptide infusion on time in glycaemic range in patients with type 1 diabetes: a randomised, double-blind, placebo-controlled crossover trial.

Diabetologia 2021 Nov 17;64(11):2425-2431. Epub 2021 Aug 17.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Aims/hypothesis: Type 1 diabetes is characterised by reduced glucagon response to hypoglycaemia, increasing the risk of insulin treatment-associated hypoglycaemia known to hamper glycaemic control. We previously reported a glucagonotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) during insulin-induced hypoglycaemia in individuals with type 1 diabetes. Here we investigate the effect of a 6-day s.c. GIP infusion on time in glycaemic range as assessed by continuous glucose monitoring (CGM) in individuals with type 1 diabetes.

Methods: In a randomised, placebo-controlled, double-blind crossover study, time in glycaemic range (assessed by double-blinded CGM) was evaluated in 20 men with type 1 diabetes (18-75 years, stable insulin treatment ≥3 months, diabetes duration 2-15 years, fasting plasma C-peptide below 200 pmol/l, BMI 20-27 kg/m, HbA <69 mmol/mol [8.5%]) during two × 6 days of continuous s.c. GIP (6 pmol kg min) and placebo (saline [154 mmol/l NaCl]) infusion, respectively, with an interposed 7-day washout period. The primary outcome was glycaemic time below range, time in range and time above range.

Results: There were no significant differences in time below range (<3.9 mmol/l, p = 0.53) or above range (>10 mmol/l, p = 0.32) during night-time or daytime, in mean glucose, or in hypoglycaemic events as assessed by CGM. GIP altered neither self-reported hypoglycaemia nor safety measures. Compared with placebo, GIP significantly increased time in tight range (3.9-7.8 mmol/l) during daytime (06:00-23:59 hours) by [mean ± SEM] 11.2 ± 5.1% [95% CI 0.41, 21.9] (p = 0.02).

Conclusions/interpretation: Six-day s.c. GIP infusion in men with type 1 diabetes did not procure convincing effect on overall time in range, but increased time in tight glycaemic range during daytime by ~2 h per day.

Trial Registration: ClinicalTrials.gov NCT03734718.

Funding: The study was funded by grants from The Leona M. and Harry B. Helmsley Charitable Trust and Aase og Ejnar Danielsens Fond.
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http://dx.doi.org/10.1007/s00125-021-05547-8DOI Listing
November 2021

MECHANISMS IN ENDOCRINOLOGY: The physiology of neuronostatin.

Eur J Endocrinol 2021 Sep 1;185(4):R93-R101. Epub 2021 Sep 1.

Center for Clinical Metabolic Research, Department of Medicine, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability.
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http://dx.doi.org/10.1530/EJE-21-0347DOI Listing
September 2021

Exendin(9-39)NH : Recommendations for clinical use based on a systematic literature review.

Diabetes Obes Metab 2021 11 23;23(11):2419-2436. Epub 2021 Aug 23.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Aim: To present an overview of exendin(9-39)NH usage as a scientific tool in humans and provide recommendations for dosage and infusion regimes.

Methods: We systematically searched the literature on exendin(9-39)NH and included for review 44 clinical studies reporting use of exendin(9-39)NH in humans.

Results: Exendin(9-39)NH binds to the orthosteric binding site of the glucagon-like peptide-1 (GLP-1) receptor with high affinity. The plasma elimination half-life of exendin(9-39)NH after intravenous administration is ~30 minutes, requiring ~2.5 hours of constant infusion before steady-state plasma concentrations can be expected. Studies utilizing infusions with exendin(9-39)NH in humans have applied varying regimens (priming with a bolus or constant infusion) and dosages (continuous infusion rate range 30-900 pmol/kg/min) with subsequent differences in effects. Administration of exendin(9-39)NH in healthy individuals, patients with diabetes, obese patients, and patients who have undergone bariatric surgery significantly increases fasting and postprandial levels of glucose and glucagon, but has inconsistent effects on circulating concentrations of insulin and C-peptide, gastric emptying, appetite sensations, and food intake. Importantly, exendin(9-39)NH induces secretion of all L cell products (ie, in addition to GLP-1, also peptide YY, glucagon-like peptide-2, oxyntomodulin, and glicentin) complicating use of exendin(9-39)NH as a tool to study the isolated effect of GLP-1.

