The analysis of advanced glycation endproducts Citation for published version (APA): Scheijen, J. J. L. J. M. (2017). The analysis of advanced glycation endproducts: a mass spectrometry–based approach & its applications. Datawyse / Universitaire Pers Maastricht. https://doi.org/10.26481/dis.20170621js Document status and date: Published: 01/01/2017 DOI: 10.26481/dis.20170621js Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. 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Scheijen Layout & Cover design: Jean Scheijen | vierdrie.nl Production: Datawyse | Universitaire Pers Maastricht ISBN: 978 94 6159 703 8 The analysis of ADVANCED GLYCATION ENDPRODUCTS A mass spectrometry-based approach & its applications PROEFSCHRIFT Ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van de Rector Magnificus, Prof. dr. Rianne M. Letschert, volgens het besluit van het College van Decanen, in het openbaar te verdedigen op woensdag 21 juni 2017 om 16:00 uur door JEAN JOHANNES LAMBERTUS JOSEPH MARIE SCHEIJEN Promotores Prof. dr. C.G. Schalkwijk Prof. dr. C.D.A. Stehouwer Beoordelingscommissie Prof. dr. T.M. Hackeng (Voorzitter) Prof. dr. V. Fogliano (Wageningen University and Research, WUR) Prof. dr. R.M.A. Heeren Prof. dr. H.W.M. Niessen (University Medical Center Amsterdam, VUmc) Prof. dr. A. Opperhuizen (Nederlandse Voedsel en Warenautoriteit, NVWA) Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged. CONTENTS CHAPTER 1 General introduction 7 CHAPTER 2A Measurement of pentosidine in human plasma protein by 29 a single-column High-Performance Liquid Chromatography method with fluorescence detection CHAPTER 2B Measurement of advanced glycation endproducts in human 43 plasma by ultra-performance liquid chromatography tandem mass spectrometry CHAPTER 3 Plasma levels of advanced glycation endproducts 59 Nɸ-(carboxymethyl)lysine, Nɸ-(carboxyethyl)lysine and pentosidine are not independently associated with cardiovascular disease in individuals with or without type 2 diabetes: the Hoorn and CODAM Studies CHAPTER 4 L(+) and D(-) Lactate are increased in plasma and urine samples 81 of type 2 diabetes as measured by a simultaneous quantification of L(+) and D(-) Lactate by Reversed Phase Liquid Chromatography Tandem Mass Spectrometry CHAPTER 5 Higher plasma concentrations of the methylglyoxal metabolite 99 D-lactate are independently associated with insulin resistance: the CODAM study CHAPTER 6 Quantification of glyoxal, methylglyoxal and 3 deoxyglucosone in 111 blood and plasma by ultra performance liquid chromatography tandem mass spectrometry; evaluation of blood specimen CHAPTER 7 Post-glucose load plasma ɲ-dicarbonyl concentrations are 125 increased in individuals with impaired glucose metabolism and type 2 diabetes: The CODAM study CHAPTER 8 Analysis of advanced glycation endproducts in selected food 145 items by ultra-performance liquid chromatography tandem mass spectrometry; presentation of a dietary AGE database CONTENTS CHAPTER 9 Dietary intake of advanced glycation endproducts is associated 169 with higher levels of advanced glycation endproducts in plasma and urine: the CODAM study CHAPTER 10 Summary & general discussion 185 & Samenvatting 207 Valorization 215 Curriculum vitae 223 Scientific output 227 Dankwoord 233 Foods & Polaroid 239 8~Chapter 1 1 1 General introduction General introduction ~9 General Introduction 1 Diabetes, vascular disease and advanced glycation endproducts Age-related, non-communicable chronic inflammatory diseases like cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) represent a major 21st century health problem. The prevalence of these diseases is exponentially rising as the population ages. Diabetes is a common metabolic disease affecting approximately 422 million people worldwide in 20141, which is predicted to rise to 600 million in 2040. In the Netherlands, one million people have diabetes, which is predicted to rise to 1.3 million in 20252. Diabetes is a serious chronic disease characterized by elevated plasma glucose levels. There are two main types of diabetes: type 1 diabetes mellitus (T1DM) and T2DM. T1DM is characterized by an absolute insulin deficiency as caused by an autoimmune destruction of the pancreatic beta cells. T1DM accounts for approximately 10% of the prevalence of diabetes 3. T2DM is characterized by insulin resistance despite of high levels of insulin. This will ultimately result in an absolute defective insulin secretion. T2DM accounts for approximately 90% of all individuals with diabetes and is primarily caused by lifestyle factors, such as overweight and lack of physical activity3. The current obesity epidemic has led to a strong increase in the prevalence of T2DM4. The burden of T2DM is mainly determined by macro- and microvascular diseases. Macrovascular disease affects larger blood vessels through atherosclerosis and affects the coronary, the carotid and the peripheral arteries, thus increasing the risk for heart attack, stroke and diabetic foot. Individuals with diabetes are at a 2- to 4-fold increased risk of cardiovascular events compared to non-diabetic individuals5,6. CVDs are the number 1 cause of death globally, an estimated 17.5 million deaths were directly caused by CVD in 20127. Microvascular disease affects smaller blood vessels of the eyes, kidneys, and nerves8 increasing the risk of retinopathy, nephropathy and neuropathy, respectively 9. Diabetes and its associated complications leads to a permanent and significant loss of quality of life and are acknowledged to be among the highest burden for health care costs10. Therefore, prevention of diabetes and in case of diabetes, prevention of cardiovascular disease is of highest importance and clearly represents a medical and economical need. Future strategies should therefore focus primarily on the prevention of diabetes and improved stratification algorithms to allow identification of those who are at risk for developing vascular complications. Early identification of vascular risk is a cornerstone of diabetes management and facilitates tailored intervention at an early stage of disease when a useful response is more likely to be obtained. Given the enormous impact of vascular disease, it is of utmost importance to find biomarkers for the identification of diabetic individuals at high risk of developing vascular complications and morbidity; i.e. to improve risk prediction11. So far, the established cardiovascular risk factors and the derived algorithms do not fully explain vascular risk12. It is very likely that markers of pathophysiological pathways, which are not covered by the well-known risk factors, will improve risk score. 10~Chapter 1 Various mechanisms have been proposed to explain how hyperglycaemia directly causes 1 diabetic vascular complications, including the polyol pathway, an increase in glucosamine- 6-phosphate via the hexosamine pathway, the activation of protein kinase C (PKC) via de novo synthesis of diacylglycerol (DAG) and the non-enzymatic glycation of proteins13. The biochemical process of the formation of advanced glycation endproducts (AGEs), which is accelerated in patients with diabetes as a result of elevated plasma glucose levels and increased oxidative stress, has been related to diabetic complications8,13. Increased formation and accumulation of AGEs is common in patients with diabetes, and, because of impaired clearance, in particular those