Metabolomics in cardiometabolic diseases: Key biomarkers and therapeutic implications for insulin resistance and diabetes

Abstract

Cardiometabolic diseases-including Type 2 diabetes and obesity-remain leading causes of global mortality. Recent advancements in metabolomics have facilitated the identification of metabolites that are integral to the development of insulin resistance, a characteristic feature of cardiometabolic disease. Key metabolites, such as branched-chain amino acids (BCAAs), ceramides, glycine, and glutamine, have emerged as valuable biomarkers for early diagnosis, risk stratification, and potential therapeutic targets. Elevated BCAAs and ceramides are strongly associated with insulin resistance and Type 2 diabetes, whereas glycine exhibits an inverse relationship with insulin resistance, making it a promising therapeutic target. Metabolites involved in energy stress, including ketone bodies, lactate, and nicotinamide adenine dinucleotide (NAD⁺), regulate insulin sensitivity and metabolic health, with ketogenic diets and NAD⁺ precursor supplementation showing potential benefits. Additionally, the novel biomarker N-lactoyl-phenylalanine further underscores the complexity of metabolic regulation and its therapeutic potential. This review underscores the potential of metabolite-based diagnostics and precision medicine, which could enhance efforts in the prevention, diagnosis, and treatment of cardiometabolic diseases, ultimately improving patient outcomes and quality of life.

Keywords: biomarkers; cardiometabolic diseases; insulin resistance; metabolomics; therapeutic targets.

Fig. 1

Metabolite‐mediated regulation of cellular function. Metabolites regulate cellular processes through four main mechanisms: (1) Substrate availability—metabolites act as precursors or intermediates in enzymatic reactions, thereby controlling the production of downstream products and influencing metabolic flux. (2) Allosteric regulation—metabolites bind to enzymes at non‐active sites, altering the conformation and activity of proteins to fine‐tune metabolic flux based on cellular demands. (3) Signaling molecules—metabolites act as signaling molecules by interacting with receptors or proteins to activate pathways that regulate cellular processes, such as energy balance, growth, and stress responses. (4) Post‐translational modifications—metabolites such as glucose (Glu), acetate (Ac), lipids (Lip), glucose derivatives (Glc), lactate (Lac), and methyl groups (Me) directly modify proteins, thereby altering function, stability, or localization, to regulate cellular activities. Additionally, the metabolic flux between anaplerosis (replenishment of intermediates) and cataplerosis (removal of intermediates) ensures mitochondrial metabolic balance. Therefore, alterations in metabolite levels can trigger widespread disruptions in cellular processes, amplifying effects through changes in enzyme activity, signaling pathways, and protein function. Source: Created in BioRender. Rizo Roca, D. (2025) https://BioRender.com/v67h675.

Fig. 2

Metabolites associated with insulin resistance. (a) Amino acids—role of amino acids, particularly branched‐chain amino acids (BCAAs), glutamine (Gln), glycine (Gly), and phenylalanine (Phe), in insulin resistance. Impaired BCAA catabolism leads to the accumulation of intermediates such as 3‐hydroxyisobutyrate (3‐HIB), which facilitates fatty acid (FA) uptake and contributes to lipotoxicity in skeletal muscle. Low levels of glutamine are associated with inflammation and decreased production of glucagon‐like peptide‐1 (GLP‐1). Changes in gut microbiota and increased degradation lead to lower levels of glycine in individuals with insulin resistance. These changes are potentially associated with increased food intake and hepatic glucose production. Lysine phenylalanylation of the β‐subunit of the insulin receptor increases in a dose‐dependent manner and inhibits insulin signaling. (b) Lipids—Lipid metabolism and its impact on insulin resistance. Increased ceramide (Cer) synthesis contributes to insulin resistance through protein kinase C zeta (PKCζ)‐mediated inhibition of protein kinase B (Akt). Insulin resistance is further exacerbated by endoplasmic reticulum (ER) stress associated with lipid overload. Impaired BCAA catabolism and incomplete FA oxidation (FAO) enhance the production of acylcarnitines, leading to the concomitant exacerbation of Cer synthesis. Lysophosphatidylcholine (LPC) can activate G‐protein‐coupled receptor 119 (GPR119) and stimulate insulin secretion from pancreatic β‐cells. Therefore, lower circulating LPC levels observed in Type 2 diabetes may contribute to impaired insulin release and β‐cell dysfunction. (c) Energy stress—Perturbations in cellular energy homeostasis, including alterations in nicotinamide adenine dinucleotide (NAD⁺)‐dependent pathways and lactate production, may exacerbate insulin resistance. Increased reliance on glycolysis, especially under insulin‐resistant conditions, leads to enhanced lactate production, which in turn contributes to hepatic glucose production via the Cori cycle. Reduced NAD⁺ levels lead to decreased activity of insulin‐sensitizing sirtuins (SIRTs), such as SIRT1, impairing metabolic regulation and contributing to the development of insulin resistance. Under certain dietary conditions, such as caloric restriction or ketogenic diets, ketogenesis is enhanced, leading to the production of ketone bodies like β‐hydroxybutyrate (3HB), which can modulate key metabolic regulators such as peroxisome proliferator‐activated receptors (PPARs) and AMP‐activated protein kinase (AMPK), potentially improving insulin sensitivity and metabolic flexibility. (d) Metabolite network: Overview of the interconnected metabolite network associated with insulin resistance. This network illustrates the complex interplay between different metabolic pathways, including gluconeogenic and ketogenic amino acids, glycolysis, the tricarboxylic acid (TCA) cycle, ketogenesis, and lipolysis. CERS6, ceramide synthase 6; CNDP2, carnosine dipeptidase; FFA, free fatty acids; GCS, glycine cleavage system; GLS, glutaminase; Glu, glutamate; HMG‐CoA, 3‐hydroxy‐3‐methylglutaryl coenzyme A; NMDA, N‐methyl‐d‐aspartate; PKA, protein kinase A; PAH, phenylalanine hydroxylase; SMase, sphingomyelinase. Source: Created in BioRender. Rizo Roca, D. (2025) https://BioRender.com/v15d089.