Table 1.
Summary of metabolite associations with diabetes risk and with diabetes complications.
| Metabolite class/pathway | Example metabolite(s) | Associated phenotypes | Adverse direction | Potential mechanisms and biological implications |
|---|---|---|---|---|
| Branched-chain & aromatic amino acids | Branched-chain: Val, Leu, Ile | T2D, T1D, IR, retinopathy | ↑ (↓ for tyrosine and retinopathy) | From diet or microbial metabolism; ↑ levels in blood from ↓ adipose and liver metabolism; lead to ↑ gluconeogenesis (via mTOR), ↑ de novo lipogenesis (via ChREBP)(15, 16) |
| Aromatic: Phe, Tyr | ||||
| Glutamate/glutamine cycle | Glutamate | T2D, T1D, retinopathy | ↑ (↓ for retinopathy) | Glutamate promotes gluconeogenesis, muscle proteolysis, inflammation (via glutathione synthase)(20) Glutamine regulates insulin secretion, pancreatic β-cell function(4); contributes to cellular metabolism (anaplerosis) |
| Glutamine | ↓ (↑ for retinopathy) | |||
| Amino acid | Glycine | T2D, IR, hepatic steatosis | ↓ | Glycine involved in many homeostatic processes; protective; depletion may reflect oxidative stress and ↑ gluconeogenesis(9) |
| Glycolysis & cellular respiration | Lactate, pyruvate, alanine | T2D, T1D, kidney disease, CVD | ↑ | Pyruvate formed via glycolysis, leads to aerobic or anaerobic (lactate producing) respiration; alanine a substrate for TCA, Cahill cycles; ↑ levels due to mitochondrial dysfunction, ↓ oxidative capacity(3, 25) |
| ADMA metabolism | DMGV | Hepatic steatosis, fitness, T2D, CVD | ↑ | Formed by transamination of ADMA; dynamic to lifestyle changes(28, 29) |
| ADMA | Retinopathy, CVD | ADMA is an inhibitor of nitric oxide (NO) synthase, noted to be elevated in diabetes | ||
| NO metabolism | Arginine, citrulline | Retinopathy | ↑ | Arginine and citrulline are NO precursors; ↑ levels in microvascular complications reflects altered NO metabolism |
| Lysine metabolism | Lysine | T2D, CVD | ↑ (T2D)/ ↓ (CVD) | Amino acid, theorized to be elevated in T2D as response to upregulation of 2-AAA (for which it is precursor) |
| 2-alpha aminoadipic acid (2-AAA) | T2D | ↑ | Function is incompletely understood; produced by oxidative stress; promotes adipogenesis(33) | |
| Vitamin C metabolism | Dehydroascorbic acid (DHAA) | T1D | ↑ | Oxidized form of vitmin C; substrate for glutathione; may inhibit insulin secretion(42) |
| Hydroxy acids and derivatives | 3,4 dihydroxybutyric acid (DHBA) | Retinopathy | ↑ | Related to ketone bodies, may be higher in high fat diet; related to dyslipidemia(55) |
| Triglyceride metabolism | Triacylglycerols (TAGs) with ↓ carbon and double bond numbers | Hepatic steatosis, T2D, T1D, retinopathy, neuropathy, kidney disease | ↑ | Hypothesized to primarily reflect IR in the liver, may contribute to lipotoxicity |
| Additional lipid species | Phospthatidylcholines (PCs) and lysoPCs | T2D, kidney disease | ↑/↓ | Similar to TAGs, ↓carbon number and double bond content are linked with adverse outcomes; choline containing lipids, components of cell membrane and lipid metabolism(9) |
| Acylcarnitines | T2D, neuropathy, CVD | ↑ | Reflection of impaired mitochondrial function, reduced oxidative capacity |
This table is not an exhaustive list of all metabolites that have been associated with diabetes or its complications. It is intended to highlight metabolites discussed in this review and to demonstrate their links to relevant metabolic pathways.
Abbreviations: Val, valine; Leu, leucine; Ile, isoleucine; Phe, phenylalanine; Tyr, tyrosine; T2D, type 2 diabetes; T1D, type 1 diabetes; IR, insulin resistance; TCA, ticarboxylic acid; DMGV, dimethylguanidino valeric acid; ADMA, asymmetric dimethylarginine;