Altered metabolites and their potential origins in type 2 diabetes and insulin resistance
In recent years, a large number of cross-sectional and prospective studies have revealed specific metabolites and pathways that are altered by, or predictive of, T2DM and insulin resistance.
Human insulin resistance, T2DM, and prediabetes involve significant perturbations in multiple metabolic systems, as reflected in positive associations with blood long- and medium-chain acylcarnitines, branched-chain amino acids (BCAAs) or their derivatives, methionine/threonine-derived 2-hydroxybutyrate (2-HB), phenylalanine or tyrosine, and negative associations with blood glycine and select phospholipids [13–27]. These metabolites reflect underlying processes that are impacted by or participate in T2DM or insulin resistance pathophysiology. Based on current knowledge, however, it is unclear which, if any, of the metabolites themselves contribute as a root cause of disease.
As noted above, a perturbation in fatty acid metabolism is a hallmark of insulin resistance and T2DM. The weight of evidence from metabolomics studies and tissue biochemical determinations points to a mismatch of fatty acid fuel delivery (due to elevated lipolysis and circulating fatty acids) relative to complete combustion in mitochondria in situ . This leads
to accumulation of muscle and blood long- and medium-chain fatty acylcarnitine metabolites that report on tissue fatty acyl-CoA status [14,28]. The tissue origins of higher systemic blood acylcarnitines in T2DM remain to be confirmed, but muscle is a known site of robust acylcarnitine generation. However, mitochondrial mismatch and the incomplete oxidative catabolism of fatty acids likely occurs in all tissues including liver, supported by consistent observations of higher blood ketone bodies in T2DM. Other metabolite derivatives that result from excess tissue fatty acid availability and that have been proposed to be associated with insulin resistance phenotypes include ceramides and diacylglycerols .
Both targeted metabolic profiling and global metabolomics experiments have indicated that amino acids should be considered alongside glucose and lipids in the context of the dysmetabolic insulin resistant or T2DM states. In the late 1960s it was observed that BCAAs are increased in the blood of obese, insulin-resistant subjects , but only recently did comprehensive metabolite profiling place BCAAs into the spotlight as metabolites associated with insulin resistance . Other essential amino acids such as phenylalanine, tyrosine, methionine and/or the methionine derivatives cysteine-cystine and 2-HB have also been reported to be modestly increased in blood from T2DM and/or insulin resistance conditions (reviewed in ).
In the case of associations of elevated blood amino acids with insulin resistance and T2DM phenotypes, a growing body of evidence suggests that reductions in tissue utilization and/or incomplete oxidation (due to lower enzyme activities) could play a role. For instance, insulin resistance in a human cohort (highest insulin concentration) was associated with significantly attenuated post-oral glucose tolerance test (OGTT) reductions in blood leucine/isoleucine , supporting the idea that lower insulin-stimulated tissue BCAA utilization occurs with insulin resistance. Lower expression of mitochondrial branched chain ketoacid dehydrogenase complex (BCKDC, main control point of BCAA oxidative catabolism) and associated proteins and genes is evident in visceral white adipose tissue from obese, insulin-resistant rodents and humans [34,35] (and references therein). Reduced expression of BCKDC, and lower enzyme activity due to the high fatty acid environment of T2DM and insulin resistance, could promote increased concentration of upstream metabolites such as BCAAs, methionine/cysteine, and 2-HB/2-ketobutyrate . Recently, metabolomics analysis of blood from a large prospective study cohort (Framingham Heart Study) revealed the lysine derivative 2-aminoadipic acid (2-AAA) as predictive of T2DM development , with persons in the highest quartile of 2-AAA concentrations at fourfold greater risk. Lower blood glycine concentrations have also been reported to associate with insulin resistance or T2DM risk (e.g. [19,20,24,25]). The origins of the latter metabolic phenotypes remain unknown.
Additional metabolite classes that are coming to the fore in terms of their potential association with insulin resistance or T2DM risk include bile acids and choline-containing phospholipids. For instance, insulin-resistant individuals had a blunted increase in blood glycochenodeoxycholic acid following OGTT ; yet, fasting concentration of this metabolite was increased in a cohort of impaired glucose tolerant vs. normal glucose tolerant individuals . Phosphatidylcholine derivatives including glycerophosphatidylcholine metabolites are consistently reported to be reduced in T2DM or insulin resistance [16,18,20,25,37]. Further research is needed to determine why insulin resistance and T2DM phenotypes associate with blood patterns of bile acids and phospholipids, but it is possible that changes to the gut environment and/or gut bacteria (microbiota) play a role. Recent metabolomics results highlight that the host’s metabolic health and insulin resistance status are associated with differences in profiles of blood and urine xeno-metabolites (“nonself ” metabolites) (e.g. [18,38]). Interestingly, taxonomic diversity in the gut microbiome is significantly different in persons displaying risk markers for cardiometabolic disease including insulin resistance , and there are clear differences in gut microbe communities when comparing subjects with normal glucose tolerance, prediabetes, and T2DM [40–43].