Assessment of the Metabolic Pathways Associated With Glucose-Stimulated Biphasic Insulin Secretion

• DOI: 10.1210/en.2013-1805
• Publication Date: 2014-02-24T20:43:52Z
• Authors: Mei Huang; Jamie W. Joseph
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Citric Acid Cycle; Osmolar Concentration; Gas Chromatography-Mass Spectrometry; Hypoglycemia; Cell Line; Clone Cells; Rats; 3. Good health; Pentose Phosphate Pathway; Rats, Sprague-Dawley; Islets of Langerhans; Kinetics; 03 medical and health sciences; Glucose; Hyperglycemia; Insulin-Secreting Cells; Insulin Secretion; Metabolome; Animals; Insulin; Glycolysis

Biphasic glucose-stimulated insulin secretion involves a rapid first phase followed by a prolonged second phase of insulin secretion. The biochemical pathways that control these 2 phases of insulin secretion are poorly defined. In this study, we used a gas chromatography mass spectroscopy-based metabolomics approach to perform a global analysis of cellular metabolism during biphasic insulin secretion. A time course metabolomic analysis of the clonal β-cell line 832/13 cells showed that glycolytic, tricarboxylic acid, pentose phosphate pathway, and several amino acids were strongly correlated to biphasic insulin secretion. Interestingly, first-phase insulin secretion was negatively associated with l-valine, trans-4-hydroxy-l-proline, trans-3-hydroxy-l-proline, dl-3-aminoisobutyric acid, l-glutamine, sarcosine, l-lysine, and thymine and positively with l-glutamic acid, flavin adenine dinucleotide, caprylic acid, uridine 5′-monophosphate, phosphoglycerate, myristic acid, capric acid, oleic acid, linoleic acid, and palmitoleic acid. Tricarboxylic acid cycle intermediates pyruvate, α-ketoglutarate, and succinate were positively associated with second-phase insulin secretion. Other metabolites such as myo-inositol, cholesterol, dl-3-aminobutyric acid, and l-norleucine were negatively associated metabolites with the second-phase of insulin secretion. These studies provide a detailed analysis of key metabolites that are either negatively or positively associated with biphasic insulin secretion. The insights provided by these data set create a framework for planning future studies in the assessment of the metabolic regulation of biphasic insulin secretion.