PMID- 8200979
OWN - NLM
STAT- MEDLINE
DCOM- 19940707
LR  - 20220410
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 93
IP  - 6
DP  - 1994 Jun
TI  - Mechanisms of fatty acid-induced inhibition of glucose uptake.
PG  - 2438-46
AB  - Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms 
      responsible for this inhibition, however, remain uncertain. It was the aim of 
      this study to determine whether the FFA effect was dose dependent and to 
      investigate its mechanism. We have examined in healthy volunteers (13 male/1 
      female) the effects of three steady state plasma FFA levels (approximately 50, 
      approximately 550, approximately 750 microM) on rates of glucose uptake, 
      glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two 
      independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), 
      hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO 
      oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA 
      concentration (from approximately 50 to approximately 750 microM) decreased 
      glucose uptake in a dose-dependent fashion (from approximately 9 to approximately 
      4 mg/kg per min). The decrease was caused mainly (approximately 2/3) by a 
      reduction in glycogen synthesis and to a lesser extent (approximately 1/3) by a 
      reduction in CHO oxidation. We have identified two independent defects in 
      glycogen synthesis. The first consisted of an impairment of muscle glycogen 
      synthase activity. It required high FFA concentration (approximately 750 microM), 
      was associated with an increase in glucose-6-phosphate, and developed after 4-6 h 
      of fat infusion. The second defect, which preceded the glycogen synthase defect, 
      was seen at medium (approximately 550 microM) FFA concentration, was associated 
      with a decrease in muscle glucose-6-phosphate concentration, and was probably due 
      to a reduction in glucose transport/phosphorylation. In addition, FFA and/or 
      glycerol increased insulin-suppressed hepatic glucose output by approximately 
      50%. We concluded that fatty acids caused a dose-dependent inhibition of 
      insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO 
      oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic 
      glucose output and thus caused insulin resistance at the peripheral and the 
      hepatic level.
FAU - Boden, G
AU  - Boden G
AD  - Division of Endocrinology/Metabolism, Temple University School of Medicine, 
      Philadelphia, Pennsylvania 19140.
FAU - Chen, X
AU  - Chen X
FAU - Ruiz, J
AU  - Ruiz J
FAU - White, J V
AU  - White JV
FAU - Rossetti, L
AU  - Rossetti L
LA  - eng
GR  - R01-AG-07988/AG/NIA NIH HHS/United States
GR  - R01-DK-47477/DK/NIDDK NIH HHS/United States
GR  - R029-DK-42177/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (Insulin)
RN  - 9005-79-2 (Glycogen)
RN  - 9007-92-5 (Glucagon)
RN  - EC 2.4.1.11 (Glycogen Synthase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Adult
MH  - Carbohydrate Metabolism
MH  - Fatty Acids, Nonesterified/*blood
MH  - Female
MH  - Glucagon/blood
MH  - Glucose/*metabolism
MH  - Glycogen/biosynthesis
MH  - Glycogen Synthase/metabolism
MH  - Glycolysis/drug effects
MH  - Humans
MH  - Insulin/blood/pharmacology
MH  - Liver/metabolism
MH  - Male
MH  - Oxidation-Reduction
PMC - PMC294452
EDAT- 1994/06/01 00:00
MHDA- 1994/06/01 00:01
PMCR- 1994/06/01
CRDT- 1994/06/01 00:00
PHST- 1994/06/01 00:00 [pubmed]
PHST- 1994/06/01 00:01 [medline]
PHST- 1994/06/01 00:00 [entrez]
PHST- 1994/06/01 00:00 [pmc-release]
AID - 10.1172/JCI117252 [doi]
PST - ppublish
SO  - J Clin Invest. 1994 Jun;93(6):2438-46. doi: 10.1172/JCI117252.