Conclusions: Exendin(9-39)NH is selective for the GLP-1 receptor, with numerous and complex whole-body effects. To obtain GLP-1 receptor blockade in humans, we recommend an initial high-dose infusion, followed by a continuous infusion rate aiming at a ratio of exendin(9-39)NH to GLP-1 of 2000:1. Highlights Exendin(9-39)NH is a competitive antagonist of the human GLP-1 receptor. Exendin(9-39)NH has been used as a tool to delineate human GLP-1 physiology since 1998. Exendin(9-39)NH induces secretion of GLP-1 and other L cell products. Reported effects of exendin(9-39)NH on insulin levels and food intake are inconsistent. Here, we provide recommendations for the use of exendin(9-39)NH in clinical studies.
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http://dx.doi.org/10.1111/dom.14507DOI Listing
November 2021

Low-dose aspirin for primary and secondary prevention of cardiovascular events in Denmark 1998-2018.

Sci Rep 2021 06 30;11(1):13603. Epub 2021 Jun 30.

Department of Cardiology, Aarhus University Hospital, 8200, Aarhus, Denmark.

Randomised controlled trials have shown a neutral or even unfavourable risk-benefit balance of aspirin for primary prevention of cardiovascular events. Using Danish nationwide registries, we investigated aspirin use and associated risks during the past two decades (1998-2018). We linked individual patient data on repeated aspirin redemptions with registered hospital ICD-10 diagnoses of atherosclerotic cardiovascular disease and bleedings. The prevalence of aspirin use among 1.1 million Danish adults fluctuated over the 20-year study period peaking in 2008 with 8.5% (5.4% primary prevention) and dropping to 5.1% (3.1% primary prevention) in 2018. Aspirin use showed strong age dependency, and 21% of individuals > 80 years were treated with aspirin for primary prevention in 2018. Medication adding to bleeding risk was used concurrently by 21% of all aspirin users in 2018. The incidence of major bleedings were similar with primary and secondary prevention aspirin use and highest in elderly (2 per 100 patient years among individuals > 80 years in 2018). In conclusion, low-dose aspirin use for primary prevention of cardiovascular events remains prevalent. The widespread use of aspirin, especially among older adults, and substantial concomitant use of medications adding to bleeding risk warrant increased focus on discontinuation of inappropriate aspirin use.
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http://dx.doi.org/10.1038/s41598-021-93179-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245534PMC
June 2021

Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity.

Expert Opin Emerg Drugs 2021 Sep 6;26(3):231-243. Epub 2021 Jul 6.

Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.

: Obesity is a growing threat to public health, increasing risks of numerous diseases and mortality, and impairing quality of life. If current trends continue, more than 1.1 billion individuals will have obesity in 2030, corresponding to almost 2.5 times the number of adults currently living with diabetes. There is a strong interest in developing obesity treatments based on glucagon-like peptide-1 (GLP-1) agonism, which have proved to limit morbidity and mortality in type 2 diabetes.: This review provides an overview of current compounds containing GLP-1 receptor agonism in clinical development for obesity, with mono-activity at the GLP-1 receptor (PF-0688296, glutazumab, semaglutide) or engaging one or more other endogenous hormonal systems involved in energy balance and metabolism, including glucagon, oxyntomodulin, glucose-dependent inhibitory peptide and amylin (CT-868, CT-388, AMG 133, tirzepatide, NNC9204-1177, JNJ-54,728,518, SAR425899, pegapamodutide, MK8521, cotadutide, efinopegdutide, BI-456,906, cagrilintide + semaglutide 2,4 mg, HM15211, NNC9204-1706).: Many novel compounds employing GLP-1 receptor agonism are in clinical development. Semaglutide is farthest in clinical development and will presumably become a benchmark for this class of novel anti-obesity compounds.
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http://dx.doi.org/10.1080/14728214.2021.1947240DOI Listing
September 2021

Causes of discrepancies between medications listed in the national electronic prescribing system and patients' actual use of medications.

Basic Clin Pharmacol Toxicol 2021 Sep 28;129(3):221-231. Epub 2021 Jun 28.

Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark.

