Metabolomics Identifies Distinctive Metabolite Signatures for Measures of Glucose Homeostasis: The Insulin Resistance Atherosclerosis Family Study (IRAS-FS)

Abstract

Context: Metabolomics provides a biochemical fingerprint that, when coupled with clinical phenotypes, can provide insight into physiological processes.

Objective: Survey metabolites associated with dynamic and basal measures of glucose homeostasis.

Design: Analysis of 733 plasma metabolites from the Insulin Resistance Atherosclerosis Family Study.

Setting: Community based.

Participants: One thousand one hundred eleven Mexican Americans.

Main outcome: Dynamic measures were obtained from the frequently sampled intravenous glucose tolerance test and included insulin sensitivity and acute insulin response to glucose. Basal measures included homeostatic model assessment of insulin resistance and β-cell function.

Results: Insulin sensitivity was associated with 99 metabolites (P < 6.82 × 10-5) explaining 28% of the variance (R2adj) beyond 28% by body mass index. Beyond branched chain amino acids (BCAAs; P = 1.85 × 10-18 to 1.70 × 10-5, R2adj = 8.1%) and phospholipids (P = 3.51 × 10-17 to 3.00 × 10-5, R2adj = 14%), novel signatures of long-chain fatty acids (LCFAs; P = 4.49 × 10-23 to 4.14 × 10-7, R2adj = 11%) were observed. Conditional analysis suggested that BCAA and LCFA signatures were independent. LCFAs were not associated with homeostatic model assessment of insulin resistance (P > 0.024). Acute insulin response to glucose was associated with six metabolites; glucose had the strongest association (P = 5.68 × 10-16). Homeostatic model assessment of β-cell function had significant signatures from the urea cycle (P = 9.64 × 10-14 to 7.27 × 10-6, R2adj = 11%). Novel associations of polyunsaturated fatty acids (P = 2.58 × 10-13 to 6.70 × 10-5, R2adj = 10%) and LCFAs (P = 9.06 × 10-15 to 3.93 × 10-7, R2adj = 10%) were observed with glucose effectiveness. Assessment of the hyperbolic relationship between insulin sensitivity and secretion through the disposition index revealed a distinctive signature of polyunsaturated fatty acids (P = 1.55 × 10-12 to 5.81 × 10-6; R2adj = 3.8%) beyond that of its component measures.

Conclusions: Metabolomics reveals distinct signatures that differentiate dynamic and basal measures of glucose homeostasis and further identifies new metabolite classes associated with dynamic measures, providing expanded insight into the metabolic basis of insulin resistance.

Figure 1.

Overlap of significant metabolites between dynamic and basal measures of glucose homeostasis.

Figure 2.

(A) Opposed plot of metabolite associations with S_I and HOMA_IR. Log-transformed P values are shown for association with S_I (top) and HOMA_IR (bottom). Metabolites are plotted by superpathway: amino acids (blue), carbohydrates (orange), cofactors and vitamins (green), energy (yellow), lipids (pink), nucleotides (turquoise), and peptides (purple). The gray lines correspond to statistical significance (P < 6.82 × 10⁻⁵, corrected for 733 metabolites) in each direction. (B) Opposed plot of metabolite associations with AIR_g and HOMA_B. Log-transformed P values are shown for association with AIR_g (top) and HOMA_B (bottom). Metabolites are plotted by superpathway: amino acids (blue), carbohydrates (orange), cofactors and vitamins (green), energy (yellow), lipids (pink), nucleotides (turquoise), and peptides (purple). The gray lines correspond to statistical significance (P < 6.82 × 10⁻⁵, corrected for 733 metabolites) in each direction. (C) Manhattan plot of metabolite associations with S_G. Log-transformed P values are shown for association with S_G. Metabolites are plotted by superpathway: amino acids (blue), carbohydrates (orange), cofactors and vitamins (green), energy (yellow), lipids (pink), nucleotides (turquoise), and peptides (purple). The gray lines correspond to statistical significance (P < 6.82 × 10⁻⁵, corrected for 733 metabolites). (D) Manhattan plot of metabolite associations with DI. Log-transformed P values are shown for association with DI. Metabolites are plotted by superpathway: amino acids (blue), carbohydrates (orange), cofactors and vitamins (green), energy (yellow), lipids (pink), nucleotides (turquoise), and peptides (purple). The gray lines correspond to statistical significance (P < 6.82 × 10⁻⁵, corrected for 733 metabolites).