Dose-response effect of elevated plasma free fatty acid on insulin signaling

Renata Belfort, Lawrence Mandarino, Sangeeta Kashyap, Kelly Wirfel, Thongchai Pratipanawatr, Rachele Berria, Ralph A Defronzo, Kenneth Cusi

Research output: Contribution to journalArticle

228 Citations (Scopus)

Abstract

The dose-response relationship between elevated plasma free fatty acid (FFA) levels and impaired insulin-mediated glucose disposal and insulin signaling was examined in 21 lean, healthy, normal glucose-tolerant subjects. Following a 4-h saline or Liposyn infusion at 30 (n = 9), 60 (n = 6), and 90 (n = 6) ml/h, subjects received a 2-h euglycemic insulin (40 mU · m -2 · min-1) clamp. Basal plasma FFA concentration (∼440 μmol/l) was increased to 695, 1,251, and 1,688 μmol/l after 4 h of Liposyn infusion and resulted in a dose-dependent reduction in insulin-stimulated glucose disposal (Rd) by 22, 30, and 34%, respectively (all P < 0.05 vs. saline control). At the lowest lipid infusion rate (30 ml/h), insulin receptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity associated with IRS-1, and Akt serine phosphorylation were all significantly impaired (P < 0.05-0.01). The highest lipid infusion rate (90 ml/h) caused a further significant reduction in all insulin signaling events compared with the low-dose lipid infusion (P < 0.05-0.01) whereas the 60-ml/h lipid infusion caused an intermediate reduction in insulin signaling. However, about two-thirds of the maximal inhibition of insulin-stimulated glucose disposal already occurred at the rather modest increase in plasma FFA induced by the low-dose (30-ml/h) lipid infusion. Insulin-stimulated glucose disposal was inversely correlated with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.50, P = 0.001) and the plasma FFA level during the last 30 min of the insulin clamp (r = -0.54, P < 0.001). PI 3-kinase activity associated with IRS-1 correlated with insulin-stimulated glucose disposal (r = 0.45, P < 0.01) and inversely with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.39, P = 0.01) and during the last 30 min of the insulin clamp (r = -0.43, P < 0.01). In summary, in skeletal muscle of lean, healthy subjects, a progressive increase in plasma FFA causes a dose-dependent inhibition of insulin-stimulated glucose disposal and insulin signaling. The inhibitory effect of plasma FFA was already significant following a rather modest increase in plasma FFA and develops at concentrations that are well within the physiological range (i.e., at plasma FFA levels observed in obesity and type 2 diabetes).

Original languageEnglish (US)
Pages (from-to)1640-1648
Number of pages9
JournalDiabetes
Volume54
Issue number6
DOIs
StatePublished - Jun 2005

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Nonesterified Fatty Acids
Insulin
Lipids
Glucose
Insulin Receptor Substrate Proteins
Phosphatidylinositol 3-Kinase
Phosphorylation
Insulin Receptor
Serine
Type 2 Diabetes Mellitus
Tyrosine
Healthy Volunteers
Skeletal Muscle
Obesity

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Belfort, R., Mandarino, L., Kashyap, S., Wirfel, K., Pratipanawatr, T., Berria, R., ... Cusi, K. (2005). Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes, 54(6), 1640-1648. https://doi.org/10.2337/diabetes.54.6.1640

Dose-response effect of elevated plasma free fatty acid on insulin signaling. / Belfort, Renata; Mandarino, Lawrence; Kashyap, Sangeeta; Wirfel, Kelly; Pratipanawatr, Thongchai; Berria, Rachele; Defronzo, Ralph A; Cusi, Kenneth.

In: Diabetes, Vol. 54, No. 6, 06.2005, p. 1640-1648.

