Time-course effects of physiological free fatty acid surges on insulin sensitivity in humans.
OBJECTIVE
Physiological elevations of free fatty acids (FFAs) occur in bell-shaped surges lasting some hours, observed nocturnally, during exercise and inflammation. The time-course effects of such FFA surges on insulin sensitivity are unknown. We therefore aimed to define the effects of a graded 4-h FFA elevation intended to mimick physiological excursions.


METHODS
Eight lean, healthy men were studied on two occasions: (1) control (saline) and (2) 4 h graded infusion of intralipid (20%)/heparin. Insulin sensitivity was continuously assessed by isotope dilution (3H-glucose) during an 8 h hyperinsulinemic-euglycaemic clamp (0.5 mU kg(-1) min(-1) ). Phosphorylation of Akt and ERK1/2 was measured in muscle biopsies taken at 0 and 120 min. Inflammatory cytokines were assessed with a Luminex Suspension Array System.


RESULTS
Infusion of intralipid caused a bell-shaped increase in FFA levels reaching peak levels ~1.9 mmol L(-1) and markedly impairing insulin sensitivity. Impairment of insulin sensitivity was apparent (P>0.05) 120 min after initiation of FFA infusion, significant after 270 min (P < 0.001) and peaked after 360 min. FFA induced insulin resistance prevailed 210 min after cessation of FFA infusion. No effect was observed on Akt and ERK1/2 phosphorylation.


CONCLUSIONS
(1) Physiological FFA elevations require at least 120 min to induce insulin resistance, (2) that insulin resistance peaks 360 min after initiation of FFA exposure and (3) ceases 210 min after termination of the FFA infusion. These observations add to our understanding of FFA induced insulin resistance in relation to circadian variations, exercise, generalized inflammation and exposure to stress hormones such as growth hormone.
Gormsen
L C
LC
Department M (Endocrinology and Diabetes), Aarhus University Hospital, Skejby, Aarhus C, Denmark. lars.christian.gormsen@ki.au.dk
Nielsen
C
C
Jessen
N
N
Jørgensen
J O L
JO
Møller
N
N
D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D055815:Young Adult
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D005947:Glucose