Plasma Ceramides Are Elevated in Obese Subjects With Type 2 Diabetes and Correlate With the Severity of Insulin Resistance

  1. Jacob M. Haus12,
  2. Sangeeta R. Kashyap3,
  3. Takhar Kasumov4,
  4. Renliang Zhang5,
  5. Karen R. Kelly16,
  6. Ralph A. DeFronzo7 and
  7. John P. Kirwan1246
  1. 1Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
  2. 2Department of Physiology, Case Western Reserve University School of Medicine, Cleveland, Ohio
  3. 3Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, Ohio
  4. 4Department of Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, Ohio
  5. 5Department of Cardiovascular Medicine and Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio
  6. 6Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio
  7. 7Division of Diabetes, University of Texas Health Science Center, San Antonio, Texas
  1. Corresponding author: John P. Kirwan, kirwanj{at}ccf.org

Abstract

OBJECTIVE—To quantitate plasma ceramide subspecies concentrations in obese subjects with type 2 diabetes and relate these plasma levels to the severity of insulin resistance. Ceramides are a putative mediator of insulin resistance and lipotoxicity, and accumulation of ceramides within tissues in obese and diabetic subjects has been well described.

RESEARCH DESIGN AND METHODS—We analyzed fasting plasma ceramide subspecies by quantitative tandem mass spectrometry in 13 obese type 2 diabetic patients and 14 lean healthy control subjects. Results were related to insulin sensitivity measured with the hyperinsulinemic-euglycemic clamp technique and with plasma tumor necrosis factor-α (TNF-α) levels, a marker of inflammation. Ceramide species (C18:1, 18:0, 20:0, 24:1, and 24:0) were quantified using electrospray ionization tandem mass spectrometry after separation with high-performance liquid chromatography.

RESULTS—Insulin sensitivity (mg · kg−1 · min−1) was lower in type 2 diabetic patients (4.90 ± 0.3) versus control subjects (9.6 ± 0.4) (P < 0.0001). Type 2 diabetic subjects had higher (P < 0.05) concentrations of C18:0, C20:0, C24:1, and total ceramide. Insulin sensitivity was inversely correlated with C18:0, C20:0, C24:1, C24:0, and total ceramide (all P < 0.01). Plasma TNF-α concentration was increased (P < 0.05) in type 2 diabetic subjects and correlated with increased C18:1 and C18:0 ceramide subspecies.

CONCLUSIONS—Plasma ceramide levels are elevated in type 2 diabetic subjects and may contribute to insulin resistance through activation of inflammatory mediators, such as TNF-α.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 13 November 2008.

    J.M.H., and S.R.K. contributed equally to this work.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted November 5, 2008.
    • Received September 4, 2008.
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  1. Diabetes vol. 58 no. 2 337-343
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