31 results on '"E. J. P. de Koning"'
Search Results
2. Associated auto-immune disease in type 1 diabetes patients: a systematic review and meta-analysis
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E. J. P. de Koning, Olaf M. Dekkers, Bas S Uitbeijerse, Christa Nederstigt, Eleonora P M Corssmit, and L G M Janssen
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Disease ,Vitiligo ,Autoimmune Diseases ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Diabetes mellitus ,medicine ,Adrenal insufficiency ,Humans ,Autoantibodies ,pernicious anemia ,Type 1 diabetes ,business.industry ,Thyroid disease ,General Medicine ,medicine.disease ,Observational Studies as Topic ,Diabetes Mellitus, Type 1 ,030220 oncology & carcinogenesis ,Meta-analysis ,business - Abstract
Introduction The association between type 1 diabetes (T1D) and other auto-immune diseases is well known. However, a quantitative overview of all associated auto-immune diseases and their prevalence in T1D is lacking. Methods We searched PubMed, Web of Science, EMBASE and Cochrane library in September 2018 to identify relevant articles about the prevalence of the following associated auto-immune diseases in T1D cohorts: auto-immune thyroid disease, celiac disease, gastric autoimmunity including pernicious anemia, vitiligo and adrenal gland insufficiency. A meta-analysis was performed to estimate pooled prevalence using a random-effects model. Furthermore, random-effects meta-regression analysis was performed to assess the association between prevalence and mean age or diabetes duration. Results One hundred eighty articles were eligible including a total of 293 889 type 1 diabetes patients. Hypothyroidism (65 studies) was prevalent in 9.8% (95% CI: 7.5–12.3) of patients. Meta-regression showed that for every 10-year age increase, hypothyroidism prevalence increased 4.6% (95% CI: 2.6–6.6, P Conclusions The prevalence of antibody-mediated auto-immune disease is high among type 1 diabetes patients. Especially hypothyroidism and celiac disease are frequently found.
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- 2019
3. Human islets and dendritic cells generate post-translationally modified islet autoantigens
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E. J. P. de Koning, A.H. de Ru, P.A. van Veelen, A de Haan, Bart O. Roep, Rene J. Mclaughlin, M van Lummel, Arnaud Zaldumbide, and Hubrecht Institute for Developmental Biology and Stem Cell Research
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0301 basic medicine ,endocrine system ,Proteome ,endocrine system diseases ,type 1 diabetes ,Tissue transglutaminase ,T-Lymphocytes ,Immunology ,030209 endocrinology & metabolism ,Autoantigens ,DC ,Proinflammatory cytokine ,Immune tolerance ,Islets of Langerhans ,03 medical and health sciences ,HLA-DR3 Antigen ,0302 clinical medicine ,HLA-DQ Antigens ,Immune Tolerance ,medicine ,Humans ,Immunology and Allergy ,Deamidation ,Inflammation ,islets ,geography ,Transglutaminases ,geography.geographical_feature_category ,C-Peptide ,biology ,Pancreatic islets ,T-cell receptor ,nutritional and metabolic diseases ,Peripheral tolerance ,Dendritic Cells ,Original Articles ,Islet ,Amides ,HLA ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,medicine.anatomical_structure ,post-translational modification ,biology.protein ,Protein Processing, Post-Translational - Abstract
Summary The initiation of type 1 diabetes (T1D) requires a break in peripheral tolerance. New insights into neoepitope formation indicate that post-translational modification of islet autoantigens, for example via deamidation, may be an important component of disease initiation or exacerbation. Indeed, deamidation of islet autoantigens increases their binding affinity to the T1D highest-risk human leucocyte antigen (HLA) haplotypes HLA-DR3/DQ2 and -DR4/DQ8, increasing the chance that T cells reactive to deamidated autoantigens can be activated upon T cell receptor ligation. Here we investigated human pancreatic islets and inflammatory and tolerogenic human dendritic cells (DC and tolDC) as potential sources of deamidated islet autoantigens and examined whether deamidation is altered in an inflammatory environment. Islets, DC and tolDC contained tissue transglutaminase, the key enzyme responsible for peptide deamidation, and enzyme activity increased following an inflammatory insult. Islets treated with inflammatory cytokines were found to contain deamidated insulin C-peptide. DC, heterozygous for the T1D highest-risk DQ2/8, pulsed with native islet autoantigens could present naturally processed deamidated neoepitopes. HLA-DQ2 or -DQ8 homozygous DC did not present deamidated islet peptides. This study identifies both human islets and DC as sources of deamidated islet autoantigens and implicates inflammatory activation of tissue transglutaminase as a potential mechanism for islet and DC deamidation.
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- 2016
4. [Transplantation of islets of Langerhans: procedure, indications and challenges]
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M F, Nijhoff, V A L, Huurman, J, Dubbeld, A R, van Erkel, T A, Rabelink, M A, Engelse, and E J P, de Koning
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Treatment Outcome ,Diabetes Mellitus ,Disease Progression ,Islets of Langerhans Transplantation ,Humans ,Hypoglycemic Agents ,Insulin ,Hypoglycemia - Abstract
Pancreatic islet isolation and transplantation are complicated procedures, indicated for a carefully selected group of patients. After isolation from the pancreas, the islets are infused into the portal vein. Allogeneic islet transplantation is performed in patients with diabetes mellitus, who suffer from severe hypoglycaemic events and/or progressive complications. One or more donor pancreases are used, which necessitates immunosuppressive treatment. In autologous islet transplantation, which is performed in patients in whom the pancreas has to be removed due to a non-malignant disease, the patients' own islets are isolated and reinfused. No immunosuppressive treatment is required. Reconstitution of endogenous insulin production in allogeneic islet transplantation leads to marked improvements in glycaemic regulation, protection against severe hypoglycaemic episodes and fewer diabetes-related complications. Autologous islet transplantation allows for preservation of endogenous insulin production, which prevents (unstable) diabetes from occurring. This article describes the indications, procedure and pitfalls of islet isolation and transplantation, including three representative cases.
