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

  1. Jacob M. Haus1,2,
  2. Sangeeta R. Kashyap3,
  3. Takhar Kasumov4,
  4. Renliang Zhang5,
  5. Karen R. Kelly1,6,
  6. Ralph A. DeFronzo7 and
  7. John P. Kirwan (kirwanj{at}ccf.org)1,2,4,6
  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

    Abstract

    Abstract 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.

    Objective: To quantitate plasma ceramide subspecies concentrations in obese subjects with type 2 diabetes mellitus (T2DM), and relate these plasma levels to the severity of insulin resistance.

    Research Design and Methods: We analyzed fasting plasma ceramide subspecies by quantitative tandem mass spectrometry in 13 obese T2DM and 14 lean healthy control subjects. Results were related to insulin sensitivity measured with the hyperinsulinemic-euglycemic clamp technique and with plasma TNF-α levels, a marker of inflammation. Ceramide species (C18:1, 18:0, 20:0, 24:1, 24:0) were quantified using ESI-MS/MS after separation with HPLC.

    Results: Insulin sensitivity (mg/kg•min) was lower in T2DM (4.90 ± 0.3) versus controls (9.6 ± 0.4) (p<0.0001). T2DM 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 T2DM subjects and correlated with increased C18:1 and C18:0 ceramide subspecies.

    Conclusion: Plasma ceramide levels are elevated in T2DM subjects and may contribute to insulin resistance through activation of inflammatory mediators such as TNF-α.

    Footnotes

      • Received September 4, 2008.
      • Accepted November 5, 2008.

    This Article

    1. Published online before print November 13, 2008, doi: 10.2337/db08-1228
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