Discrepancies between registered prescriptions and patients' actual use of medications are described as frequent and often resulting in adverse medication events. We aimed to assess the extent of and causes behind discrepancies between medications listed in the Danish national prescription system (Shared Medication Record) and patients' actual use of medications. We prospectively reconciled medication for 260 consecutively admitted polypharmacy patients (>50 years and ≥5 prescriptions) at two hospitals in the Capital Region of Denmark. The type of discrepancies were determined and the cause of the discrepancies were evaluated as primarily caused by (1) the patient (i.e., intentional or unintentional non-adherence) or (2) the health care system (i.e., lack of appropriate update of the SMR by physicians in primary or secondary care). There was a median of 12 [IQR 9-15] medications listed and 3 [IQR 1-5] medication discrepancies per patient (total n = 925). The majority (53%) of discrepancies were caused by the health care system, 32% were caused by the patients, of which 70% were intentional non-adherence, and 15% had an indeterminable cause. In conclusion, discrepancies between medications listed in the Shared Medication Record and actual use of medications were frequent and were most often caused by clinicians not updating the prescription information.
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http://dx.doi.org/10.1111/bcpt.13626DOI Listing
September 2021

Acute hypoglycemia and risk of cardiac arrhythmias in insulin-treated type 2 diabetes and controls.

Eur J Endocrinol 2021 Jul 21;185(2):343-353. Epub 2021 Jul 21.

Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark.

Objective: Hypoglycemia is associated with an increased risk of cardiovascular disease including cardiac arrhythmias. We investigated the effect of hypoglycemia in the setting of acute glycemic fluctuations on cardiac rhythm and cardiac repolarization in insulin-treated patients with type 2 diabetes compared with matched controls without diabetes.

Design: A non-randomized, mechanistic intervention study.

Methods: Insulin-treated patients with type 2 diabetes (n = 21, age (mean ± s.d.): 62.8 ± 6.5 years, BMI: 29.0 ± 4.2 kg/m2, HbA1c: 6.8 ± 0.5% (51.0 ± 5.4 mmol/mol)) and matched controls (n = 21, age: 62.2 ± 8.3 years, BMI 29.2 ± 3.5 kg/m2, HbA1c: 5.3 ± 0.3% (34.3 ± 3.3 mmol/mol)) underwent a sequential hyperglycemic and hypoglycemic clamp with three steady-states of plasma glucose: (i) fasting plasma glucose, (ii) hyperglycemia (fasting plasma glucose +10 mmol/L) and (iii) hyperinsulinemic hypoglycemia (plasma glucose < 3.0 mmol/L). Participants underwent continuous ECG monitoring and blood samples for counterregulatory hormones and plasma potassium were obtained.

Results: Both groups experienced progressively increasing heart rate corrected QT (Fridericia's formula) interval prolongations during hypoglycemia ((∆mean (95% CI): 31 ms (16, 45) and 39 ms (24, 53) in the group of patients with type 2 diabetes and controls, respectively) with similar increases from baseline at the end of the hypoglycemic phase (P = 0.43). The incidence of ventricular premature beats increased significantly in both groups during hypoglycemia (P = 0.033 and P < 0.0001, respectively). One patient with type 2 diabetes developed atrial fibrillation during recovery from hypoglycemia.

Conclusions: In insulin-treated patients with type 2 diabetes and controls without diabetes, hypoglycemia causes clinically significant and similar increases in cardiac repolarization that might increase vulnerability for serious cardiac arrhythmias and sudden cardiac death.
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http://dx.doi.org/10.1530/EJE-21-0232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345897PMC
July 2021

The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide.

Front Mol Biosci 2021 22;8:657946. Epub 2021 Apr 22.

Department of Chemistry, Aarhus University, Aarhus, Denmark.