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- 2018
5. Pancreas Transplantation With Grafts From Donors Deceased After Circulatory Death: 5 Years Single-Center Experience
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Alexander F. Schaapherder, E. J. P. de Koning, Andries E. Braat, Wouter H. Kopp, A. G. Baranski, J.W. de Fijter, P.J.M. van der Boog, Hwai-Ding Lam, Volkert A L Huurman, and Hubrecht Institute for Developmental Biology and Stem Cell Research
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Delayed Graft Function ,Economic shortage ,030230 surgery ,Pancreas transplantation ,Single Center ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Journal Article ,Humans ,Young adult ,Child ,Retrospective Studies ,Transplantation ,business.industry ,Retrospective cohort study ,Middle Aged ,Circulatory death ,Tissue Donors ,Surgery ,Female ,030211 gastroenterology & hepatology ,Pancreas Transplantation ,business - Abstract
INTRODUCTION: Donation after circulatory death (DCD) pancreas transplantation has been shown to be an additional way to deal with donor organ shortages. The results of 5-year DCD pancreas transplantation are presented. METHODS: A retrospective, single center analysis (2011 - 2015) was performed to compare the results of donation after brain death (DBD) to DCD pancreas transplantation. RESULTS: During the study period, 104 pancreas transplantations (83 from DBD and 21 from DCD) were performed. Median pancreas donor risk index (PDRI) was 1.47, (DBD 1.61 vs. DCD 1.35 (p=0.144)). Without the factor DCD, PDRI from DCD donors was significantly lower (DBD 1.61 vs DCD 0.97 (p
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- 2018
6. Interrelationship of the rs7903146 TCF7L2 gene variant with measures of glucose metabolism and adiposity: The NEO study
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K. Willems van Dijk, Dennis O. Mook-Kanamori, E. J. P. de Koning, H.J. Lamb, Raymond Noordam, C.P.A. Zwetsloot, D. van Heemst, R. de Mutsert, A. de Roos, and F. R. Rosendaal
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0301 basic medicine ,Blood Glucose ,Male ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Medicine (miscellaneous) ,Logistic regression ,Body Mass Index ,0302 clinical medicine ,Risk Factors ,Insulin ,Netherlands ,Adiposity ,Nutrition and Dietetics ,Diabetes ,Middle Aged ,Phenotype ,Female ,Cardiology and Cardiovascular Medicine ,Transcription Factor 7-Like 2 Protein ,endocrine system ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Polymorphism, Single Nucleotide ,Risk Assessment ,03 medical and health sciences ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Obesity ,Genetic Association Studies ,business.industry ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,Odds ratio ,medicine.disease ,Confidence interval ,TCF7L2 ,030104 developmental biology ,Endocrinology ,Cross-Sectional Studies ,Glucose ,Diabetes Mellitus, Type 2 ,business ,Body mass index ,Biomarkers - Abstract
Background and aims We investigated the interrelationship of rs7903146-T in TCF7L2 with measures of glucose metabolism and measures of adiposity. Methods and results This cross-sectional analysis was conducted in 5744 middle-aged participants (mean (standard deviation [SD]) age is 55.9 (6.0) years) from the Netherlands Epidemiology of Obesity (NEO) Study. Associations between rs7903146-T and Type 2 diabetes mellitus (T2D) were assessed with logistic regression. Additive (per-allele) associations with measures of glucose metabolism (e.g., fasting insulin) and adiposity (e.g., body mass index [BMI]) were examined with multivariable linear regression. In the total study population, rs7903146-T was associated with a higher risk of T2D (additive odds ratio: 1.42; 95% confidence interval: 1.17; 1.72), and specifically with T2D treated with insulin analogs (2.31 [1.19; 4.46]). After exclusion of participants treated with glucose-lowering medication, rs7903146-T was associated with lower mean insulin concentration (additive mean difference: −0.07 SD [−0.14; 0.00]), but not with higher mean glucose concentration (0.03 SD [−0.01; 0.07]). Furthermore, rs7903146-T was associated with, among other measures of adiposity, a lower mean BMI (−0.04 SD [−0.09; −0.00]), and a lower mean total body fat (−0.04 SD [−0.08; −0.00]). The association between rs7903146-T and T2D increased after adjustment for BMI (odds ratio: 1.51 [1.24; 1.86]); the association between rs7903146-T and fasting insulin diminished after adjustment (−0.05 SD [−0.11; 0.02]). Conclusion rs7903146-T is associated with a decreased insulin concentration and increased risk of T2D with opposing effects of adjustment for adiposity.
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- 2018
7. [From annual check-up to annual appraisal: personalised diabetes care]
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G E H M, Rutten, H A, van Vugt, I, de Weerdt, S W J, Lamberts, and E J P, de Koning
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Physicians ,Diabetes Mellitus ,Humans ,Patient Preference ,Precision Medicine ,Delivery of Health Care - Abstract
Diabetes care is shifting from disease management to personalised care. Internationally, diabetes care providers are advised to integrate the patient's preferences, wishes and possibilities into diabetes care in order to improve its efficiency. The Dutch Diabetes Federation has developed a specifically patient-centred conversation model that can be systematically applied. At an annual appraisal, the physician and the patient make decisions on the treatment goals to set, and on the treatment and professional support needed to achieve these goals. In this way person-centred and efficient care may become reality. The first results of a pilot study are promising. Currently the applicability and added value of the model are being tested on a large scale. The model is more broadly applicable, which means this could be a new perspective for everyone with a chronic disease.
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- 2016
8. Distinct activation of primary human BDCA1(+) dendritic cells upon interaction with stressed or infected beta cells
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Barbara M. Schulte, E. J. P. de Koning, Marten A. Engelse, Jochem M. D. Galama, Jon D. Piganelli, Rita Bottino, Gosse J. Adema, Esther D. Kers-Rebel, and Hubrecht Institute for Developmental Biology and Stem Cell Research
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0301 basic medicine ,Chemokine ,Myeloid ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Interleukin-1beta ,Gene Expression ,Cell Communication ,Culture Media, Serum-Free ,Antigens, CD1 ,Mice ,Interferon ,Insulin-Secreting Cells ,Immunology and Allergy ,BDCA1(+) myeloid DC ,Non-U.S. Gov't ,BDCA1+ myeloid DC DC maturation enterovirus human islets of Langerhans beta cells ,Lymph node ,Enterovirus ,biology ,enterovirus ,Research Support, Non-U.S. Gov't ,Mixed lymphocyte reaction ,β cells ,Enterovirus B, Human ,medicine.anatomical_structure ,Host-Pathogen Interactions ,islets of Langerhans ,medicine.drug ,Signal Transduction ,Human ,Ultraviolet Rays ,Primary Cell Culture ,Immunology ,Research Support ,Proinflammatory cytokine ,03 medical and health sciences ,Interferon-gamma ,Islets of Langerhans ,Immune system ,Phagocytosis ,Stress, Physiological ,medicine ,Journal Article ,Animals ,Humans ,human ,DC maturation ,Glycoproteins ,Follicular dendritic cells ,business.industry ,Tumor Necrosis Factor-alpha ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Dendritic Cells ,Original Articles ,Coculture Techniques ,beta cells ,030104 developmental biology ,Poly I-C ,BDCA1 myeloid DC ,biology.protein ,business - Abstract
Contains fulltext : 172329.pdf (Publisher’s version ) (Closed access) Derailment of immune responses can lead to autoimmune type 1 diabetes, and this can be accelerated or even induced by local stress caused by inflammation or infection. Dendritic cells (DCs) shape both innate and adaptive immune responses. Here, we report on the responses of naturally occurring human myeloid BDCA1(+) DCs towards differentially stressed pancreatic beta cells. Our data show that BDCA1(+) DCs in human pancreas-draining lymph node (pdLN) suspensions and blood-derived BDCA1(+) DCs both effectively engulf beta cells, thus mimicking physiological conditions. Upon uptake of enterovirus-infected, but not mock-infected cells, BDCA1(+) DCs induced interferon (IFN)-alpha/beta responses, co-stimulatory molecules and proinflammatory cytokines and chemokines. Notably, induction of stress in beta cells by ultraviolet irradiation, culture in serum-free medium or cytokine-induced stress did not provoke strong DC activation, despite efficient phagocytosis. DC activation correlated with the amount of virus used to infect beta cells and required RNA within virally infected cells. DCs encountering enterovirus-infected beta cells, but not those incubated with mock-infected or stressed beta cells, suppressed T helper type 2 (Th2) cytokines and variably induced IFN-gamma in allogeneic mixed lymphocyte reaction (MLR). Thus, stressed beta cells have little effect on human BDCA1(+) DC activation and function, while enterovirus-infected beta cells impact these cells significantly, which could help to explain their role in development of autoimmune diabetes in individuals at risk.