Research output: Contribution to journalArticle

Belfort, R, Mandarino, L, Kashyap, S, Wirfel, K, Pratipanawatr, T, Berria, R, Defronzo, RA & Cusi, K 2005, 'Dose-response effect of elevated plasma free fatty acid on insulin signaling', Diabetes, vol. 54, no. 6, pp. 1640-1648. https://doi.org/10.2337/diabetes.54.6.1640
Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R et al. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes. 2005 Jun;54(6):1640-1648. https://doi.org/10.2337/diabetes.54.6.1640
Belfort, Renata ; Mandarino, Lawrence ; Kashyap, Sangeeta ; Wirfel, Kelly ; Pratipanawatr, Thongchai ; Berria, Rachele ; Defronzo, Ralph A ; Cusi, Kenneth. / Dose-response effect of elevated plasma free fatty acid on insulin signaling. In: Diabetes. 2005 ; Vol. 54, No. 6. pp. 1640-1648.
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abstract = "The dose-response relationship between elevated plasma free fatty acid (FFA) levels and impaired insulin-mediated glucose disposal and insulin signaling was examined in 21 lean, healthy, normal glucose-tolerant subjects. Following a 4-h saline or Liposyn infusion at 30 (n = 9), 60 (n = 6), and 90 (n = 6) ml/h, subjects received a 2-h euglycemic insulin (40 mU · m -2 · min-1) clamp. Basal plasma FFA concentration (∼440 μmol/l) was increased to 695, 1,251, and 1,688 μmol/l after 4 h of Liposyn infusion and resulted in a dose-dependent reduction in insulin-stimulated glucose disposal (Rd) by 22, 30, and 34{\%}, respectively (all P < 0.05 vs. saline control). At the lowest lipid infusion rate (30 ml/h), insulin receptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity associated with IRS-1, and Akt serine phosphorylation were all significantly impaired (P < 0.05-0.01). The highest lipid infusion rate (90 ml/h) caused a further significant reduction in all insulin signaling events compared with the low-dose lipid infusion (P < 0.05-0.01) whereas the 60-ml/h lipid infusion caused an intermediate reduction in insulin signaling. However, about two-thirds of the maximal inhibition of insulin-stimulated glucose disposal already occurred at the rather modest increase in plasma FFA induced by the low-dose (30-ml/h) lipid infusion. Insulin-stimulated glucose disposal was inversely correlated with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.50, P = 0.001) and the plasma FFA level during the last 30 min of the insulin clamp (r = -0.54, P < 0.001). PI 3-kinase activity associated with IRS-1 correlated with insulin-stimulated glucose disposal (r = 0.45, P < 0.01) and inversely with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.39, P = 0.01) and during the last 30 min of the insulin clamp (r = -0.43, P < 0.01). In summary, in skeletal muscle of lean, healthy subjects, a progressive increase in plasma FFA causes a dose-dependent inhibition of insulin-stimulated glucose disposal and insulin signaling. The inhibitory effect of plasma FFA was already significant following a rather modest increase in plasma FFA and develops at concentrations that are well within the physiological range (i.e., at plasma FFA levels observed in obesity and type 2 diabetes).",
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N2 - The dose-response relationship between elevated plasma free fatty acid (FFA) levels and impaired insulin-mediated glucose disposal and insulin signaling was examined in 21 lean, healthy, normal glucose-tolerant subjects. Following a 4-h saline or Liposyn infusion at 30 (n = 9), 60 (n = 6), and 90 (n = 6) ml/h, subjects received a 2-h euglycemic insulin (40 mU · m -2 · min-1) clamp. Basal plasma FFA concentration (∼440 μmol/l) was increased to 695, 1,251, and 1,688 μmol/l after 4 h of Liposyn infusion and resulted in a dose-dependent reduction in insulin-stimulated glucose disposal (Rd) by 22, 30, and 34%, respectively (all P < 0.05 vs. saline control). At the lowest lipid infusion rate (30 ml/h), insulin receptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity associated with IRS-1, and Akt serine phosphorylation were all significantly impaired (P < 0.05-0.01). The highest lipid infusion rate (90 ml/h) caused a further significant reduction in all insulin signaling events compared with the low-dose lipid infusion (P < 0.05-0.01) whereas the 60-ml/h lipid infusion caused an intermediate reduction in insulin signaling. However, about two-thirds of the maximal inhibition of insulin-stimulated glucose disposal already occurred at the rather modest increase in plasma FFA induced by the low-dose (30-ml/h) lipid infusion. Insulin-stimulated glucose disposal was inversely correlated with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.50, P = 0.001) and the plasma FFA level during the last 30 min of the insulin clamp (r = -0.54, P < 0.001). PI 3-kinase activity associated with IRS-1 correlated with insulin-stimulated glucose disposal (r = 0.45, P < 0.01) and inversely with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.39, P = 0.01) and during the last 30 min of the insulin clamp (r = -0.43, P < 0.01). In summary, in skeletal muscle of lean, healthy subjects, a progressive increase in plasma FFA causes a dose-dependent inhibition of insulin-stimulated glucose disposal and insulin signaling. The inhibitory effect of plasma FFA was already significant following a rather modest increase in plasma FFA and develops at concentrations that are well within the physiological range (i.e., at plasma FFA levels observed in obesity and type 2 diabetes).

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