Islet amyloid polypeptide (IAPP) is a proposed cause of the decreased beta-cell mass in patients with type-II diabetes. The molecular composition of the cell-membrane is important for regulating IAPP cytotoxicity and aggregation. Cholesterol is present at high concentrations in the pancreatic beta-cells, and in-vitro experiments have indicated that it affects the amyloid formation of IAPP either by direct interactions or by changing the properties of the membrane. In this study we apply atomistic, unbiased molecular dynamics simulations at a microsecond timescale to investigate the effect of cholesterol on membrane bound IAPP. Simulations were performed with various combinations of cholesterol, phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. In all simulations, the helical structure of monomer IAPP was stabilized by the membrane. We found that cholesterol decreased the insertion depth of IAPP compared to pure phospholipid membranes, while PS lipids counteract the effect of cholesterol. The aggregation propensity has previously been proposed to correlate with the insertion depth of IAPP, which we found to decrease with the increased ordering of the lipids induced by cholesterol. Cholesterol is depleted in the vicinity of IAPP, and thus our results suggest that the effect of cholesterol is indirect.
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http://dx.doi.org/10.3389/fmolb.2021.657946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100463PMC
April 2021

Pancreatic polypeptide: A potential biomarker of glucose-dependent insulinotropic polypeptide receptor activation in vivo.

Diabet Med 2021 Aug 17;38(8):e14592. Epub 2021 May 17.

Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark.

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http://dx.doi.org/10.1111/dme.14592DOI Listing
August 2021

Medication errors in residential facilities based on Danish Poison Information Center inquiries.

Dan Med J 2021 Apr 28;68(5). Epub 2021 Apr 28.

Introduction: This study describes the types and health consequences of medication errors in residential facilities for which the Danish Poison Information Center (DPIC) was contacted.

Methods: This study is based on all inquiries made by residential facilities to the DPIC during a 13-month period. Information about inquirers and residents, data related to the medication error, symptoms, risk assessments and recommendations was collected, and a follow-up phone call was made to evaluate the clinical outcomes, preferably within one week.

Results: During the study period, the DPIC received 146 inquiries concerning medication errors in residential facilities. Nearly all inquiries concerned excess administration of medication (96%) and often involved medications targeting the nervous system (65%). In 9% of cases, the DPIC recommended hospitalisation. Most medication errors (92%) were considered of "no or minor risk". Administration of medication to the wrong resident is a frequent reason for consulting the DPIC (45%) in cases with medication errors.

Conclusions: In this study, we inventoried the inquiries made to the DPIC about medication errors in residential facilities in Denmark. Most medication errors did not carry a risk of serious health consequences, but continued monitoring is warranted to minimise risk in this vulnerable population.

Funding: Copenhagen Center for Health Technology (5001105002), Department of Clinical Pharmacology (Bispebjerg Hospital, The Capital Region) (1152871001).

Trial Registration: not relevant.
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April 2021

Effects of endogenous GIP in patients with type 2 diabetes.

Eur J Endocrinol 2021 May 21;185(1):33-45. Epub 2021 May 21.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Objective: The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved.

Design: A randomized, double-blinded, placebo-controlled, crossover study.

Methods: Ten patients with overweight/obesity and type 2 diabetes (mean±s.d.; HbA1c 52 ± 11 mmol/mol; BMI 32.5 ± 4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1200 pmol/kg/min), or placebo (saline) during two separate, 230-min, standardized, liquid mixed meal tests followed by a meal ad libitum. Subcutaneous adipose tissue biopsies were analyzed.

Results: Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide% ± s.e.m.; -14 ± 6%, P = 0.021) and peak glucagon (Δ% ± s.e.m.; -11 ± 6%, P = 0.046) but had no effect on plasma glucose (P = 0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX; ±s.e.m.; -4.9 ± 2 ng/mL × min, P = 0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, meal consumption ad libitum or adipose tissue triglyceride content.

Conclusions: Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycaemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.
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http://dx.doi.org/10.1530/EJE-21-0135DOI Listing
May 2021

An overview of obesity mechanisms in humans: Endocrine regulation of food intake, eating behaviour and common determinants of body weight.

Diabetes Obes Metab 2021 02;23 Suppl 1:17-35

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Obesity is one of the biggest health challenges of the 21st century, already affecting close to 700 million people worldwide, debilitating and shortening lives and costing billions of pounds in healthcare costs and loss of workability. Body weight homeostasis relies on complex biological mechanisms and the development of obesity occurs on a background of genetic susceptibility and an environment promoting increased caloric intake and reduced physical activity. The pathophysiology of common obesity links neuro-endocrine and metabolic disturbances with behavioural changes, genetics, epigenetics and cultural habits. Also, specific causes of obesity exist, including monogenetic diseases and iatrogenic causes. In this review, we provide an overview of obesity mechanisms in humans with a focus on energy homeostasis, endocrine regulation of food intake and eating behavior, as well as the most common specific causes of obesity.
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http://dx.doi.org/10.1111/dom.14270DOI Listing
February 2021

[Local anaesthetic systemic toxicity].