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- 2016
9. Peritubular endothelium: The Achilles heel of the kidney?
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E. J. P. de Koning, Ton J. Rabelink, and D.C. Wijewickrama
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Nephrology ,medicine.medical_specialty ,Pathology ,endothelium ,Endothelium ,Nephron ,End stage renal disease ,Endothelial activation ,vascular ,Ischemia ,Internal medicine ,medicine ,Animals ,Humans ,Kidney Medulla ,Kidney ,end-stage renal disease ,Renal ischemia ,business.industry ,medicine.disease ,Capillaries ,Kidney Tubules ,medicine.anatomical_structure ,Endocrinology ,Disease Progression ,tubular epithelium ,Kidney Diseases ,Endothelium, Vascular ,business ,Kidney disease - Abstract
The development of renal ischemia has been postulated to be a main cause of the progressive nature of kidney diseases. In recent years, it has become clear that inappropriate and sustained activation of the endothelium could mediate this phenomenon. Endothelial activation will result in leucostasis and can compromise peritubular flow. The associated sustained redox signaling will also accelerate the development of endothelial senescence. In addition, risk factors for renal disease progression can reduce endothelial repair. In the course of these events, loss of capillary structure and rarefaction develops, which drives the further development of nephron loss. In this mini review, the evidence for this pathophysiological concept as well as the possibility to detect such endothelial activation in the clinical arena is summarized.
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- 2007
10. Circulating MicroRNAs Associate With Diabetic Nephropathy and Systemic Microvascular Damage and Normalize After Simultaneous Pancreas-Kidney Transplantation
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Roel Bijkerk, C. J. H. ter Horst, A.J. van Zonneveld, Meriem Khairoun, Marlies E.J. Reinders, Jacques M.G.J. Duijs, Joris I. Rotmans, E. J. P. de Koning, Marko J.K. Mallat, Ton J. Rabelink, A. P. J. de Vries, P. van der Pol, and J.W. de Fijter
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Adult ,Male ,Oncology ,Pathology ,medicine.medical_specialty ,Adolescent ,Disease ,Diabetic nephropathy ,Young Adult ,Internal medicine ,microRNA ,medicine ,Humans ,Immunology and Allergy ,Diabetic Nephropathies ,Pharmacology (medical) ,Transplantation ,Type 1 diabetes ,business.industry ,Middle Aged ,medicine.disease ,Kidney Transplantation ,Pathophysiology ,MicroRNAs ,Circulating MicroRNA ,Biomarker (medicine) ,Female ,Pancreas Transplantation ,business - Abstract
Because microvascular disease is one of the most important drivers of diabetic complications, early monitoring of microvascular integrity may be of clinical value. By assessing profiles of circulating microRNAs (miRNAs), known regulators of microvascular pathophysiology, in healthy controls and diabetic nephropathy (DN) patients before and after simultaneous pancreas-kidney transplantation (SPK), we aimed to identify differentially expressed miRNAs that associate with microvascular impairment. Following a pilot study, we selected 13 candidate miRNAs and determined their circulating levels in DN (n = 21), SPK-patients (n = 37), healthy controls (n = 19), type 1 diabetes mellitus patients (n = 15) and DN patients with a kidney transplant (n = 15). For validation of selected miRNAs, 14 DN patients were studied longitudinally up to 12 months after SPK. We demonstrated a direct association of miR-25, -27a, -126, -130b, -132, -152, -181a, -223, -320, -326, -340, -574-3p and -660 with DN. Of those, miR-25, -27a, -130b, -132, -152, -320, -326, -340, -574-3p and -660 normalized after SPK. Importantly, circulating levels of some of these miRNAs tightly associate with microvascular impairment as they relate to aberrant capillary tortuosity, angiopoietin-2/angiopoietin-1 ratios, circulating levels of soluble-thrombomodulin and insulin-like growth factor. Taken together, circulating miRNA profiles associate with DN and systemic microvascular damage, and might serve to identify individuals at risk of experiencing microvascular complications, as well as give insight into underlying pathologies.
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- 2015
11. Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data
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Johannes W. J. Bijlsma, Kenneth G. Saag, J. A. P. Da Silva, Frank Buttgereit, Maurizio Cutolo, John R. Kirwan, H Capell, E J P de Koning, Luís Inês, Maarten Boers, Rolf Rau, and J. W. G. Jacobs
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medicine.medical_specialty ,Immunology ,Arthritis ,Review ,Placebo ,Drug Administration Schedule ,General Biochemistry, Genetics and Molecular Biology ,Arthritis, Rheumatoid ,Rheumatology ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Musculoskeletal Diseases ,Adverse effect ,Glucocorticoids ,Randomized Controlled Trials as Topic ,Evidence-Based Medicine ,business.industry ,Incidence (epidemiology) ,medicine.disease ,Clinical trial ,Cardiovascular Diseases ,Antirheumatic Agents ,Rheumatoid arthritis ,business ,Glucocorticoid ,medicine.drug - Abstract
Adverse effects of glucocorticoids have been abundantly reported. Published reports on low dose glucocorticoid treatment show that few of the commonly held beliefs about their incidence, prevalence, and impact are supported by clear scientific evidence. Safety data from recent randomised controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo.
- Published
- 2006
12. Catheter replacement in continuous arteriovenous hemodiafiltration: The balance between infectious and mechanical complications*
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B. M. De Jongh, H. H. Vincent, A. B. M. Geers, J. P. J. Wester, J. A. Leusink, E. J. P. De Koning, and M. Tersmette
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Adult ,Male ,Catheterization, Central Venous ,medicine.medical_specialty ,Vascular catheter ,Hemodiafiltration ,Critical Care and Intensive Care Medicine ,Sepsis ,Intensive care ,medicine ,Humans ,Prospective Studies ,APACHE ,Aged ,Continuous arteriovenous hemodiafiltration ,Aged, 80 and over ,Cross Infection ,Respiratory Distress Syndrome ,Critically ill ,business.industry ,Middle Aged ,medicine.disease ,Surgery ,Intensive Care Units ,Catheter ,Equipment Contamination ,Equipment Failure ,Female ,Catheter replacement ,Complication ,business ,Kidney disease - Abstract
To assess the optimal moment of central vascular catheter replacement balancing infectious and mechanical complications in continuous renal replacement therapies in critically ill patients with acute renal failure.Prospective sequential trial with historical controls to compare liberal catheter replacement when clinically indicated with routine catheter replacement every 5 days in consecutive patients treated by continuous arteriovenous hemodiafiltration in a level I secondary referral intensive care unit of a university-affiliated teaching hospital. Intention-to-treat analysis.Twenty-two patients underwent catheter replacement when clinically indicated (group II), and 21 patients served as historical controls (group I). The groups were comparable for sex, age, Acute Physiology and Chronic Health Evaluation II scores, comorbidity, and creatinin and urea levels at the start of continuous arteriovenous hemodiafiltration. In group I, 71 catheters were used for 346 treatment days, and in group II, 68 catheters were used for 495 treatment days. The mean duration of catheterization was 4.9 +/- 2.0 days vs. 7.3 +/- 4.5 days, respectively (Student's t-test p.001). There was no significant difference between the incidence of colonization of catheters (46.8% in group I vs. 39.1% in group II; chi-square p =.35) In group I, bacteremia and catheter sepsis occurred in two patients, whereas this did not occur in group II. The occurrence of mechanical complications was comparable in both groups (15.5% in group I vs. 19.1% in group II). There were significantly more mechanical complications with arterial vs. venous catheters (17 vs. 7; chi-square p =.027).When catheters were changed as clinically indicated, they remained significantly longer in situ vs. being replaced routinely every 5 days; infectious and mechanical complications were comparable. The incidence of catheter sepsis was low (2.2%), and no prosthesis infection occurred. Catheter replacement when clinically indicated seems to be as safe as routine replacement every 5 days.
