Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity

Abstract

Glucose ingestion after an overnight fast triggers an insulin-dependent, homeostatic program that is altered in diabetes. The full spectrum of biochemical changes associated with this transition is currently unknown. We have developed a mass spectrometry-based strategy to simultaneously measure 191 metabolites following glucose ingestion. In two groups of healthy individuals (n¼22 and 25), 18 plasma metabolites changed reproducibly, including bile acids, urea cycle intermediates, and purine degradation products, none of which were previously linked to glucose homeostasis. The metabolite dynamics also revealed insulin's known actions along four key axesproteolysis, lipolysis, ketogenesis, and glycolysis-reflecting a switch from catabolism to anabolism. In pre-diabetics (n¼25), we observed a blunted response in all four axes that correlated with insulin resistance. Multivariate analysis revealed that declines in glycerol and leucine/isoleucine (markers of lipolysis and proteolysis, respectively) jointly provide the strongest predictor of insulin sensitivity. This observation indicates that some humans are selectively resistant to insulin's suppression of proteolysis, whereas others, to insulin's suppression of lipolysis. Our findings lay the groundwork for using metabolic profiling to define an individual's 'insulin response profile', which could have value in predicting diabetes, its complications, and in guiding therapy.

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells

“…Although our first human cohort was not balanced with respect to recent food intake, replication of the Cr elevation in a second cohort, which was balanced in that respect, has increased our confidence that the elevation observed in the first cohort was not caused by dietary Cr. In addition, we have reported previously on the effect of glucose ingestion on the plasma levels of metabolites (14); although Cr was measured in plasma, glucose ingestion did not affect Cr plasma levels. We also considered as potential confounders age and gender, which were balanced in one of two cohorts (Materials and Methods).…”

“…This hypothesis stems from the notion that the net sum of secretion and consumption by all body cells determines the concentration of metabolites in plasma. We recently have developed a targeted mass spectrometry (MS) method capable of measuring 191 metabolites in biological samples (13,14). Importantly, this method spans a wide biochemical spectrum including amino acids, organic acids, nucleotides, and sugars, enabling simultaneous monitoring of multiple pathways.…”

The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice

“…Several important functions in the liver are regulated by insulin, including protein and lipid synthesis, lipid storage, glycolysis, glucose storage, gluconeogenesis and the inhibition of ketogenesis (Shaham et al ., 2008). With age, insulin resistance and visceral adiposity increase, this can cause an increase in inflammation and interfere with systemic glucose and lipid metabolism (Shoelson et al ., 2006; Sepe et al ., 2011).…”

Lactation is associated with altered metabolomic signatures in women with gestational diabetes

“…A decrease in plasma leucine concentrations after a glucose challenge has been reported in healthy adults [35]. In contrast, increased concentrations of (iso)leucine have been reported after a glucose challenge and standardised meal challenge in individuals with insulin resistance and in patients with type 2 diabetes [33,36].…”