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Which metabolites most strongly predict type 2 diabetes risk beyond traditional factors
Most informative predictors come from amino acids, carbohydrate/energy metabolites, and specific lipid classes measured in large prospective cohorts.
Key multimetabolite signatures
Plasma 44-metabolite panel (Nature Medicine)
In
23,000 adults without baseline diabetes, a 44-metabolite blood signature predicted incident type 2 diabetes (T2D) with AUC 0.62–0.86 across independent cohorts and conferred ~5-fold higher risk in the top vs bottom decile (risk ratio 5.07, 95% CI 4.02–6.39).1 This signature improved risk prediction beyond traditional clinical factors (BMI, lifestyle, etc.).1 Individual metabolite classes most strongly linked to T2D risk Based on a meta-analysis of 61 prospective reports (71,196 participants; 11,771 T2D cases; 412 metabolites analyzed):2 Metabolites associated with higher T2D risk (HR ≈1.07–2.58 per SD): - Amino acids - Branched-chain AAs: leucine, isoleucine, valine - Aromatic AAs: phenylalanine, tyrosine - Others: alanine, glutamate, lysine, methionine2 - Carbohydrate/energy-related metabolites - Mannose, trehalose, pyruvate2 - Acylcarnitines - C4-DC, C4-OH, C5, C5-OH, C8:12 - Lipid species - Most glycerolipids (diacylglycerols, triacylglycerols) - (Lyso)phosphatidylethanolamines - Ceramides2 Metabolites associated with lower T2D risk (HR ≈0.69–0.90 per SD): - Amino acids and related: glycine, glutamine, betaine2 - Microbial/tryptophan-derived: indolepropionate2 - Lipid species: multiple (lyso)phosphatidylcholines2 Interpretation for risk stratification These metabolites collectively reflect insulin resistance, β‑cell stress, ectopic fat, and hepatic dysfunction, and, when combined into multi-metabolite scores, materially enhance discrimination of future T2D beyond standard clinical models.1,2
23,000 adults without baseline diabetes, a 44-metabolite blood signature predicted incident type 2 diabetes (T2D) with AUC 0.62–0.86 across independent cohorts and conferred ~5-fold higher risk in the top vs bottom decile (risk ratio 5.07, 95% CI 4.02–6.39).1 This signature improved risk prediction beyond traditional clinical factors (BMI, lifestyle, etc.).1 Individual metabolite classes most strongly linked to T2D risk Based on a meta-analysis of 61 prospective reports (71,196 participants; 11,771 T2D cases; 412 metabolites analyzed):2 Metabolites associated with higher T2D risk (HR ≈1.07–2.58 per SD): - Amino acids - Branched-chain AAs: leucine, isoleucine, valine - Aromatic AAs: phenylalanine, tyrosine - Others: alanine, glutamate, lysine, methionine2 - Carbohydrate/energy-related metabolites - Mannose, trehalose, pyruvate2 - Acylcarnitines - C4-DC, C4-OH, C5, C5-OH, C8:12 - Lipid species - Most glycerolipids (diacylglycerols, triacylglycerols) - (Lyso)phosphatidylethanolamines - Ceramides2 Metabolites associated with lower T2D risk (HR ≈0.69–0.90 per SD): - Amino acids and related: glycine, glutamine, betaine2 - Microbial/tryptophan-derived: indolepropionate2 - Lipid species: multiple (lyso)phosphatidylcholines2 Interpretation for risk stratification These metabolites collectively reflect insulin resistance, β‑cell stress, ectopic fat, and hepatic dysfunction, and, when combined into multi-metabolite scores, materially enhance discrimination of future T2D beyond standard clinical models.1,2
References at link.
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