- Published
- 2002
13. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice
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E. J. P. de Koning, Françoise Carlotti, Maaike Hanegraaf, M. J. A. Westerouen van Meeteren, Johanne H. Ellenbroek, Hendrica A. Töns, N. de Graaf, Ton J. Rabelink, and Hubrecht Institute for Developmental Biology and Stem Cell Research
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Glucagon-like peptide-1 ,Male ,endocrine system ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Incretin ,Type 2 diabetes ,Diet, High-Fat ,Glucagon-Like Peptide-1 Receptor ,Beta cell adaptation ,Pancreatic islet ,Mice ,Glucagon-Like Peptide 1 ,Internal medicine ,Diabetes mellitus ,Insulin-Secreting Cells ,Internal Medicine ,Receptors, Glucagon ,Medicine ,Animals ,Receptor ,Beta cell mass ,Glucagon-like peptide 1 receptor ,Cell Proliferation ,business.industry ,Liraglutide ,digestive, oral, and skin physiology ,Beta cell function ,Glucose Tolerance Test ,medicine.disease ,GLP-1RA ,Insulin sensitivity ,Immunohistochemistry ,Mice, Inbred C57BL ,Endocrinology ,High-fat diet ,Beta cell ,Insulin Resistance ,business ,Beta cell proliferation ,GLP-1 ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
AIMS/HYPOTHESIS: Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in non-diabetic individuals with obesity and cardiovascular disease. However, their effect on beta cell mass in normoglycaemic conditions is not clear. Here, we investigate the effects of the GLP-1RA liraglutide on beta cell mass and function in normoglycaemic mice. METHODS: C57BL/6J mice were treated with the GLP-1RA liraglutide or PBS and fed a control or high-fat diet (HFD) for 1 or 6 weeks. Glucose and insulin tolerance tests were performed after 6 weeks. BrdU was given to label proliferating cells 1 week before the animals were killed. The pancreas was taken for either histology or islet isolation followed by a glucose-induced insulin-secretion test. RESULTS: Treatment with liraglutide for 6 weeks led to increased insulin sensitivity and attenuation of HFD-induced insulin resistance. A reduction in beta cell mass was observed in liraglutide-treated control and HFD-fed mice at 6 weeks, and was associated with a lower beta cell proliferation rate after 1 week of treatment. A similar reduction in alpha cell mass occurred, resulting in an unchanged alpha to beta cell ratio. In contrast, acinar cell proliferation was increased. Finally, islets isolated from liraglutide-treated control mice had enhanced glucose-induced insulin secretion. CONCLUSIONS/INTERPRETATION: Our data show that GLP-1RA treatment in normoglycaemic mice leads to increases in insulin sensitivity and beta cell function that are associated with reduced beta cell mass to maintain normoglycaemia.
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- 2013
14. High prevalence of pancreatic islet amyloid in patients with end-stage renal failure on dialysis treatment
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A Clark, E. J. P. de Koning, D. W. R. Gray, and Kenneth A. Fleming
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Adult ,Male ,Amyloid ,endocrine system ,medicine.medical_specialty ,Pancreatic disease ,Type 2 diabetes ,Pathology and Forensic Medicine ,Immunoenzyme Techniques ,Islets of Langerhans ,Insulin resistance ,Renal Dialysis ,Internal medicine ,Diabetes mellitus ,Humans ,Medicine ,Aged ,Aged, 80 and over ,geography ,geography.geographical_feature_category ,business.industry ,Pancreatic islets ,Pancreatic Diseases ,Amyloidosis ,Middle Aged ,medicine.disease ,Islet ,Islet Amyloid Polypeptide ,medicine.anatomical_structure ,Endocrinology ,Diabetes Mellitus, Type 2 ,Kidney Failure, Chronic ,Female ,business ,Pancreas - Abstract
Islet amyloid polypeptide (IAPP) is the main proteinaceous component of pancreatic islet amyloid, which is a characteristic feature of type 2 diabetes. The factors responsible for amyloid deposition are unclear. Patients with end-stage renal failure (ESRF) on dialysis treatment have increased insulin resistance which is associated with hypersecretion of beta-cell products. Furthermore, elevated concentrations of circulating IAPP are found in these patients due to reduced renal clearance of IAPP. To determine the prevalence of islet amyloid in this group of patients, pancreas was examined from 23 non-diabetic [aged 62 (29-79) years, median and range] and four type 2 diabetic [aged 67 (56-72) years] patients with ESRF on dialysis treatment. Pancreatic specimens from 30 non-diabetic control subjects [aged 67.5 (56-86) years] and 14 type 2 diabetic subjects without renal disease [aged 69 (48-86) years] were used as control groups. Islet amyloid was present in all type 2 diabetic patients with ESRF and in 12 out of 14 type 2 diabetic control subjects (86 per cent). Amyloid deposits were found in 8 out of 23 non-diabetic patients with ESRF (35 per cent), which was a higher prevalence than that found in non-diabetic control subjects (3 per cent) (P < 0.01). This may be related to undiagnosed (pre)diabetes. Elevated secretion rates of IAPP due to insulin resistance and high circulating IAPP concentrations as a result of severely reduced renal clearance of IAPP will cause high pericellular concentrations of IAPP. This condition is likely to enhance amyloid fibril formation in pancreatic islets similar to that observed in type 2 diabetes.
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- 1995
15. Pancreatic pathology in non-insulin dependent diabetes (NIDDM)
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E. J. P. de Koning, Joanna Poulton, Barbara C. Hansen, Anne Clark, Andrew T. Hattersley, and C.S. Yajnik
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Amyloid ,endocrine system ,medicine.medical_specialty ,Pathology ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,DNA, Mitochondrial ,Maturity onset diabetes of the young ,Islets of Langerhans ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Insulin Secretion ,Internal Medicine ,medicine ,Animals ,Humans ,Insulin ,Pancreas ,geography ,geography.geographical_feature_category ,business.industry ,Amyloidosis ,General Medicine ,medicine.disease ,Islet ,Islet Amyloid Polypeptide ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Pancreatitis ,Chronic Disease ,Mutation ,Immunology ,business - Abstract
NIDDM is a heterogeneous disease and subgroups of NIDDM include MODY (Maturity Onset Diabetes of the Young), Malnutrition-related diabetes (MRDM) and Fibrocalculus pancreatic diabetes (FCPD). Endocrine cell population is relatively unchanged in NIDDM: B-cells are reduced by up to 30% and A-cells increased by 10%. Islet amyloid is found in 96% of subjects occupying up to 80% of the islet associated with a reduction in B-cells. Amyloid formation is unlikely to cause diabetes but progressive accumulation increases the severity of the disease. Islet amyloid is formed from the islet amyloid polypeptide (IAPP), a normal constituent of B-cells, co-secreted with insulin. The causal factors for IAPP fibrillogenesis are unknown but abnormal synthesis or overproduction could be involved: stimulation of B-cell secretion in NIDDM by obesity, hyperglycaemia or suphonylurea therapy may promote amyloidosis and further aggravate islet pathology. A mutation of the glucokinase gene in MODY leads to diminished B-cell secretion but not amyloid formation. Diabetes and mutations of mitochondrial DNA is associated with poorly developed islet structure. Exocrine pancreatic size is reduced and there is evidence of sub-clinical chronic pancreatitis in NIDDM. In MRDM and FCPD, chronic pancreatitis and exocrine necrosis is associated with reduced insulin secretion. Unlike cystic fibrosis where islet amyloid is present in diabetic individuals, amyloid is absent from subjects with FCPD. Pathological changes in the exocrine and endocrine pancreas in NIDDM results from and contributes to the pathophysiology of insulin secretion in NIDDM.
