Metabolic Signature Shift in Type 2 Diabetes Mellitus Revealed by Mass Spectrometry-based Metabolomics

Abstract

Metabolic profiling of small molecules offers a snapshot of physiological processes. To identify metabolic signatures associated with type 2 diabetes and impaired fasting glucose (IFG) beyond differences in glucose, we used mass spectrometry-based metabolic profiling. Individuals attending an institutional health screen were enrolled. IFG (n = 24) was defined as fasting glucose (FG) of 6.1 to 6.9 mmol/L and 2-hour post glucose load <11.1 mmol/L or glycosylated hemoglobin <6.5%, type 2 diabetes (n = 27), FG ≥7.0 mmol/L, or 2-hour post glucose load ≥11.1 mmol/L, or glycosylated hemoglobin ≥6.5%, and healthy controls (n = 60), FG <6.1 mmol/L. Fasting serum metabolomes were profiled and compared using gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. Compared to healthy controls, those with IFG and type 2 diabetes had significantly raised fructose, α-hydroxybutyrate, alanine, proline, phenylalanine, glutamine, branched-chain amino acids (leucine, isoleucine, and valine), low carbon number lipids (myristic, palmitic, and stearic acid), and significantly reduced pyroglutamic acid, glycerophospohlipids, and sphingomyelins, even after adjusting for age, gender, and body mass index. Using 2 highly sensitive metabolomic techniques, we report distinct serum profile change of a wide range of metabolites from healthy persons to type 2 diabetes mellitus. Apart from glucose, IFG and diabetes mellitus are characterized by abnormalities in amino acid, fatty acids, glycerophospholipids, and sphingomyelin metabolism. These early broad-spectrum metabolic changes emphasize the complex abnormalities present in a disease defined mainly by elevated blood glucose levels.