Case Study

Gut Microbiome and Diabetes

When microbiota were isolated from type 2 diabetics and fed with histidine, they produced the metabolite imidazole propionate, revealing an exciting connection between diet, the gut microbiota, and type 2 diabetes.

Using Metabolon’s proprietary Global Discovery Panel, capable of detecting and identifying over 5400 metabolites within a single sample, global metabolomics profiling identified imidazole propionate as a microbially produced metabolite that is uniquely increased in the portal blood of subjects with type 2 diabetes.

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Using Metabolon’s proprietary Global Discovery Panel, capable of detecting and identifying over 5400 metabolites within a single sample, global metabolomics profiling identified imidazole propionate as a microbially produced metabolite that is uniquely increased in the portal blood of subjects with type 2 diabetes.

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The Challenge: What Metabolites Contribute to Diabetes?

Recent studies have revealed that the gut microbiota can contribute to the development of metabolic diseases, but the identity of specific metabolites within the gut microbiota that contribute to diabetes is unknown.

Metabolon Insight: A Metabolite that is Increased in Diabetes is Identified

Using Metabolon’s proprietary Metabolon Discovery: Global Panel, based on a database of over 5400 metabolites, global metabolomics profiling identified imidazole propionate as a microbially produced metabolite that is uniquely increased in the portal blood of subjects with type 2 diabetes.2 Metabolomics also showed that imidazole propionate is depleted from the portal vein and vena cava of gnotobiotic mice.

The Solution: Mice Fed Histine Produce Imidazole Propionate

The researchers used bioreactors that simulate the anaerobic environment of the human gut to demonstrate that microbiota isolated and grown from subjects with type 2 diabetes produce high levels of imidazole propionate from the amino acid histidine. When microbiota were isolated from type 2 diabetics and fed with histidine, they produced the metabolite imidazole propionate, revealing an exciting connection between diet, the gut microbiota, and type 2 diabetes.

The researchers then tested whether imidazole propionate impairs glucose tolerance and insulin signaling, which are important mechanisms in the development of type 2 diabetes. Injecting mice with imidazole propionate induced glucose intolerance and impaired insulin signaling through activation of the mTORC1 pathway, supporting the idea that imidazole propionate plays a role in the development of type 2 diabetes.

The Outcome: Diabetes Pathway Identified

Translational research tools like the Metabolon Discovery: Global Platform offer the ability to identify other microbially produced metabolites that are associated with not only type 2 diabetes, but also other metabolic disorders such as obesity and cardiovascular diseases.

The relationship between the diet, the intestinal microbiota, and type 2 diabetes remains mostly unknown, but this study presented demonstrates how global metabolomics is beginning to fill this information gap. This study demonstrates the signaling potential of imidazole propionate by identifying mTORC1 as its target. Further identification of other signaling pathways induced by imidazole propionate may reveal drug targets to tackle human diseases associated with altered microbial metabolism.

References

1. Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of Type 2 Diabetes – Global Burden of Disease and Forecasted Trends. J Epidemiol Glob Health. 03 2020;10(1):107-111. doi:10.2991/jegh.k.191028.001

 

2. Koh A, Molinaro A, Ståhlman M, et al. Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. Cell. 2018;175(4):947-961.e17. doi:10.1016/j.cell.2018.09.055

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