Abstract
Current diagnostic tests such as glycemic indicators have limitations for early detection of impaired glucose tolerance (IGT), which leads to diabetes. Oxidative stress induced by various oxidants in a random and destructive manner is considered to play an important role in the pathophysiology of a number of human disorders and diseases such as impaired glucose tolerance. We have developed an improved method for the measurement of in vivo lipid peroxidation, where the presence of 8-iso-prostaglandin F2α (8-iso-PGF2α), hydroxyoctadecadienoic acids (HODEs), hydroxyeicosatetraenoic acids (HETEs), and 7-hydroxycholesterol (7-OHCh), as well as their parent molecules, linoleic acid (LA) and cholesterol (Ch), was determined by performing LC-MS/MS (for 8-iso-PGF2α, HODE, and HETE) and GC-MS (for 7-OHCh, LA, and Ch) after reduction with triphenyl phosphine and saponification by potassium hydroxide. We then applied this method to volunteers (n = 57), including normal type (n = 43), “high-normal” (fasting plasma glucose, 100–109 mg/dL, n = 7), pre-diabetic type (IGT, n = 5), and diabetic type (n = 2) subjects who are diagnosed by performing oral glucose tolerance tests (OGTTs). Several biomarkers in plasma, such as insulin, leptin, adiponectin, interleukin-6, tumor necrosis factor-α, high sensitivity-C-reactive protein, HbA1c, and glucose levels were measured during OGTT. We found that the fasting levels of (10- and 12-(Z,E)- HODE)/LA increased significantly with increasing levels of HbA1c and glucose during OGTT and with insulin secretion and resistance index. In conclusion, 10- and 12-(Z,E)-HODE may be prominent biomarkers for the early detection of IGT and “high-normal” type without OGTT.
Highlights
In 2011, there were about 366 million diabetes patients ages 20– 79 years worldwide, but it was estimated that there will be 552 million diabetes patients worldwide within the 20 years [International Diabetes Federation
We focused on the detection of the impaired glucose tolerance (IGT) and ‘‘highnormal’’ states by using the lipid peroxidation biomarkers mentioned above, clarifying the pathogenic mechanisms promoting oxidative stress, and determining the method of early detection of the disease
Materials 8-iso-PGF2a, 8-iso-PGF2a-d4, 5-hydroxyeicosatetraenoic acids (HETEs), 12-HETE, 15-HETE, 13-hydroxy-9Z, 11E-octadecadienoic acid (13-(Z,E)-hydroxyoctadecadienoic acids (HODEs)), 9(Z,E)-HODE, and 13-HODE-d4 were obtained from Cayman Chemical Company (MI, USA). 9-(E,E)-HODE, 13-(E,E)HODE, 10-(Z,E)-HODE, and 12-(Z,E)-HODE were obtained from Larodan Fine Chemicals AB (Malmo, Sweden). 7b-OHCh were obtained from Steraloid Inc. (RI, USA), and their isotopes 7b-OHCh-d7 were obtained from Medical Isotopes Inc
Summary
In 2011, there were about 366 million diabetes patients ages 20– 79 years worldwide, but it was estimated that there will be 552 million diabetes patients worldwide within the 20 years [International Diabetes Federation. The committee of the Japan Diabetic Society recommends that subjects with a fasting plasma glucose (FPG) value of 100–109 mg/dL be classified as ‘‘high-normal’’ in the normal range of glucose metabolism disorders and that subjects with a ‘‘high-normal’’ FPG values undergo a 75 g OGTT for diagnosis as normal-, pre-diabetic-, or diabetic- type [1]. It is very important to clarify the states of pre-diabetes, determined as both impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG), and ‘‘high-normal’’. It is highly crucial to identify potent biomarkers that would enable us to determine glucose homeostasis disorder at its early stage. From this point of view, several traditional biomarkers have been proposed, such as malondialdehyde, catalase [2], thioredoxin [3], cholesterol oxides
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