Additional Analyte for Understanding Glucose Tolerance

Research connects impaired glucose tolerance to a variety of adverse outcomes, including diabetes, heart disease, and neuropathy, but the molecular mechanisms driving glucose tolerance remain poorly understood.^1-4 The array of complex factors influencing glucose tolerance, and metabolites’ relationship to that tolerance are now being studied is an important area of study.^5,6 These results can have implications for diabetes as well as other disorders where glucose tolerance and insulin resistance correlate with disease development.⁷ A recent Stanford University School of Medicine and Baylor College of Medicine study published in Nature details metabolites’ involvement in biochemical pathways and their impact on glucose tolerance.⁷

New Metabolites for Insulin Resistance Biomarkers

Researchers can leverage metabolite analysis to diagnose insulin resistance in patients. Untargeted metabolomics correlated fasting levels of a panel of metabolites to insulin resistance as measured by oral glucose tolerance test (OGTT), the gold standard for the diagnosis of diabetes, for the development of a clinical test.⁸ Additional research may present the opportunity to report on organs related to glucose homeostasis, including liver, kidney and muscle.

Aromatic Metabolite Lactoyl-Phenylalanine Improves Glucose Homeostasis

Aromatic amino acids have been implicated in playing a role in obesity and metabolic disease. Certain aromatic metabolites correlate with impaired glucose tolerance and accumulate in the urine of obese patients, including N-lactoyl-phenylalanine (Lac-Phe). In particular, research identifies aromatic metabolites resulting from excessive intake of protein and fat.⁹ Further, data connect mitochondrial overload and impairment of insulin signaling to such aromatic metabolites.⁹ 

Lac-Phe, a blood-borne aromatic metabolite, is created by the conjugation of phenylalanine and lactate presumably catalyzed by cytosolic nonspecific dipeptidase 2 (CNDP2).¹⁰ Lac-Phe is increased with exercise and has been shown to suppress appetite and reduce obesity in mouse models.⁷ Lac-Phe is synthesized in CNDP2⁺ cells, such as monocytes, macrophages, as well as other epithelial and immune cells.⁷ Administration of Lac-Phe to mice resulted in improved glucose metabolism suggesting a causative role for this metabolite in improving metabolic health.⁷ Further, studies connect Lac-Phe with insulin resistance, offering applications for predicting prediabetes as well as type 2 diabetes.¹¹

Implications of Metabolites for Glucose Research

Given the different impacts of specific metabolites, research analysis could leverage these findings to drive new insights about the role of metabolites in glucose homeostasis for therapeutic indications. Metabolon offers several assays to support metabolomic analysis for research endeavors throughout the life sciences, including metabolomic analysis for diabetes. Contact the team at Metabolon to see how metabolomics and our platform can empower your research, too. 

Ready to see what new insights metabolomics can help your research reveal? Contact us today to learn more.

References

1. Schnell O, Standl E. Impaired glucose tolerance, diabetes, and cardiovascular disease. Endocr Pract. 2006;12 Suppl 1:16-19. doi:10.4158/EP.12.S1.16.
2. Ceriello A. Impaired glucose tolerance and cardiovascular disease: the possible role of post-prandial hyperglycemia. Am Heart J. 2004;147(5):803-807. doi:10.1016/j.ahj.2003.11.020.
3. Boulton AJ, Malik RA. Neuropathy of impaired glucose tolerance and its measurement. Diabetes Care. 2010 Jan;33(1):207-9. doi: 10.2337/dc09-1728. 
4. Neufer PD, Bamman MM, Muoio DM, et al. Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits. Cell Metab. 2015;22(1):4-11. doi:10.1016/j.cmet.2015.05.011.
5. Sanford JA, Nogiec CD, Lindholm ME, et al. Molecular Transducers of Physical Activity Consortium (MoTrPAC): Mapping the Dynamic Responses to Exercise. Cell. 2020; 181(7):1464-1474. doi:10.1016/j.cell.2020.06.004.
6. Schranner D, Kastenmüller G, Schönfelder M, et al. Metabolite Concentration Changes in Humans After a Bout of Exercise: a Systematic Review of Exercise Metabolomics Studies. Sports Med – Open. 2020; 6(11). doi:10.1186/s40798-020-0238-4.
7. Li VL, He Y, Contrepois K. et al. An exercise-inducible metabolite that suppresses feeding and obesity. Nature. 2022; 606:785–790. doi:10.1038/s41586-022-04828-5.
8. Cobb J, Eckhart A, Perichon R, et al. A Novel Test for IGT Utilizing Metabolite Markers of Glucose Tolerance. Jour of Diabetes Sci and Tech. 2015;9(1):69-76. doi:10.1177/1932296814553622.
9. Newgard CB, An J, Bain JR, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance [published correction appears in Cell Metab. 2009 Jun;9(6):565-6]. Cell Metab. 2009;9(4):311-326. doi:10.1016/j.cmet.2009.02.002
10. Jansen RS, Addie R, Merkx R, et al. N-lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids. Proc Natl Acad Sci U S A. 2015;112(21):6601-6606. doi:10.1073/pnas.1424638112.
11. Cobb J, Gall W, Adam K-P, et al. A Novel Fasting Blood Test for Insulin Resistance and Prediabetes. Jour of Diabetes Sci and Tech. 2013;7(1):100-110. doi:10.1177/193229681300700112.