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Cited by 379Adipokines, Inflammation, and Metabolic DiseasesDiabetes, Cardiovascular Risks, and LipoproteinsLiver Disease Diagnosis and Treatment

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Plasma Fetuin-A Levels and the Risk of Type 2 Diabetes

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Stefan, Norbert, Fritsche, Andreas, Weikert, Cornelia, Boeing, Heiner, Joost, Hans-Georg, Häring, Hans-Ulrich, Schulze, Matthias B.·2008·Diabetes
DOI 10.2337/db08-0538PMC PMC2551687
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Abstract

OBJECTIVE: The liver-secreted protein fetuin-A induces insulin resistance in animals, and circulating fetuin-A is elevated in insulin resistance and fatty liver in humans. We investigated whether plasma fetuin-A levels predict the incidence of type 2 diabetes in a large prospective, population-based study. RESEARCH DESIGN AND METHODS: A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising 27,548 subjects was designed. We randomly selected a subcohort of 2,500 individuals of whom 2,164 were diabetes free at baseline and had anamnestic, anthropometrical, and metabolic data for analysis. Of the 849 incident diabetic case subjects identified in the full cohort during 7 years of follow-up, 703 remained for analyses after similar exclusions. RESULTS: Plasma fetuin-A levels were positively associated with diabetes risk after adjustment for age (relative risk [RR] for extreme quintiles 1.75 [95% CI 1.32-2.31]; RR for 10 mug/ml 1.04 [1.03-1.06]). The association remained significant after adjustment for sex, BMI, waist circumference, and lifestyle risk factors (RR for 10 mug/ml 1.03 [1.01-1.06]). Adjustment for glucose, triglycerides, HDL cholesterol, A1C, gamma-glutamyltransferase, or high-sensitivity C-reactive protein or mutual adjustment for these biomarkers did not appreciably change this result (RR for 10 mug/ml full adjusted model 1.05 [1.02-1.07]). Furthermore, fetuin-A was associated with increased diabetes risk particularly in individuals with elevated plasma glucose. CONCLUSIONS: Our data suggest that fetuin-A is an independent risk factor of type 2 diabetes.

