Type 2 Diabetes and insulin resistance are associated with low grade inflammation and hypertriglyceridaemia but whether or not peripherally-derived cytokines contribute to the diabetic dyslipidaemia is unclear. 

We employed a rat model of the metabolic syndrome, the PEPCK transgenic rat, to determine whether pro-inflammatory cytokines produced in excess in obesity-induced insulin resistance contribute to fasting hypertriglyceridaemia. Lean controls and obese PEPCK rats were fasted overnight and insulin-sensitive tissues were excised for the assessment of cytokine production using real time PCR. Hepatic triglyceride secretion rate was determined in control and PEPCK rats following intravenous injection of Triton WR-1339, a non-ionic detergent that prevents triglyceride clearance. To determine whether cytokines produced in obese tissues can alter hypertriglyceridaemia, overnight-fasted rats were administered lipopolysaccharide (LPS 1μg) or a cocktail of TNFα and IL-1β (1μg) prior to estimation of hepatic triglyceride secretion rate.

Compared to freely fed controls, obese PEPCK transgenic rats fed ad libitum displayed elevated body mass and raised fasting plasma triglycerides, which were abolished by food restriction. Pro-inflammatory cytokine mRNAs (IL-1β, IL-6, TNFα) were significantly increased across muscle and adipose tissue of dyslipidaemic rats versus controls and this was associated with a significantly elevated baseline rate of hepatic triglyceride secretion.  However, administration of a cytokine cocktail comprising TNFα and IL-1β to lean or obese rats failed to alter the rate of fasting hepatic triglyceride secretion. In contrast, a mild increase in fasting hepatic triglyceride secretion rate was observed in response to LPS.

Our data demonstrate that obesity-induced insulin resistance is associated with increased production of pro-inflammatory cytokines, but administration of these cytokines, unlike LPS, does not significantly alter the fasting rate of hepatic triglyceride secretion in vivo.   Further studies are required to determine the significance of chronic low-grade inflammation to the pathogenesis of the diabetic dyslipidaemia.