Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance

Jacob M Haus, Sangeeta R Kashyap, Takhar Kasumov, Renliang Zhang, Karen R Kelly, Ralph A Defronzo, John P Kirwan, Jacob M Haus, Sangeeta R Kashyap, Takhar Kasumov, Renliang Zhang, Karen R Kelly, Ralph A Defronzo, John P Kirwan

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-alpha (TNF-alpha) 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 x kg(-1) x 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-alpha 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-alpha.

Figures

FIG. 1.
FIG. 1.
Plasma concentration of ceramide subspecies in obese type 2 diabetic patients (n = 13) compared with lean healthy control subjects (n = 14). Plasma concentrations were determined by quantitative tandem mass spectrometry. Data are expressed as means ± SE. *P < 0.05 type 2 diabetes vs. control; Mann-Whitney unpaired test.
FIG. 2.
FIG. 2.
Correlation of individual ceramide subspecies with the insulin-stimulated rate of glucose disposal (Rd). ○, control subjects; •, type 2 diabetic patients. Spearman's rank correlation was used to access the relationships between datasets. All correlations were significant, P < 0.05.
FIG. 3.
FIG. 3.
Correlation between individual ceramide species and plasma TNF-α concentration. Spearman's rank correlation was used to access the relationships between datasets. ○, control subjects; •, type 2 diabetic patients. TNF-α correlations between C18:1 and C18:0 ceramide subspecies were significant, P < 0.05. TNF-α correlations between C20: and C24:1 ceramide subspecies did not reach significance but displayed a trend toward significance: P = 0.08 and 0.06, respectively.

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