Inflammatory Cytokines and the Risk to Develop Type 2 Diabetes
Open accessAbstract
A subclinical inflammatory reaction has been shown to precede the onset of type 2 (non-insulin-dependent) diabetes. We therefore examined prospectively the effects of the central inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) on the development of type 2 diabetes. We designed a nested case-control study within the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study including 27,548 individuals. Case subjects were defined to be those who were free of type 2 diabetes at baseline and subsequently developed type 2 diabetes during a 2.3-year follow-up period. A total of 192 cases of incident type 2 diabetes were identified and matched with 384 non-disease-developing control subjects. IL-6 and TNF-α levels were found to be elevated in participants with incident type 2 diabetes, whereas IL-1β plasma levels did not differ between the groups. Analysis of single cytokines revealed IL-6 as an independent predictor of type 2 diabetes after adjustment for age, sex, BMI, waist-to-hip ratio (WHR), sports, smoking status, educational attainment, alcohol consumption, and HbA1c (4th vs. the 1st quartile: odds ratio [OR] 2.6, 95% CI 1.2–5.5). The association between TNF-α and future type 2 diabetes was no longer significant after adjustment for BMI or WHR. Interestingly, combined analysis of the cytokines revealed a significant interaction between IL-1β and IL-6. In the fully adjusted model, participants with detectable levels of IL-1β and elevated levels of IL-6 had an independently increased risk to develop type 2 diabetes (3.3, 1.7–6.8), whereas individuals with increased concentrations of IL-6 but undetectable levels of IL-1β had no significantly increased risk, both compared with the low-level reference group. These results were confirmed in an analysis including only individuals with HbA1c <5.8% at baseline. Our data suggest that the pattern of circulating inflammatory cytokines modifies the risk for type 2 diabetes. In particular, a combined elevation of IL-1β and IL-6, rather than the isolated elevation of IL-6 alone, independently increases the risk of type 2 diabetes. These data strongly support the hypothesis that a subclinical inflammatory reaction has a role in the pathogenesis of type 2 diabetes.
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Acute phase reactants and proinflammatory cytokines, such as CRP and IL-6, predict the development of T2DM in addition to the risk of complications.
“Furthermore, acute phase reactants and proinflammatory cytokines, such as C-reactive protein (CRP) and interleukin-6 (IL-6) predict the development of T2DM in addition to the risk of complications. 3,4”
From <scp>Glucagon‐like peptide‐1 receptor agonists</scp> improve biomarkers of inflammation and oxidative stress: A systematic review and meta‐analysis of randomised controlled trials (2021) · cites this paper as [3]
The Clinical parameters section reports that elevated CRP was associated with increased risk of developing type 2 diabetes, and the Abstract identifies IL-6 as an independent predictor. The Discussion qualifies the IL-6 finding: elevated IL-6 alone, without detectable IL-1β, did not substantially increase risk. The paper does not report whether CRP or IL-6 predicts the risk of diabetes complications. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAccumulating evidence suggests that a subclinical inflammatory reaction participates in the pathogenesis of T2DM and its cardiorenal complications, with elevated plasma levels of pro-inflammatory cytokines.
“Accumulating evidence suggests that a subclinical inflammatory reaction participates in the pathogenesis of T2DM and its cardiorenal complications, with elevated plasma levels of pro-inflammatory cytokines, including tumour necrosis factor-alpha (TNF-α), 11 interleukin-1 beta (IL-1β), 12 IL-6 13,14 and other IL-1-dependent pro-inflammatory cytokines and chemokines.[15][16][17][18]”
From The effect of <scp>GLP</scp> ‐1 receptor agonists on circulating inflammatory markers in type 2 diabetes patients: A systematic review and meta‐analysis (2025) · cites this paper as [12]
The Abstract reports that a subclinical inflammatory reaction may contribute to type 2 diabetes and links circulating IL-6 and IL-1β patterns to future diabetes risk. The paper does not address cardiorenal complications or establish that all the listed cytokines are individually elevated: its Results report no significant difference in IL-1β levels between cases and controls. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCase-control studies have found that elevated IL-6 and combined elevation of IL-6 and IL-1β are independent predictors of diabetes.
“Case-control studies have found that elevated IL-6 and the combined elevation of IL-6 and IL-1β, both SASP factors, are independent predictors of diabetes (55,56).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [56]
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- Authors
- Spranger, J., Kroke, A., Möhlig, M., Hoffmann, K., Bergmann, M. M., Ristow, M., Boeing, H., & Pfeiffer, A. F. H.
- Affiliations
- German Institute of Human Nutrition (DE)
- Department of Endocrinology, Diabetes and Nutrition, Benjamin Franklin Medical Center, Free University Berlin, Berlin, Germany
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2003-03-01
- Volume
- 52
- Issue
- 3
- Pages
- 812-817
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2411826498
- Semantic Scholar
- ba63b23b15b455b70a37e36c39ae43e1456a8e06
- Cited by
- 1,493
- References
- 25
- Citations by year
- 2026: 23 · 2025: 48 · 2024: 75 · 2023: 64 · 2022: 69 · 2021: 80 · 2020: 79 · 2019: 78 · 2018: 72 · 2017: 65 · 2016: 90 · 2015: 85 · 2014: 96 · 2013: 75 · 2012: 70
- FWCI
- 27.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- European Commission
- Deutsche Forschungsgemeinschaft (1076/1)
- Deutsche Krebshilfe
- Universität Greifswald
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- type 2 diabetes, inflammatory cytokines, interleukin-6, IL-1β, TNF-α, subclinical inflammation, diabetes risk, cytokine interactions, HbA1c, adiposity, waist-to-hip ratio, diabetes pathogenesis, biomarkers of disease risk, prospective cohort, nested case-control
- MeSH terms
- Adult, Aged, Blood Glucose, Body Constitution, C-Reactive Protein, Diabetes Mellitus, Type 2, Europe, Female, Glycated Hemoglobin, Humans, Inflammation, Interleukin-1, Male, Middle Aged, Neoplasms, Nutritional Physiological Phenomena, Prospective Studies, Risk Factors, Tumor Necrosis Factor-alpha, Exercise, Interleukin-6, Body Mass Index, Case-Control Studies, Cytokines
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