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- 1995
16. Human Islet Amyloid Polypeptide Accumulates at Similar Sites in Islets of Transgenic Mice and Humans
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K. L. Van Hulst, C. Oosterwijk, Jwm Hoppener, J. S. Verbeek, John F. Morris, A Clark, E. J. P. de Koning, C. A. Baker, and Cornelis J.M. Lips
- Subjects
Male ,Genetically modified mouse ,Amyloid ,endocrine system ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Immunoelectron microscopy ,Transgene ,Amylin ,Mice, Transgenic ,Biology ,Gene product ,Islets of Langerhans ,Mice ,Species Specificity ,Internal medicine ,Gene expression ,Internal Medicine ,medicine ,Animals ,Humans ,Microscopy, Immunoelectron ,Aged ,geography ,geography.geographical_feature_category ,Islet ,Islet Amyloid Polypeptide ,Cell biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Female - Abstract
The cellular mechanisms responsible for conversion of islet amyloid polypeptide (IAPP) into insoluble amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM) are not clear. Overexpression of IAPP and the amino acid sequence of human IAPP (hIAPP) have both been implicated. To examine factors involved in amyloid formation, transgenic mice expressing the hIAPP or rat IAPP (rIAPP) gene were generated. These mice had elevated plasma IAPP concentrations, and they were normoglycemic and normoinsulinemic. No amyloid deposits were detected by light microscopy. To examine the ultrastructure of islets, pancreatic tissue was studied from hIAPP and rIAPP transgenic mice and from age-matched control mice by immunoelectron microscopy. IAPP was immunolocalized in β-cell secretory granules of all mice, and the COOH- and NH2-terminal flanking peptides of hIAPP were localized in β-cell granules of hIAPP mice. Accumulations of nonfibrillar perivascular IAPP-immunoreactive material were found between capillaries and β-cells in hIAPP transgenic mice but not in rIAPP transgenic or control mice. Similar nonfibrillar masses were identified in islets of an NIDDM patient. Secondary lysosomes in β-cells and macrophages of hIAPP transgenic mice showed dense labeling for IAPP. We suggest that hIAPP is degraded more slowly than rIAPP or mouse IAPP by β-cell lysosomes. Accumulations of IAPP in islet perivascular spaces may represent the early stages of islet amyloid formation.
- Published
- 1994
17. Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia
- Author
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E. J. P. de Koning, Frans M. A. Hofhuis, S. van Gaalen, Cornelis J.M. Lips, K. L. Van Hulst, John F. Morris, A Clark, Jwm Hoppener, W. H. L. Hackeng, M. J. H. Berends, Peter J.A. Capel, H. J. Visser-Vernooy, C. Oosterwijk, H.S. Jansz, and J. S. Verbeek
- Subjects
Male ,Amyloid ,endocrine system ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Restriction Mapping ,BACE1-AS ,Radioimmunoassay ,Amylin ,Mice, Transgenic ,Islets of Langerhans ,Mice ,Insulin resistance ,Internal medicine ,mental disorders ,Internal Medicine ,medicine ,Amyloid precursor protein ,Animals ,Humans ,Microscopy, Immunoelectron ,Pancreatic hormone ,geography ,geography.geographical_feature_category ,biology ,Insulin ,Exons ,medicine.disease ,Islet ,Islet Amyloid Polypeptide ,Rats ,Mice, Inbred C57BL ,Endocrinology ,Mice, Inbred CBA ,biology.protein ,Female ,Lysosomes ,Plasmids - Abstract
Type 2 (non-insulin-dependent) diabetes mellitus is characterised by hyperglycaemia, peripheral insulin resistance, impaired insulin secretion and pancreatic islet amyloid formation. The major constituent of islet amyloid is islet amyloid polypeptide (amylin). Islet amyloid polypeptide is synthesized by islet beta cells and co-secreted with insulin. The ability of islet amyloid polypeptide to form amyloid fibrils is related to its species-specific amino acid sequence. Islet amyloid associated with diabetes is only found in man, monkeys, cats and racoons. Pharmacological doses of islet amyloid polypeptide have been shown to inhibit insulin secretion as well as insulin action on peripheral tissues (insulin resistance). To examine the role of islet amyloid polypeptide in the pathogenesis of Type 2 diabetes, we have generated transgenic mice with the gene encoding either human islet amyloid polypeptide (which can form amyloid) or rat islet amyloid polypeptide, under control of an insulin promoter. Transgenic islet amyloid polypeptide mRNA was detected in the pancreas in all transgenic mice. Plasma islet amyloid polypeptide levels were significantly elevated (up to 15-fold) in three out of five transgenic lines, but elevated glucose levels, hyperinsulinaemia and obesity were not observed. This suggests that insulin resistance is not induced by chronic hypersecretion of islet amyloid polypeptide. Islet amyloid polypeptide immunoreactivity was localized to beta-cell secretory granules in all mice. Islet amyloid polypeptide immunoreactivity in beta-cell lysosomes was seen only in mice with the human islet amyloid polypeptide gene, as in human beta cells, and might represent an initial step in intracellular formation of amyloid fibrils.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1993
18. Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population
- Author
-
E. J. P. de Koning, Barbara C. Hansen, A Clark, and Noni L. Bodkin
- Subjects
Blood Glucose ,Aging ,Amyloid ,endocrine system ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Population ,Biology ,Islets of Langerhans ,Reference Values ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Hyperinsulinemia ,Animals ,education ,geography ,education.field_of_study ,geography.geographical_feature_category ,Amyloidosis ,Insulin ,Monkey Diseases ,Islet ,medicine.disease ,Macaca mulatta ,Islet Amyloid Polypeptide ,Endocrinology ,Diabetes Mellitus, Type 2 ,Beta cell - Abstract
Diabetes mellitus in Macaca mulatta rhesus monkeys is preceded by phases of obesity and hyperinsulinaemia and is similar to Type 2 (non-insulin-dependent) diabetes mellitus in man. To relate the progression of the disease to quantitative changes in islet morphology, post-mortem pancreatic tissue from 26 monkeys was examined. Four groups of animals were studied: group I--young, lean and normal (n = 3); group II--older (> 10 years), lean and obese, normoglycaemic (n = 9); group III--normoglycaemic and hyperinsulinaemic (n = 6); group IV--diabetic (n = 8). Areas of islet amyloid, beta cells and islets were measured on stained histological sections. Islet size was larger in animals from groups III (p < 0.01) and IV (p < 0.0001) compared to groups I and II. The mean beta-cell area per islet in micron 2 was increased in group III (p < 0.05) and reduced in group IV (p < 0.001) compared to groups I and II. Mean beta-cell area per islet correlated with fasting plasma insulin (r = 0.76, p < 0.001) suggesting that hyper- and hypoinsulinaemia are related to the beta-cell population. Amyloid was absent in group I but small deposits were present in three of nine (group II) and in four of six (group III) animals, occupying between 0.03-45% of the islet space. Amyloid was present in eight of eight diabetic animals (group IV) occupying between 37-81% of the islet area. Every islet was affected in seven of eight diabetic monkeys. There was no correlation of degree of amyloidosis with age, body weight, body fat proportion or fasting insulin. Islet amyloid appears to precede the development of overt diabetes in Macaca mulatta and is likely to be a factor in the destruction of islet cells and onset of hyperglycaemia.