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FIG. 1. Age-adjusted RR of type 2 diabetes by quintiles of plasma fetuin-A (μg/ml) among men and women in the EPIC-Potsdam Study. P for trend <0.001. Medians (ranges) for quintiles are as follows: quintile 1, 162 μg/ml (14–184); quintile 2, 202 μg/ml (185–214); quintile 3, 227 μg/ml (215–240); quintile 4, 255 μg/ml (241–271); quintile 5, 295 μg/ml (272–442).
FIG. 1. Age-adjusted RR of type 2 diabetes by quintiles of plasma fetuin-A (μg/ml) among men and women in the EPIC-Potsdam Study. P for trend <0.001. Medians (ranges) for quintiles are as follows: quintile 1, 162 μg/ml (14–184); quintile 2, 202 μg/ml (185–214); quintile 3, 227 μg/ml (215–240); quintile 4, 255 μg/ml (241–271); quintile 5, 295 μg/ml (272–442).CC BY-NC-ND · PubMed Central
FIG. 2. RR of type 2 diabetes per 1 SD of plasma fetuin-A with varying adjustment for metabolic risk markers among men and women in the EPIC-Potsdam Study. RRs were adjusted for age, sex, BMI, waist circumference, education (in or no training, vocational training, technical school, or technical college or university degree), occupational activity (light, moderate, or heavy), sport activity (0, 0.1–4, or >4 h/week), cycling (0, 0.1–2.4, 2.5–4.9, or ≥5 h/week), smoking (never, past, or current <20 cigarettes/day or current ≥20 cigarettes/day), and alcohol intake (0, 0.1–5, 5.1–10, 10.1–20, 20.1–40, or >40 g/day).
FIG. 2. RR of type 2 diabetes per 1 SD of plasma fetuin-A with varying adjustment for metabolic risk markers among men and women in the EPIC-Potsdam Study. RRs were adjusted for age, sex, BMI, waist circumference, education (in or no training, vocational training, technical school, or technical college or university degree), occupational activity (light, moderate, or heavy), sport activity (0, 0.1–4, or >4 h/week), cycling (0, 0.1–2.4, 2.5–4.9, or ≥5 h/week), smoking (never, past, or current <20 cigarettes/day or current ≥20 cigarettes/day), and alcohol intake (0, 0.1–5, 5.1–10, 10.1–20, 20.1–40, or >40 g/day).CC BY-NC-ND · PubMed Central
FIG. 3. RR of type 2 diabetes per 1 SD of plasma fetuin-A for subgroups of sex, fasting status, abdominal obesity, and glucose levels in the EPIC-Potsdam Study. RRs were adjusted for age, sex BMI, waist circumference, education (in or no training, vocational training, technical school, or technical college or university degree), occupational activity (light, moderate, or heavy), sport activity (0, 0.1–4, or >4 h/week), cycling (0, 0.1–2.4, 2.5–4.9, or ≥5 h/week), smoking (never, past, or current <20 cigarettes/day or current ≥20 cigarettes/day), and alcohol intake (0, 0.1–5, 5.1–10, 10.1–20, 20.1–40, or >40 g/day), HDL cholesterol, triglycerides, glucose, A1C, γ-glutamyltransferase, and hs-CRP (all log transformed). Abdominal obesity was defined as waist ≥102 cm among men or ≥88 cm among women. High glucose was defined as ≥100 mg/dl.
FIG. 3. RR of type 2 diabetes per 1 SD of plasma fetuin-A for subgroups of sex, fasting status, abdominal obesity, and glucose levels in the EPIC-Potsdam Study. RRs were adjusted for age, sex BMI, waist circumference, education (in or no training, vocational training, technical school, or technical college or university degree), occupational activity (light, moderate, or heavy), sport activity (0, 0.1–4, or >4 h/week), cycling (0, 0.1–2.4, 2.5–4.9, or ≥5 h/week), smoking (never, past, or current <20 cigarettes/day or current ≥20 cigarettes/day), and alcohol intake (0, 0.1–5, 5.1–10, 10.1–20, 20.1–40, or >40 g/day), HDL cholesterol, triglycerides, glucose, A1C, γ-glutamyltransferase, and hs-CRP (all log transformed). Abdominal obesity was defined as waist ≥102 cm among men or ≥88 cm among women. High glucose was defined as ≥100 mg/dl.CC BY-NC-ND · PubMed Central
FIG. 4. Schematic overview of the effects of circulating fetuin-A on target tissues. Increase in obesity, particularly in visceral fat mass, results in an increase of liver fat. By yet-unknown mechanisms, this is associated with increased production of fetuin-A (11,23). Elevated circulating fetuin-A directly inhibits insulin signaling in muscle and liver (7–9) and results in systemic subclinical and adipose tissue inflammation (19). Under a normal β-cell function, fetuin-A–induced insulin resistance and effects of subclinical inflammation on the β-cells may be compensated; however, the existence of impaired β-cell function results in fetuin-A–induced type 2 diabetes.
FIG. 4. Schematic overview of the effects of circulating fetuin-A on target tissues. Increase in obesity, particularly in visceral fat mass, results in an increase of liver fat. By yet-unknown mechanisms, this is associated with increased production of fetuin-A (11,23). Elevated circulating fetuin-A directly inhibits insulin signaling in muscle and liver (7–9) and results in systemic subclinical and adipose tissue inflammation (19). Under a normal β-cell function, fetuin-A–induced insulin resistance and effects of subclinical inflammation on the β-cells may be compensated; however, the existence of impaired β-cell function results in fetuin-A–induced type 2 diabetes.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Stefan, N., Fritsche, A., Weikert, C., Boeing, H., Joost, H.-G., Häring, H.-U., & Schulze, M. B.
Affiliations
  • University of Tübingen (DE)
  • German Institute of Human Nutrition (DE)
  • Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University of Tübingen, Tübingen, Germany
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2008-10-01
Volume
57
Issue
10
Pages
2762-2767
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db08-0538
PMC
PMC2551687
OpenAlex
W2130626015
Cited by
379
References
32
Citations by year
2026: 9 · 2025: 11 · 2024: 15 · 2023: 14 · 2022: 15 · 2021: 13 · 2020: 18 · 2019: 13 · 2018: 26 · 2017: 26 · 2016: 26 · 2015: 31 · 2014: 28 · 2013: 34 · 2012: 28
FWCI
17.82
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft
  • Deutsche Krebshilfe
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Keywords
fetuin-A, type 2 diabetes, diabetes risk, insulin resistance, plasma biomarkers, hyperglycemia, EPIC-Potsdam cohort
MeSH terms
Adult, Age Factors, Aged, Blood Proteins, Diabetes Mellitus, Type 2, Female, Germany, Humans, Life Style, Male, Middle Aged, Risk Factors, Cohort Studies, alpha-2-HS-Glycoprotein

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