Metabolomics in Diabetes and Diabetic Complications: Insights from Epidemiological Studies

Abstract

The increasing prevalence of diabetes and its complications, such as cardiovascular and kidney disease, remains a huge burden globally. Identification of biomarkers for the screening, diagnosis, and prognosis of diabetes and its complications and better understanding of the molecular pathways involved in the development and progression of diabetes can facilitate individualized prevention and treatment. With the advancement of analytical techniques, metabolomics can identify and quantify multiple biomarkers simultaneously in a high-throughput manner. Providing information on underlying metabolic pathways, metabolomics can further identify mechanisms of diabetes and its progression. The application of metabolomics in epidemiological studies have identified novel biomarkers for type 2 diabetes (T2D) and its complications, such as branched-chain amino acids, metabolites of phenylalanine, metabolites involved in energy metabolism, and lipid metabolism. Metabolomics have also been applied to explore the potential pathways modulated by medications. Investigating diabetes using a systems biology approach by integrating metabolomics with other omics data, such as genetics, transcriptomics, proteomics, and clinical data can present a comprehensive metabolic network and facilitate causal inference. In this regard, metabolomics can deepen the molecular understanding, help identify potential therapeutic targets, and improve the prevention and management of T2D and its complications. The current review focused on metabolomic biomarkers for kidney and cardiovascular disease in T2D identified from epidemiological studies, and will also provide a brief overview on metabolomic investigations for T2D.

Keywords: biomarkers; cardiovascular disease; chronic kidney disease; metabolomics; type 2 diabetes.

Figure 1

Metabolomics provide a comprehensive molecular profile of a phenotype by integrating both endogenous and exogenous information. Metabolites are the downstream products of the genome, transcriptome, proteome, and enzymatic reactions, which are also affected by environmental exposures, such as environmental pollution, physical activities, medications, and diet. The metabolome is closely correlated with genes in which even one single base change in a protein-coding gene can result in 10,000-fold change in the level of a metabolite. In contrast to the relatively simple chemical constitutions of genome (4 nucleotide bases) and proteome (20 proteogenic amino acids), the metabolome consists of thousands of different chemical classes and the number of metabolites is estimated to be around 1 million, while the number of genes and proteins are about 20,000 and 620,000, respectively. Thus, metabolomics provides a comprehensive molecular profile of a phenotype.

Figure 2

The role of BCAAs in the progression from insulin resistance to type 2 diabetes. In mendelian randomization studies, genetically predicted insulin resistance increased BCAAs, rather than the reverse. BCAAs oxidation in adipose tissue and liver was decreased in people with insulin resistance, leading to elevated circulating BCAAs. Obese microbiomes could elevate BCAAs. One of the BCAAs, leucine, could activate the mTOR pathway. The above findings suggest a potential mediating role of BCAAs in the progression from insulin resistance to type 2 diabetes. Increased BCAAs oxidation in skeletal muscle depletes the intracellular pool of glycine and increases 3-hydroxyisobutyrate production, resulting in skeletal muscle lipotoxicity, which may be the mechanism linking BCAAs and insulin resistance. BCAAs, branched-chain amino acids; MR, mendelian randomization; mTOR, mechanistic target of rapamycin.

Figure 3

Tryptophan metabolic pathway and development and progression of CKD. Tryptophan is an essential amino acid that cannot be synthesized in the body. A minor fraction of tryptophan (<5%) is metabolized by the indole pathway to produce indoxyl sulfate. Most tryptophan (around 95%) is metabolized by the kynurenine pathway. Downstream metabolites of tryptophan, including indoxyl sulfate, kynurenic acid, picolinic acid, xanthurenic acid, quinolinic acid, and NAD, contribute to oxidative stress, inflammation, and immune response, which lead to the development and progression of CKD. CKD, chronic kidney disease; NAD, nicotinamide adenine dinucleotide.

Figure 4

Dysfunctional HDL and cardiovascular disease. HDL are highly heterogeneous in size, structure, composition, and function. Altered lipid composition, protein components, and sizes result in dysfunctional HDL. Decreased cholesterol efflux from macrophages, antioxidant and anti-inflammatory capacity, and endothelial protective function of HDL induce atherosclerosis and cardiovascular disease. HDL, high-density lipoprotein.