- Published
- 1993
19. Formation of islet amyloid from islet amyloid polypeptide
- Author
-
John F. Morris, E. J. P. de Koning, and Andrew R. Clark
- Subjects
Amyloid ,geography ,geography.geographical_feature_category ,Sequence Homology, Amino Acid ,Chemistry ,Molecular Sequence Data ,P3 peptide ,Islet ,Biochemistry ,Islet Amyloid Polypeptide ,Cell biology ,Islets of Langerhans ,Diabetes Mellitus, Type 2 ,Animals ,Humans ,Amino Acid Sequence ,Protein Precursors ,Protein Processing, Post-Translational - Published
- 1993
20. Hypothermic machine perfusion of the pancreas; a promising preservation method for islet isolation
- Author
-
Marjolein Leemkuil, Henri G. D. Leuvenink, Christina Krikke, Rutger J. Ploeg, Marten A. Engelse, and E. J. P. de Koning
- Subjects
Transplantation ,Machine perfusion ,Pathology ,medicine.medical_specialty ,geography ,geography.geographical_feature_category ,Isolation (health care) ,business.industry ,Immunology ,Islet ,medicine.anatomical_structure ,medicine ,Immunology and Allergy ,Pancreas ,business - Published
- 2014
21. Pancreas Allograft Biopsies with Positive C4d Staining and Anti-Donor Antibodies Related to Worse Outcome for Patients
- Author
-
Stefan P Berger, E. J. P. de Koning, H. de Kort, Ingeborg M. Bajema, Rolf N. Barth, Michael Eikmans, A. van der Wal, C. van Kooten, Jan A. Bruijn, Cinthia B. Drachenberg, Benjamin Philosophe, E. de Heer, R. Munivenkatappa, Other departments, ACS - Amsterdam Cardiovascular Sciences, and Pathology
- Subjects
Adult ,Graft Rejection ,Male ,medicine.medical_specialty ,Pathology ,Time Factors ,medicine.medical_treatment ,Biopsy ,Pancreas transplantation ,Gastroenterology ,Article ,Postoperative Complications ,Interquartile range ,HLA Antigens ,Internal medicine ,medicine ,Acinar cell ,Complement C4b ,Immunology and Allergy ,Electronic Health Records ,Humans ,Transplantation, Homologous ,Pharmacology (medical) ,Coloring Agents ,Survival rate ,Inflammation ,Transplantation ,medicine.diagnostic_test ,business.industry ,Histocompatibility Testing ,Middle Aged ,Allograft failure antibodies antibody-mediated rejection classification complement C4d donor-specific antibodies histopathology humoral rejection immunohistochemistry pancreas transplantation mediated rejection kidney-transplantation deposition recipients ,Peptide Fragments ,body regions ,medicine.anatomical_structure ,Treatment Outcome ,Histopathology ,Female ,Pancreas Transplantation ,Pancreas ,business ,Immunosuppressive Agents ,Follow-Up Studies - Abstract
C4d+ antibody-mediated rejection following pancreas transplantation has not been well characterized. Therefore, we assessed the outcomes of 27 pancreas transplantation patients (28 biopsies), with both C4d staining and donor-specific antibodies (DSA) determined, from a cohort of 257 patients. The median follow-up was 50 (interquartile range [IQR] 8-118) months. Patients were categorized into 3 groups: group 1, patients with minimal or no C4d staining and no DSA (n = 13); group 2, patients with either DSA present but no C4d, diffuse C4d+ and no DSA or focal C4d+ and DSA (n = 6); group 3, patients with diffuse C4d+ staining and DSA (n = 9). Active septal inflammation, acinar inflammation and acinar cell injury/necrosis were significantly more abundant in group 3 than in group 2 (respective p-values: 0.009; 0.033; 0.025) and in group 1 (respective p-values: 0.034; 0.009; 0.002). The overall uncensored pancreas graft survival rate for groups 1, 2 and 3 were 53.3%, 66.7% and 34.6%, respectively (p = 0.044). In conclusion, recipients of pancreas transplants with no C4d or DSA had excellent long-term graft survival in comparison with patients with both C4d+ and DSA present. Hence, C4d should be used as an additional marker in combination with DSA in the evaluation of pancreas transplant biopsies.
- Published
- 2010
22. Reversibility of capillary density after discontinuation of bevacizumab treatment
- Author
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Hans Gelderblom, E. J. P. de Koning, F.H.M. Cluitmans, E. Batman, Ton J. Rabelink, Neeltje Steeghs, J. op 't Roodt, and N.I. Weijl
- Subjects
Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Bevacizumab ,Angiogenesis ,Urology ,Angiogenesis Inhibitors ,Blood Pressure ,Breast Neoplasms ,Antibodies, Monoclonal, Humanized ,chemistry.chemical_compound ,angiogenesis bevacizumab capillary density hypertension rarefaction vascular endothelial growth factor inhibitor metastatic colorectal-cancer renal-cell carcinoma randomized phase-iii breast-cancer hypertension microcirculation inhibition combination paclitaxel pressure ,Medicine ,Humans ,Pulse wave velocity ,Aged ,business.industry ,Microcirculation ,Repeated measures design ,Antibodies, Monoclonal ,Hematology ,Middle Aged ,Lip ,Discontinuation ,Surgery ,Capillaries ,Vascular endothelial growth factor ,Blood pressure ,Treatment Outcome ,Oncology ,chemistry ,Capillary density ,Female ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
BACKGROUND: Vascular endothelial growth factor (VEGF) inhibition is known to decrease capillary density. Decreased capillary density may be the basis for VEGF inhibitor-related side-effects. We investigated whether the effects of bevacizumab on capillary density are reversible. PATIENTS AND METHODS: Capillary density, assessed by sidestream dark field imaging of the mucosal surface of the lip, was measured at baseline, after 6 weeks of bevacizumab treatment and >3 months after discontinuation. Additional measurements included blood pressure (BP) measurements, flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD) and aortic pulse wave velocity (PWV). RESULTS: Fourteen patients were included. Seven patients completed measurements at all three predefined time points. Capillary density significantly decreased after 6 weeks of bevacizumab treatment and was reversible after discontinuation of bevacizumab (P = 0.00001 using a general linear model repeated measures test). BP, FMD and NMD remained unchanged. Mean PWV increased after 6 weeks of treatment (P = 0.027) and decreased after bevacizumab discontinuation. Among the six patients with the best response were the three patients showing the clearest decrease in capillary density after 6 weeks of bevacizumab treatment. CONCLUSIONS: Bevacizumab-induced decrease in capillary density is reversible. Noninvasive assessment of capillary density during treatment with antiangiogenic drugs may be useful as a marker of treatment efficacy.
- Published
- 2010
23. The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation
- Author
-
I. Cnop, E. J. P. de Koning, John F. Morris, Michael B. Hoppa, Jennifer H. Gunter, Miriam Cnop, S. J. Hughes, Miriam Pipeleers-Marichal, Gerard V Walls, Anna Clark, Mariana Igoillo-Esteve, Barbara C. Hansen, F. Sayyed, D. W. G. Gray, L. van de Laar, Paul Johnson, Analysis, Mathematics in Education, and Pathological Anatomy
- Subjects
Adult ,Senescence ,Aging ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Population ,Longevity ,030209 endocrinology & metabolism ,Type 2 diabetes ,Biology ,Neogenesis ,Lipofuscin ,Mice ,03 medical and health sciences ,Age Distribution ,0302 clinical medicine ,Cause of Death ,Insulin-Secreting Cells ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Animals ,Humans ,Ageing Human Islet Longevity Mathematical modelling Monkey Mouse Neogenesis Pancreatic beta cell Type 2 diabetes low-density-lipoprotein oxidative stress partial-pancreatectomy insulin-secretion mass age proliferation regeneration apoptosis birth ,Beta (finance) ,education ,Pancreas ,030304 developmental biology ,0303 health sciences ,geography ,education.field_of_study ,geography.geographical_feature_category ,islet ,Mathematical modelling ,Models, Theoretical ,Islet ,medicine.disease ,biology.organism_classification ,Macaca mulatta ,Tissue Donors ,Mice, Inbred C57BL ,Ageing ,Endocrinology ,Diabetes Mellitus, Type 2 ,Beta cell ,Biomarkers ,Cell Division ,Human - Abstract
AIMS/HYPOTHESIS: Defects in pancreatic beta cell turnover are implicated in the pathogenesis of type 2 diabetes by genetic markers for diabetes. Decreased beta cell neogenesis could contribute to diabetes. The longevity and turnover of human beta cells is unknown; in rodents or=90% (or=97% (>20 years) and remained constant thereafter. CONCLUSIONS/INTERPRETATION: Human beta cells, unlike those of young rodents, are long-lived. LB proportions in type 2 diabetes and obesity suggest that little adaptive change occurs in the adult human beta cell population, which is largely established by age 20 years.
