Differential effect of saturated and polyunsaturated fatty acids on hepatic glucose metabolism in humans

Abstract

. Differential effect of saturated and polyunsaturated fatty acids on hepatic glucose metabolism in humans. Am J Physiol Endocrinol Metab 287: E358 -E365, 2004. First published April 13, 2004 10.1152/ajpendo.00360.2003.-Prolonged infusions of lipid and heparin that achieve high physiological free fatty acid (FFA) concentrations inhibit hepatic (and peripheral) insulin sensitivity in humans. These infusions are composed largely of polyunsaturated fatty acids (PUFA; linoleic and linolenic). It is not known whether fatty acid composition per se affects hepatic glucose metabolism in humans. To address this issue, we examined the impact of enteral infusions of either palm oil (48% palmitic, 35% oleic, and 8% linoleic acids) or safflower oil (6% palmitic, 12% oleic, 74% linoleic acids) in 14 obese nondiabetic subjects.2 H2O was administered to determine the contribution of gluconeogenesis to endogenous glucose production (EGP), and a primed continuous infusion of [6,6-2 H]glucose was administered to assess glucose appearance. As a result of the lipid infusions, plasma FFA concentrations increased significantly in both the palm oil (507.5 Ϯ 47.4 to 939.3 Ϯ 61.3 mol/l, P Ͻ 0.01) and safflower oil (588.2.0 Ϯ 43.0 to 857.8 Ϯ 68.7 mol/l, P Ͻ 0.01) groups after 4 h. EGP was similar at baseline (12.4 Ϯ 1.8 vs. 11.2 Ϯ 1.0 mol ⅐ kg FFM Ϫ1 ⅐ min Ϫ1 ). During a somatostatin-insulin clamp, the glucose infusion rate was significantly lower (AUC glucose infusion rate 195.8 Ϯ 50.7 vs. 377.8 Ϯ 38.0 mol/kg FFM, P Ͻ 0.01), and rates of EGP were significantly higher (10.7 Ϯ 1.4 vs. 6.5 Ϯ 1.5 mol ⅐ kg FFM Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.01) after palm oil compared with safflower oil, respectively. Baseline rates of gluconeogenesis and glycogenolysis were also similar. However, after lipid infusion, rates of glycogenolysis were suppressed by safflower oil but not by palm oil. Thus these studies demonstrate, for the first time in humans, a differential effect of saturated fatty acids and PUFA on hepatic glucose metabolism. hepatic autoregulation; gluconeogenesis; glycogenolysis A ROLE FOR FATTY ACIDS in hepatic insulin resistance is well established (22,45). Experimental elevations in plasma free fatty acids (FFA) are associated with impaired suppression of endogenous glucose production (EGP) by insulin (7,22). There is also evidence for a link between increased FFA availability and increased gluconeogenesis in humans (13,17,48,52). However, the stimulation or suppression of gluconeogenesis in vivo is not generally associated with changes in EGP. In fact, gluconeogenesis is increased in obese nondiabetic individuals without an increase in EGP (21, 25). Thus regulation of hepatic glycogen storage is increasingly recognized as a critical component to the regulation of EGP and fasting hyperglycemia (17,25,52). Evidence that fatty acids play an important role in the regulation of liver glycogen is provided by recent studies that examined glycogenolysis directly by nuclear magnetic resonance during infusions of saline or Intralipid. In association with the...

Differential sensitivities of the NCX1.1 and NCX1.3 isoforms of the Na+–Ca2+ exchanger to α-linolenic acid

“…In normal individuals, the free plasma concentrations of ω-3 PUFA attainable in the body are in the high nanomolar range, and low micromolar concentrations are certainly possible with dietary supplementation [26,27]. Our data indicate that such concentrations could significantly inhibit NCX activity, especially NCX1.3.…”

The role of visceral and subcutaneous adipose tissue fatty acid composition in liver pathophysiology associated with NAFLD

“…[27][28][29][30][31][32][33] We and others have demonstrated that the delivery of saturated fatty acids to hepatocytes in culture or the liver in vivo induce more severe inflammation, ER stress and cell death (markers of disease severity) compared with unsaturated fatty acids. 32,33,39,41 In the present study, the high saturated fatty acid diet-induced ER stress and liver injury, therefore we wanted to examine whether the composition of circulating free fatty acids in the portal vein and/or systemic circulation explained or correlated to this response.…”

“…25,26 The composition of circulating free fatty acids and dietary lipids also appears to play an important role in the regulation of hepatic glucose production, insulin action and disease progression in NAFLD. [27][28][29][30][31][32][33] Saturated fatty acids in particular, induce more severe hepatic impairments, such as inflammation, apoptosis, insulin resistance and endoplasmic reticulum (ER) stress, compared with unsaturated fatty acids. 32,34 At least 2 studies have demonstrated that saturated fatty acids were higher in visceral compared with subcutaneous adipose tissue in non-obese 35 and obese 36 humans; although this has not been a universal observation.…”

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

“…These studies mainly focused on the role of skeletal muscle by assessing intramyocellular TG content (11), substrate oxidation, glycogen synthesis (12), or glucose disposal (13)(14)(15)(16)(17). Studies using parenteral administration of unsaturated lipids (18) or high-calorie mixed meals yielded conflicting results with regard to hepatic energy metabolism. One mixed-meal study found greater de novo lipogenesis without affecting hepatic glycogen metabolism (12), while an intravenous lipid infusion study failed to detect any effect on hepatic insulin sensitivity (19).…”