Ugeskr Laeger 2020 12;182(51)

Local anaesthetic systemic toxicity (LAST) gives rise to symptoms from the central nervous and cardiovascular systems. Knowledge about symptoms and risk factors is crucial in preventing LAST. Treatment of severe symptoms should often include vasopressors and sodium bicarbonate. In cardiac arrest the guidelines for advance life support including high-quality cardiopulmonary resuscitation (CPR) should be followed - emphasising prolonged CPR and extracorporeal life support (ECLS) in case of LAST. The conclusion of this review is that intravenous lipid emulsion should only be considered, when other interventions fail, and ECLS is unavailable.
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December 2020

[Local anaesthetic systemic toxicity].

Ugeskr Laeger 2020 12;182(51)

Local anaesthetic systemic toxicity (LAST) gives rise to symptoms from the central nervous and cardiovascular systems. Knowledge about symptoms and risk factors is crucial in preventing LAST. Treatment of severe symptoms should often include vasopressors and sodium bicarbonate. In cardiac arrest the guidelines for advance life support including high-quality cardiopulmonary resuscitation (CPR) should be followed - emphasising prolonged CPR and extracorporeal life support (ECLS) in case of LAST. The conclusion of this review is that intravenous lipid emulsion should only be considered, when other interventions fail, and ECLS is unavailable.
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December 2020

A poison information centre can provide important assessment and guidance regarding medication errors in nursing homes: A prospective cohort study.

Basic Clin Pharmacol Toxicol 2021 Mar 22;128(3):542-549. Epub 2020 Nov 22.

Department of Clinical Pharmacology, The Danish Poison Information Centre, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark.

The Danish Poison Information Centre (DPIC) regularly receives inquiries about nursing home residents who have been exposed to a medication error. The aim of this prospective cohort study was to describe and discuss the types and consequences of these errors. Data were collected from 1 March 2018 to 31 March 2019. Registered data included characteristics of caller and resident, data related to the suspected medication error, risk assessment and recommendation. Consequences and clinical outcomes were assessed by follow-up telephone calls. Over the study period, the DPIC was consulted about 145 medication errors occurring at Danish nursing homes. The median number of substances administered by error was two (interquartile range 1-5). Hospitalization was recommended in 21% of cases. In one-third of the cases where consultation with the DPIC was done with the resident either on his/her way to or in hospital, hospitalization was found unnecessary, and the resident could have stayed in accustomed surroundings for observation. Follow-up demonstrated that very few medication errors had a severe outcome. This prospective study illustrates that consulting with a poison information centre can qualify risk assessment and potentially reduce hospital admissions following medication errors in a nursing home setting.
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http://dx.doi.org/10.1111/bcpt.13529DOI Listing
March 2021

Identification and Metabolic Profiling of a Novel Human Gut-derived LEAP2 Fragment.

J Clin Endocrinol Metab 2021 01;106(2):e966-e981

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Context: The mechanisms underlying Roux-en-Y gastric bypass (RYGB) surgery-induced weight loss and the immediate postoperative beneficial metabolic effects associated with the operation remain uncertain. Enteroendocrine cell (EEC) secretory function has been proposed as a key factor in the marked metabolic benefits from RYGB surgery.

Objective: To identify novel gut-derived peptides with therapeutic potential in obesity and/or diabetes by profiling EEC-specific molecular changes in obese patients following RYGB-induced weight loss.

Subjects And Methods: Genome-wide expression analysis was performed in isolated human small intestinal EECs obtained from 20 gut-biopsied obese subjects before and after RYGB. Targets of interest were profiled for preclinical and clinical metabolic effects.

