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Inter-organ crosstalk during development and progression of type 2 diabetes mellitus

Nature Reviews Endocrinology volume 20, pages 27–49 (2024)Cite this article

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Abstract

Type 2 diabetes mellitus (T2DM) is characterized by tissue-specific insulin resistance and pancreatic β-cell dysfunction, which result from the interplay of local abnormalities within different tissues and systemic dysregulation of tissue crosstalk. The main local mechanisms comprise metabolic (lipid) signalling, altered mitochondrial metabolism with oxidative stress, endoplasmic reticulum stress and local inflammation. While the role of endocrine dysregulation in T2DM pathogenesis is well established, other forms of inter-organ crosstalk deserve closer investigation to better understand the multifactorial transition from normoglycaemia to hyperglycaemia. This narrative Review addresses the impact of certain tissue-specific messenger systems, such as metabolites, peptides and proteins and microRNAs, their secretion patterns and possible alternative transport mechanisms, such as extracellular vesicles (exosomes). The focus is on the effects of these messengers on distant organs during the development of T2DM and progression to its complications. Starting from the adipose tissue as a major organ relevant to T2DM pathophysiology, the discussion is expanded to other key tissues, such as skeletal muscle, liver, the endocrine pancreas and the intestine. Subsequently, this Review also sheds light on the potential of multimarker panels derived from these biomarkers and related multi-omics for the prediction of risk and progression of T2DM, novel diabetes mellitus subtypes and/or endotypes and T2DM-related complications.

Key points

  • Crosstalk between adipose tissue, liver, skeletal muscle, pancreas and intestine plays a key role in pathogenesis of insulin resistance and β-cell dysfunction, both of which characterize type 2 diabetes mellitus (T2DM).

  • Among metabolic mediators, bioactive lipids such as diacylglycerols and ceramides are the best described inhibitors of insulin signalling, but fatty acids such palmitic acid and myristic acid, also contribute to metabolic alterations via post-translational protein modification.

  • The current concept of the pathogenesis of T2DM postulates that adipose tissue dysfunction initiates insulin resistance and ectopic lipid storage, but also contributes to pancreatic β-cell dysfunction via long-term excessive exposure to fatty acids and glucose.

  • Multi-omics studies based on previously identified crosstalk mediators have proposed multimarker signatures, which could, in the future, help improve the prediction of risk and progression of T2DM and its subtypes, and the risk of complications.

  • Mendelian randomization studies have identified causal associations between established and novel biomarkers and the risk of T2DM and its complications, but are also critically revising previously accepted roles of several crosstalk mediators, underlining the concept of reverse causality.

  • Current studies also focus on the relevance of crosstalk mediators in understanding the subtypes of prediabetes and diabetes mellitus and for the subtype-specific differences in diabetes mellitus-related comorbidities and complications to pave the way for future precision diabetology.

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Fig. 1: Crosstalk mechanisms mediated by metabolites in the pathogenesis of type 2 diabetes mellitus.
Fig. 2: Crosstalk mechanisms mediated by cytokines in the pathogenesis of type 2 diabetes mellitus.
Fig. 3: The role of mediators originating from adipose tissue and skeletal muscle in inter-organ crosstalk.
Fig. 4: The role of mediators originating from the liver, intestine and pancreas in inter-organ crosstalk.

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Acknowledgements

The research of M.R. is supported in part by grants from the German Federal Ministry of Health (BMG), the Ministry of Culture and Science of the State Northrhine Westphalia (MKW NRW) to the German Diabetes Center (DDZ) and the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.) as well as by grants from the European Community (HORIZON-HLTH-2022-STAYHLTH-02-01: panel A) to the INTERCEPT-T2D consortium, EUREKA Eurostars-2 (E! 113230 DIA-PEP), German Science Foundation (DFG; CRC/SFB 1116/2 B12; RTG/GRK 2576 vivid, project 3), Schmutzler Stiftung and the programme ‘Profilbildung 2020’, an initiative of the Ministry of Culture and Science of the State of Northrhine Westphalia. The sole responsibility for the content of this publication lies with the authors.

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  1. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Georgia Xourafa, Melis Korbmacher & Michael Roden

  2. German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Düsseldorf, Germany

    Georgia Xourafa, Melis Korbmacher & Michael Roden

  3. Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Michael Roden

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All authors researched data for article and wrote the article. M.R. and G.X. contributed substantially to the discussion of the content and reviewed and/or edited the manuscript before submission.

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M.R. has received personal fees for consulting from Eli Lilly, Novo Nordisk, Boehringer Ingelheim and Sanofi US, and has been supported for investigator-initiated trials by Boehringer Ingelheim, Novartis Pharma and Nutricia/Danone. The other authors declare no competing interests.

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Xourafa, G., Korbmacher, M. & Roden, M. Inter-organ crosstalk during development and progression of type 2 diabetes mellitus. Nat Rev Endocrinol 20, 27–49 (2024). https://doi.org/10.1038/s41574-023-00898-1

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