- Published
- 2010
24. Effects of rosiglitazone on postprandial leukocytes and cytokines in type 2 diabetes
- Author
-
Ton J. Rabelink, M. Castro Cabezas, Blai Coll, Jorge Joven, E. J. P. de Koning, and J.P.H. van Wijk
- Subjects
Adult ,Male ,medicine.medical_specialty ,Chemokine ,medicine.medical_treatment ,Inflammation ,Type 2 diabetes ,Rosiglitazone ,Leukocyte Count ,Double-Blind Method ,Internal medicine ,Diabetes mellitus ,Leukocytes ,Medicine ,Humans ,Hypoglycemic Agents ,Prospective Studies ,Interleukin 6 ,Aged ,Cross-Over Studies ,biology ,business.industry ,Middle Aged ,medicine.disease ,Postprandial Period ,Cytokine ,Endocrinology ,Postprandial ,Treatment Outcome ,Diabetes Mellitus, Type 2 ,biology.protein ,Cytokines ,Female ,Thiazolidinediones ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,medicine.drug ,Follow-Up Studies - Abstract
We postulated that in type 2 diabetes, the postprandial phase is a pro-inflammatory state that can be modulated by PPAR-gamma agonists. For this purpose, we determined the effects of rosiglitazone (8 mg/d) on postprandial leukocyte counts and pro-inflammatory cytokines (IL-6 and IL-8) in patients with type 2 diabetes.A randomized, 8-week, cross-over, placebo-controlled, double-blind clinical trial was performed in 19 patients with type 2 diabetes. Standardized 6-h oral fat-loading tests were performed after each treatment period. During placebo treatment, blood leukocytes increased to a maximum 6-h postprandially, due to significant increases in neutrophils and lymphocytes. Concomitant postprandial increases were observed for IL-6 and IL-8, the major chemokines responsible for leukocyte recruitment. Rosiglitazone reduced the incremental area under the curves (dAUCs) for IL-6 (-63%, p0.01) and IL-8 (-16%, p0.05). The dAUC for leukocytes decreased with 37% (p0.05), due to a specific reduction of neutrophils (-39%, p0.05).Rosiglitazone attenuated the postprandial increases of neutrophils, IL-6 and IL-8 in patients with type 2 diabetes. Since inflammation is a major force driving atherosclerosis, and man lives in a postprandial period most part of the day, a reduced inflammatory response after a meal may delay progression of atherosclerosis.We postulated that in type 2 diabetes, the postprandial phase is a pro-inflammatory state that can be modulated by PPAR-gamma agonists. Rosiglitazone attenuated the postprandial increases of neutrophils, IL-6 and IL-8 in patients with type 2 diabetes. These effects may contribute to cardiovascular risk reduction.
- Published
- 2005
25. [Molecular diagnosis on indication of maturity onset diabetes of the young; results from 184 patients]
- Author
-
M, Losekoot, A J, Broekman, M H, Breuning, E J P, de Koning, J A, Romijn, and J A, Maassen
- Subjects
Adult ,Male ,Nuclear Proteins ,Phosphoproteins ,Pedigree ,DNA-Binding Proteins ,Diabetes Mellitus, Type 2 ,Hepatocyte Nuclear Factor 4 ,Glucokinase ,Hepatocyte Nuclear Factor 1 ,Mutation ,Humans ,Female ,Hepatocyte Nuclear Factor 1-alpha ,Age of Onset ,Transcription Factors - Abstract
To describe the results of mutation analysis of the genes involved in maturity onset diabetes of the young (MODY) types 1-3.Descriptive.In the period July 2000-October 2003 the DNA from 184 possible MODY patients was analysed for the presence of mutations of the genes involved in MODY types 1, 2 and 3. The patients fulfilled at least one of the following criteria: diabetes mellitus had been diagnosed before the age of 25, or at least before the age of 40, there was a family history of diabetes mellitus at an early age, there were no characteristics to indicate diabetes mellitus type 1 or 2.In the blood of 65 patients (35%) a pathogenic gene mutation was found. A total of 45 patients had a mutation in the HNF-1alpha-gene (which is linked to MODY3), 11 in the glucokinase gene (MODY2) and 9 in the HNF-4alpha-gene (MODY1). Of all the HNF-1alpha-gene mutations, the insertion of a C in codon 291 was the most frequently seen (in 11 families). A mutation in exon 9 of the HNF-1alpha-gene was also shown in 9 apparently non-related families, which probably was a founder mutation.The MODY subtype was found in one third of the selected patients. This diagnosis may have implications in the clinical management of the patient.
- Published
- 2005
26. Decreased insulin secretion in type 2 diabetes: a problem of cellular mass or function?
- Author
-
A Clark, D R Matthews, E. J. P. de Koning, L C Jones, and Barbara C. Hansen
- Subjects
medicine.medical_specialty ,Amyloid ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Cell Count ,Type 2 diabetes ,Biology ,Islets of Langerhans ,Insulin resistance ,Diabetes mellitus ,Internal medicine ,Insulin Secretion ,Internal Medicine ,medicine ,Animals ,Humans ,Insulin ,Secretion ,geography ,geography.geographical_feature_category ,medicine.disease ,Islet ,Insulin oscillation ,Disease Models, Animal ,Endocrinology ,Diabetes Mellitus, Type 2 - Abstract
Type 2 diabetes is characterized by diminished or inappropriate secretion of insulin, which could be a defect of either islet cell function or beta-cell mass. Quantitation of islet cell populations in postmortem pancreas demonstrates little change of beta-cell mass in type 2 diabetes. Reduction of islet cell mass (up to 30%) is associated largely with islet amyloid deposition, and the degree of amyloidosis is independent of the duration of the disease. Insulin secretory capacity is dependent on both function and mass of cells. beta-Cell secretion is heterogeneous; increasing glucose concentrations result in recruitment of beta-cells into the secretory pool, indicating a large reserve of secretory capacity that can be recruited in insulin resistant conditions. The Starling curve of islet function describes the relationship of insulin secretion to increasing levels of insulin resistance and hyperglycemia in type 2 diabetes. Longitudinal studies in Macaca mulatta monkeys show that insulin resistance is accompanied by increased islet mass and onset of diabetes is associated with deposition of amyloid and reduction of beta-cells. Increasing the function of unresponsive beta-cells rather than the mass of cells may be a more effective therapeutic target for type 2 diabetes.
