An Integrated Map of Molecular Mechanisms Underlying the Effect of NMN in T2DM

An Integrated Map of Molecular Mechanisms Underlying the Effect of NMN in T2DM



Introduction

Diabetes is one of the dominant causes of death and disability worldwide, greatly affecting the life quality of patients. According to the latest data on diabetes released by the Lancet (GBD Study 2021), type 2 diabetes mellitus (T2DM) cases almost makes up 96.0% of all diabetes cases, with the hallmark of impaired glucose uptake. There are approximately 529 million patients with diabetes in 2021, with age-standardized prevalence of 6.1%. Remarkably, β-nicotinamide mononucleotide (NMN) is able to ameliorate T2DM via unexpected effects on adipose tissue rather than mitochondrial biogenesis.

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Global age-standardised prevalence of type 1 and type 2 diabetes from 1990 through 2050 forecasts

Risk factors for T2DM

High body mass index (BMI) is the main risk factor for T2DM, followed by dietary risk factors, environmental or occupational factors, smoking, insufficient physical activity, alcohol consumption, etc.

The organ-specific effects of NMN treatment in T2DM

NMN alleviates the mildly impaired and energy-inefficient protein synthesis in mice with T2DM induced by high-fat food. Specifically, NMN downregulates spliceosome proteins while upregulating ribosome proteins in hepatocytes. Besides, NMN downregulates proteasome and upregulates DNA replication and cell cycle pathways in muscle cells.

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Integrated proteomics data analysis of NMN-treated HFD mouse liver.

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Integrated proteomics data analysis of mouse muscle tissue.

Adipose tissue, an energy reservoir, has been attested to be implicated with glucose metabolism. NMN boosts glucose uptake via Resistin downregulation, increased protein synthesis/degradation, fatty acid degradation, lysosome protein upregulation (most notably upregulation of the ATP6V1 proton pump), mTOR cell proliferation signaling in white adipose tissue, differentiation of preadipocytes to brown adipose cells and/or overexpression of thermogenic UCP1, a protein of the inner mitochondrial membrane of brown adipose tissue.

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Integrated proteomics data analysis of NMN-treated HFD mouse adipose tissue

Conclusion

NMN exerts organ-specific effects, with a vital role in improving glucose uptake, showing potent potential in the management of metabolic disorders including T2DM.

Reference

[1] GBD 2021 Diabetes Collaborators. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2023;402(10397):203-234. doi:10.1016/S0140-6736(23)01301-6

[2] Popescu RG, Dinischiotu A, Soare T, Vlase E, Marinescu GC. Nicotinamide Mononucleotide (NMN) Works in Type 2 Diabetes through Unexpected Effects in Adipose Tissue, Not by Mitochondrial Biogenesis. Int J Mol Sci. 2024;25(5):2594. Published 2024 Feb 23. doi:10.3390/ijms25052594

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