Results: Roux-en-Y gastric bypass consistently increased expression levels of the inverse ghrelin receptor agonist, liver-expressed antimicrobial peptide 2 (LEAP2). A secreted endogenous LEAP2 fragment (LEAP238-47) demonstrated robust insulinotropic properties, stimulating insulin release in human pancreatic islets comparable to the gut hormone glucagon-like peptide-1. LEAP238-47 showed reciprocal effects on growth hormone secretagogue receptor (GHSR) activity, suggesting that the insulinotropic action of the peptide may be directly linked to attenuation of tonic GHSR activity. The fragment was infused in healthy human individuals (n = 10), but no glucoregulatory effect was observed in the chosen dose as compared to placebo.

Conclusions: Small intestinal LEAP2 expression was upregulated after RYGB. The corresponding circulating LEAP238-47 fragment demonstrated strong insulinotropic action in vitro but failed to elicit glucoregulatory effects in healthy human subjects.
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http://dx.doi.org/10.1210/clinem/dgaa803DOI Listing
January 2021

High-Dose Glucagon Has Hemodynamic Effects Regardless of Cardiac Beta-Adrenoceptor Blockade: A Randomized Clinical Trial.

J Am Heart Assoc 2020 11 26;9(21):e016828. Epub 2020 Oct 26.

Department of Clinical Pharmacology Bispebjerg Hospital University of Copenhagen Copenhagen Denmark.

Background Intravenous high-dose glucagon is a recommended antidote against beta-blocker poisonings, but clinical effects are unclear. We therefore investigated hemodynamic effects and safety of high-dose glucagon with and without concomitant beta-blockade. Methods and Results In a randomized crossover study, 10 healthy men received combinations of esmolol (1.25 mg/kg bolus+0.75 mg/kg/min infusion), glucagon (50 µg/kg), and identical volumes of saline placebo on 5 separate days in random order (saline+saline; esmolol+saline; esmolol+glucagon bolus; saline+glucagon infusion; saline+glucagon bolus). On individual days, esmolol/saline was infused from -15 to 30 minutes. Glucagon/saline was administered from 0 minutes as a 2-minute intravenous bolus or as a 30-minute infusion (same total glucagon dose). End points were hemodynamic and adverse effects of glucagon compared with saline. Compared with saline, glucagon bolus increased mean heart rate by 13.0 beats per minute (95% CI, 8.0-18.0; <0.001), systolic blood pressure by 15.6 mm Hg (95% CI, 8.0-23.2; =0.002), diastolic blood pressure by 9.4 mm Hg (95% CI, 6.3-12.6; <0.001), and cardiac output by 18.0 % (95% CI, 9.7-26.9; =0.003) at the 5-minute time point on days without beta-blockade. Similar effects of glucagon bolus occurred on days with beta-blockade and between 15 and 30 minutes during infusion. Hemodynamic effects of glucagon thus reflected pharmacologic glucagon plasma concentrations. Glucagon-induced nausea occurred in 80% of participants despite ondansetron pretreatment. Conclusions High-dose glucagon boluses had significant hemodynamic effects regardless of beta-blockade. A glucagon infusion had comparable and apparently longer-lasting effects compared with bolus, indicating that infusion may be preferable to bolus injections. Registration Information URL: https://www.clinicaltrials.gov; Unique identifier: NCT03533179.
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http://dx.doi.org/10.1161/JAHA.120.016828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763418PMC
November 2020

GIP(3-30)NH - a tool for the study of GIP physiology.

Curr Opin Pharmacol 2020 12 11;55:31-40. Epub 2020 Oct 11.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone impacting glucose, lipid and bone metabolism through the GIP receptor (GIPR). The GIP system has key species differences complicating the translation of findings from rodent to human physiology. Furthermore, the effects of endogenous GIP in humans have been difficult to tease out due to the lack of a suitable GIPR antagonist. The naturally occurring GIP(3-30)NH has turned out to constitute a safe and efficacious GIPR antagonist for rodent and human use. To study GIP physiology, it is recommended to use the species-specific GIP(3-30)NH peptide sequence, and for human intravenous infusions, an antagonist:agonist ratio of a minimum of 600 with a 20min infusion time before the intervention of interest is recommended. Several studies using GIP(3-30)NH are coming, hopefully providing new insights into the physiology of GIP, the pathophysiologic involvement of GIP in several diseases and the therapeutic potential of the GIPR.
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http://dx.doi.org/10.1016/j.coph.2020.08.011DOI Listing
December 2020

Glucose-Dependent Insulinotropic Polypeptide (GIP) Reduces Bone Resorption in Patients With Type 2 Diabetes.