- Published
- 2001
27. Amyloid fibril formation is progressive and correlates with beta-cell secretion in transgenic mouse isolated islets
- Author
-
John F. Morris, A Clark, J. S. Verbeek, D. L. A. MacArthur, and E. J. P. de Koning
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,Amyloid ,Time Factors ,Cell Survival ,Endocrinology, Diabetes and Metabolism ,Glutamine ,Tolbutamide ,Amylin ,Mice, Transgenic ,Biology ,Fibril ,Islets of Langerhans ,Mice ,Leucine ,Internal medicine ,Internal Medicine ,medicine ,Extracellular ,Animals ,Humans ,Hypoglycemic Agents ,Insulin ,Cells, Cultured ,geography ,geography.geographical_feature_category ,Dose-Response Relationship, Drug ,Amyloidosis ,Islet ,medicine.disease ,Keto Acids ,Islet Amyloid Polypeptide ,Endocrinology ,Glucose ,Culture Media, Conditioned ,Female ,Beta cell ,Extracellular Space - Abstract
Aims/hypothesis. Amyloid fibrils are formed in islets isolated from transgenic mice expressing the gene for human islet amyloid polypeptide (IAPP) by an unknown mechanism. This model of islet amyloidosis in Type II (non-insulin-dependent) diabetes mellitus has been used to investigate the temporal and glucose dependency of fibril formation. Methods. To determine the time course and nature of amyloid-like accumulations and the role of glucose, transgenic mouse islets were cultured for 2‐12 days in medium containing glucose (4.2 mmol/l, 11.1 mmol/l or 16.7 mmol/l) or 3.3 mmol/l glucose plus non-glucose secretagogues, 10 mmol/l leucine, 10 mmol/l leucine + 0.1 mmol/l tolbutamide, 10 mmol/l alpha-ketoisocaproic acid + 10 mmol/l glutamine. The extent of fibril formation was determined by quantitative immuno-electron microscopy. Insulin and islet amyloid polypeptide secretion into the media was measured by radioimmunoassay. Results. Extracellular amyloid fibrils immunoreactive for islet amyloid polypeptide were visible initially after 6 days of culture in 11.1 mmol/l glucose and formed 2.3 ‐ 0.8 % of the islet area after 12 days; small accumulations of intracellular fibrils and amorphous extracellular islet amyloid polypeptide-immunoreactive material were present at 6‐12 days. Beta-cell secretion was increased significantly by 16.7 mmol/l glucose and by alpha-ketoisocaproic acid + glutamine. The proportion of fibrillar amyloid (amyloid area/islet area%) correlated with the amount of insulin (r = 0.55, p < 0.05) and IAPP (r = 0.5, p < 0.05) in the culture media. Evidence of cellular damage was present in less than 10 % cells and correlated with the degree of fibril deposition (r = 0.8, p < 0.0001). Conclusion/interpretation. These data suggest that islet amyloid polypeptide amyloid is formed primarily at extracellular sites in isolated transgenic mouse islets and progressive fibril formation correlates with beta-cell secretion. [Diabetologia (1999) 42: 1219‐ 1227]
- Published
- 1999
28. Islet amyloid polypeptide: actions and role in the pathogenesis of diabetes
- Author
-
E. J. P. de Koning, M. K. Badman, Sophie Chargé, D. L. A. MacArthur, and Andrew R. Clark
- Subjects
endocrine system ,medicine.medical_specialty ,Amyloid ,medicine.medical_treatment ,Molecular Sequence Data ,Biochemistry ,Models, Biological ,Pathogenesis ,Islets of Langerhans ,Insulin resistance ,Species Specificity ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Humans ,Secretion ,Nutritional Physiological Phenomena ,Amino Acid Sequence ,geography ,geography.geographical_feature_category ,Sequence Homology, Amino Acid ,Chemistry ,Insulin ,medicine.disease ,Islet ,Peptide Fragments ,Islet Amyloid Polypeptide ,Endocrinology ,Diabetes Mellitus, Type 1 ,Diabetes Mellitus, Type 2 ,Digestion ,Protein Processing, Post-Translational ,Homeostasis - Abstract
IAPP has been postulated to have a role as a modulating factor in glucose homoeostasis and to be involved in the pathophysiology of diabetes. However, the normal physiological functions of the peptide remain obscure: exogenous IAPP acts on many experimental systems to modulate nutrient supply and metabolism but there is no evidence to suggest that circulating IAPP has an aetiological role in the onset of Type-2 diabetes. Amyloid deposits formed from polymerized IAPP progressively accumulate in the islets of Type-2 diabetic patients. These insoluble deposits do not precipitate the onset of hyperglycaemia in Type-2 diabetes, but progressive accumulation of amyloid is associated with islet cell destruction and decreased islet function in the later stages of the disease. Although the causative factors of formation of the first IAPP fibril are unknown, continued high levels of insulin and IAPP secretion as a result of nutrient stimulation or insulin resistance will promote binding to preformed fibrils and extension of the deposits. It is important that methods to identify patients susceptible to amyloid deposition are developed and therapeutic agents are produced that can reduce or prevent polymerizatin of IAPP to form amyloid and minimize severe deterioration of islet function in Type-2 diabetes.
- Published
- 1996
29. PS17 - 83. Could pancreatic islets derived from pancreases from NHB-III donors be used as autonomous single islet grafts?
- Author
-
C. Vermeulen, Rutger J. Ploeg, A. G. Baranski, E. van Rossenberg, Jeroen Dubbeld, Marten A. Engelse, E. J. P. de Koning, S. Schaapherder, Cindy J.M. Loomans, Jan Ringers, Hendrica A. Töns, and Andries E. Braat
- Subjects
medicine.medical_specialty ,geography ,geography.geographical_feature_category ,business.industry ,Pancreatic islets ,medicine.disease ,Islet ,Andrology ,Organ procurement ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Diabetes mellitus ,medicine ,Pancreas ,business - Abstract
Isolation of pancreatic islets is worldwide performed on organs that are obtained from heartbeating (HB) organ procurement procedures. Distinctively, in The Netherlands and in Belgium a strong tradition has developed in the acquisition of high quality pancreas from (Non-HeartBeating type-III) NHB-III donors. In this study, the feasibility of using pancreatic islets from high quality NHB-III donors autonomously is investigated.
- Published
- 2011
30. Bevacizumab-related hypertension: Search for underlying mechanisms
- Author
-
J. op 't Roodt, Ton J. Rabelink, Hans Gelderblom, Neeltje Steeghs, and E. J. P. de Koning
- Subjects
Cancer Research ,Blood pressure ,Oncology ,Bevacizumab ,Side effect ,biology ,business.industry ,VEGF receptors ,medicine ,biology.protein ,Pharmacology ,business ,medicine.drug - Abstract
e14520 Background: Hypertension is a commonly observed side effect of inhibitors of VEGF/VEGFR-2 signaling such as bevacizumab. The mechanisms leading to this increase in blood pressure during anti-angiogenic therapy have not been elucidated. Recent studies suggest that functional rarefaction (a decrease in perfused microvessels) or anatomic rarefaction (a reduction in capillary density) may play an important role. The purpose of this study was to search for possible mechanisms that cause hypertension in patients treated with anti-angiogenic therapy and to confirm our hypothesis that systemic inhibition of VEGF inhibits vascular function and causes rarefaction. Methods: Patients treated with bevacizumab for any type of cancer were eligible. Measurements of blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), aortic pulse wave velocity (PWV), and capillary density and diameter with sidestream dark field (SDF) imaging of the mucosal microcirculation of the lip were performed at baseline, after 6 weeks of treatment, and 3 months after discontinuation of bevacizumab treatment. Results: Fourteen patients were included in this study. During bevacizumab treatment the mean systolic and diastolic blood pressure values increased, +3.4 mmHg (p=0.406), and +5.6 mmHg (p=0.023) resp. Mean FMD showed a statistically significant decrease of -3.1% (p=0.006). Mean NMD was unchanged. After 6 weeks treatment mean PWV increased significantly +0.7 m/s (p=0.0.027). A significant reduction in capillary density was seen from 18.0 capillary loops per image at baseline to 12.7 after 6 weeks (p=0.000007). Also a significant reduction in capillary diameter was seen, from 6.9 to 5.6 μm (p=0.002). Results after discontinuation of bevacizumab treatment were not yet available. Conclusions: Rarefaction (reduction in capillary density) and endothelial dysfunction observed in this study provide a plausible mechanism for the increase in blood pressure which results from treatment with bevacizumab. No significant financial relationships to disclose.
- Published
- 2009
31. 19th Anglo-Danish-Dutch Diabetes Group meeting
- Author
-
E J P de Koning, Tina Vilsbøll, and Flemming Dela
- Subjects
medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.disease ,language.human_language ,Danish ,Endocrinology ,Group (periodic table) ,Family medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,language ,business - Published
- 2002
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