Background: Mild hypertriglyceridemia is associated with reduced glucose tolerance and increased risk of type 2 diabetes, independent of obesity and insulin sensitivity, in cross-sectional and prospective studies. To what extent these effects are directly produced by triglycerides and which are the major glucose homeostatic mechanisms involved is unclear.

Methods: We examined the effects of acute triglyceride elevation on tracer-derived glucose metabolic fluxes, model-derived β-cell function, insulin sensitivity, and insulin clearance during two 3-h oral glucose tolerance tests with infusion of either normal saline or 20% Intralipid (25 ml/min/m2, without heparin) in 8 healthy lean volunteers.

Results: A 2-h Intralipid infusion increased plasma TG by 2.7-fold (from 52±7 to 192±29 mg/dl; p=0.0003) without affecting plasma FFA, glucose, or insulin levels. After glucose ingestion, the lipid infusion elicited a marked increase in plasma glucose (iAUC +60%, p=0.01) and insulin (iAUC +52%, p=0.02) levels, while FFA were similarly suppressed. The deterioration in glucose tolerance was associated with reduced insulin sensitivity (Matsuda index -22%, p=0.04) and glucose clearance (-16%, p<0.05), and occurred despite a mild inhibition of the endogenous glucose production (-17%, p<0.05). Hyperinsulinemia was produced by reduced insulin clearance (-15%, p=0.04) and enhanced insulin secretion (assessed by C-peptide deconvolution; +29%, p=0.02) due to higher glucose levels and increased β-cell potentiation (+53%; p=0.04).

Conclusions: Mild acute hypertriglyceridemia, independent of FFA, impairs glucose tolerance in healthy subjects by reducing insulin sensitivity and glucose clearance. The magnitude of these effects on glucose tolerance exceeds that of hyperinsulinemia resulting from enhanced β-cell potentiation and reduced insulin clearance.


D. Trico: None. A. Mengozzi: None. M. Seghieri: None. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. A. Natali: None.


Italian Society of Diabetology; European Foundation for the Study of Diabetes

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