J Endocr Soc 2020 Sep 16;4(9):bvaa097. Epub 2020 Jul 16.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Context: In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP's insulinotropic effect is impaired and effects on bone may be reduced.

Objective: To investigate GIP's effect on bone biomarkers in patients with T2D.

Design: Randomized, double-blinded, crossover study investigating 6 interventions.

Patients: Twelve male patients with T2D.

Interventions: A primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with "insulin-induced hypoglycemia" (PG lowered to 3 mmol/L), "fasting hyperglycemia" (mean PG ~8 mmol/L), or "aggravated hyperglycemia" (mean PG ~12 mmol/L).

Main Outcome Measures: Bone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH.

Results: On days with insulin-induced hypoglycemia, CTX was suppressed by up to 40 ± 15% during GIP administration compared with 12 ± 11% during placebo infusion ( < 0.0001). On days with fasting hyperglycemia, CTX was suppressed by up to 36 ± 15% during GIP administration, compared with 0 ± 9% during placebo infusion ( < 0.0001). On days with aggravated hyperglycemia, CTX was suppressed by up to 47 ± 23% during GIP administration compared with 10 ± 9% during placebo infusion ( = 0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes.

Conclusions: Short-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients.

Précis: Short-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.
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http://dx.doi.org/10.1210/jendso/bvaa097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458112PMC
September 2020

Medication-related experiences of patients with polypharmacy: a systematic review of qualitative studies.

BMJ Open 2020 09 6;10(9):e036158. Epub 2020 Sep 6.

The Research Unit for General Practice, Department of Public Health, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.

Background: We aimed to synthesise qualitative studies exploring medication-related experiences of polypharmacy among patients with multimorbidity.

Methods: We systematically searched PubMed, Embase and Cumulative Index to Nursing and Allied Health Literature in February 2020 for primary, peer-reviewed qualitative studies about multimorbid patients' medication-related experiences with polypharmacy, defined as the use of four or more medications. Identified studies were appraised for methodological quality by applying the Critical Appraisal Skills Programme checklist for qualitative research, and data were extracted and synthesised by the meta-aggregation approach.

Results: We included 13 qualitative studies, representing 499 patients with polypharmacy and a wide range of chronic conditions. Overall, most Critical Appraisal Skills Programme items were reported in the studies. We extracted 140 findings, synthesised these into 17 categories, and developed five interrelated syntheses: (1) patients with polypharmacy are a heterogeneous group in terms of needing and appraising medication information; (2) patients are aware of the importance of medication adherence, but it is difficult to achieve; (3) decision-making about medications is complex; (4) multiple relational factors affect communication between patients and physicians, and these factors can prevent patients from disclosing important information; and (5) polypharmacy affects patients' lives and self-perception, and challenges with polypharmacy are not limited to practical issues of medication-taking.

Discussion: Polypharmacy poses many challenges to patients, which have a negative impact on quality of life and adherence. Thus, when dealing with polypharmacy patients, it is crucial that healthcare professionals actively solicit individual patients' perspectives on challenges related to polypharmacy. Based on the reported experiences, we recommend that healthcare professionals upscale communicative efforts and involve patients' social network on an individualised basis to facilitate shared decision-making and treatment adherence in multimorbidpatients with polypharmacy.
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http://dx.doi.org/10.1136/bmjopen-2019-036158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477975PMC
September 2020

Dose-dependent efficacy of the glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist GIP(3-30)NH on GIP actions in humans.

