Metabolomics and flux analysis by mass spectrometry : Investigations of factors associated with insulin secretion and prostate cancer risk

Abstract: Two of the most common diseases associated with the Western lifestyle are type 2 diabetes (T2D) and prostate cancer (PCa). This is in large part due to decreased physical activity, surplus of dietary energy, and an ageing population. T2D and PCa are illnesses that develop during a long period of time and metabolic alterations associated with the diseases are not known in detail. Three studies investigating metabolic alterations associated with the risk of T2D and PCa were performed using liquid chromatography-high-resolution mass spectrometry-based metabolomics and stable isotope labelling.  A human intervention study investigating insulin secretion in response to breads varying in digestibility showed a decreased insulin response when rye bread was ingested in comparison with wheat bread, owing to a reduced rate of glucose appearance in blood, even though the blood glucose levels were unaffected.  Short-term incubation of human EndoC-βH1 cells with glucose and/or palmitic acid in vitro showed an increased Krebs cycle activity by glucose and an increased Krebs cycle flux by palmitate co-incubation, possibly mediated via pyruvate carboxylase. Proline containing carbon from the added glucose was also formed and excreted by the cells, uncovering a new fuel excess detoxification process. An untargeted metabolomics study using 752 case-control pairs of fasting plasma samples matched by age, BMI, and sample storage time from the Northern Sweden Health and Disease Study was conducted in order to look for metabolites prospectively associated with prostate cancer risk. This is the largest prospective untargeted metabolomics study focused on PCa risk to date. Metabolites belonging to different chemical classes i.a. aromatic amino acids, several kinds of phospholipids, and free fatty acids were found to be positively associated with the risk of future PCa, while glucose was found to be inversely associated. Stratification by disease aggressiveness and by baseline age showed variations in which metabolites were associated with PCa risk, as well as showing variations in their degrees of association. 

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