Diabetes Obes Metab 2021 01 1;23(1):68-74. Epub 2020 Oct 1.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

The glucose-dependent insulinotropic polypeptide (GIP) fragment GIP(3-30)NH is a selective, competitive GIP receptor antagonist, and doses of 800 to 1200 pmol/kg/min inhibit GIP-induced potentiation of glucose-stimulated insulin secretion by >80% in humans. We evaluated the effects of GIP(3-30)NH across a wider dose range in eight healthy men undergoing six separate and randomized 10-mmol/L hyperglycaemic clamps (A-F) with concomitant intravenous infusion of GIP (1.5 pmol/kg/min; A-E) or saline (F). Clamps A to E involved double-blinded, infusions of saline (A) and GIP(3-30)NH at four rates: 2 (B), 20 (C), 200 (D) and 2000 pmol/kg/min (E), respectively. Mean plasma concentrations of glucose (A-F) and GIP (A-E) were similar. GIP-induced potentiation of glucose-stimulated insulin secretion was reduced by 44 ± 10% and 84 ± 10% during clamps D and E, respectively. Correspondingly, the amounts of glucose required to maintain the clamp during D and E were not different from F. GIP-induced suppression of bone resorption and increase in heart rate were lowered by clamps D and E. In conclusion, GIP(3-30)NH provides extensive, dose-dependent inhibition of the GIP receptor in humans, with most pronounced effects of the doses 200 to 2000 pmol/kg/min within the tested range.
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http://dx.doi.org/10.1111/dom.14186DOI Listing
January 2021

Prevalence of polypharmacy in Denmark.

Dan Med J 2020 Jun 1;67(6). Epub 2020 Jun 1.

Introduction: Polypharmacy is associated with an increased risk of adverse health outcomes. This study aims to describe the prevalence of polypharmacy and medication use among older Danish citizens.

Methods: From national registers, we extracted medicine use in relation to age group and residential region for the entire Danish population for the first half of 2016. The most frequently redeemed medicines among older citizens (≥ 75 years) in 2016 were grouped into clinically meaningful medication classes.

Results: The prevalence of polypharmacy (> 5 different medicines) was 51% among citizens ≥ 75 years compared with 12% for the entire Danish population. The prevalence of polypharmacy increased with age and was 7% among citizens aged 40-49 years compared with 66% among citizens aged ≥ 90 years. There were only minor regional differences in the prevalence of polypharmacy. The most commonly redeemed medicine classes and individual medicines for older citizens were: 1) pain medication: paracetamol (50%) and tramadol (14%); 2) cardiovascular medicines: acetylsalicylic acid (26%), simvastatin (25%), metoprolol (22%), amlodipine (21%), furosemide (20%), bendroflumethiazide (17%), and losartan (14%); and 3) gastrointestinal medicines: pantoprazole (15%).

Conclusions: Polypharmacy is prevalent in Denmark with no relevant regional differences. The prevalence of polypharmacy increased with age, and more than half of the population aged ≥ 75 years redeemed prescriptions for > 5 different medicines. The most redeemed medicines among older citizens were against pain and cardiovascular disease.

Funding: none.

Trial Registration: not relevant.
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June 2020

Sex and age differences among tramadol users in three Nordic countries.

Dan Med J 2020 Jul 1;67(7). Epub 2020 Jul 1.

Introduction: The aim of this study was to examine the prevalence and characteristics of tramadol users in Denmark, Norway and Sweden.

Methods: Data from the national prescription databases comprising the entire population of Denmark, Norway and Sweden between 2007 and 2015 were used to assess prescription medicine use and sold amount (in defined daily doses (DDDs)) of tramadol, other opioids and non-steroidal anti-inflammatory drugs.

Results: From 2007 to 2015 the prevalence of tramadol users increased in Denmark from 45 to 52 per 1,000 residents, and in Norway from 20 to 41 per 1,000 residents. In Sweden, the prevalence decreased from 36 to 17 per 1,000 residents. In comparison, the prevalence of other opioid users decreased in Denmark and Norway, but increased in Sweden. During the study period, there were more female than male tramadol users in all three countries, and the prevalence of tramadol users tended to increase with age. The average tramadol DDD per treated patient remained fairly constant in Norway, while it increased in Denmark and Sweden. In Denmark and Norway, women received a higher DDD than men. The amount of sold tramadol and other opioids combined per 1,000 residents was highest in Denmark.

Conclusions: From 2007 to 2015, the prescription patterns of tramadol and other opioids differed between the three countries. Tramadol was generally used more frequently by women. Women received higher DDD then men in Norway and Denmark, but not in Sweden. The prevalence of tramadol users tended to increase with age in all countries.

Funding: none.

Trial Registration: not relevant.
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July 2020
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