Acute free fatty acid elevation eliminates endurance training effect on insulin sensitivity

Abstract

Context: Both training and normal body mass index are associated with high insulin sensitivity, but the mechanism may be different.

Objective: The aim of the study was to examine whether lean trained humans may be protected from acute free fatty acid (FFA)-induced insulin resistance compared with lean sedentary humans.

Design and setting: We conducted an interventional trial using either a 6-h lipid (20% Intralipid at 90 ml/h) or glycerol (2.25 g/100 ml at 90 ml/h) infusion along with a concurrent hyperinsulinemic-euglycemic clamp and serial muscle biopsies (0, 120, 360 min) at a clinical research unit at the University of Minnesota.

Patients or participants: The study included lean endurance-trained (n = 14) and sedentary (n = 14) individuals matched for age, gender, and body mass index.

Main outcome measures: We measured the decline in glucose infusion rate (GIR) during the hyperinsulinemic-euglycemic clamp.

Results: The trained group had higher baseline mitochondrial DNA copy number, mRNA of cytochrome C oxidase subunit 3, and insulin sensitivity (as measured by GIR) compared with the sedentary group. When FFA was acutely elevated to the upper physiological range (0.6-0.7 mEq/liter) by lipid infusion, the GIR in both activity groups declined similarly compared with their respective glycerol controls, although insulin signaling, as measured by Ser 473 pAKT/AKT, remained comparable. Specific to the trained group, the stimulatory effect of hyperinsulinemia on mitochondrial mRNA levels during the glycerol infusion was absent during the lipid infusion.

Conclusions: Elevated FFA had similar effects in reducing insulin sensitivity in trained and sedentary humans. In trained participants, this decline was associated with alterations in the skeletal muscle mitochondrial mRNA response to hyperinsulinemia.

Trial registration: ClinicalTrials.gov NCT00786487.

Figures

Fig. 1.

Outline of visit 3. Bedside glucose was measured every 10 min for adjustment of the GIR. Blood was collected every 30 min for measurement of glucose, insulin, and FFA. Three muscle biopsies were obtained from the vastus lateralis (biopsy 1, time 0 min; biopsy 2, time 120 min; biopsy 3, time 360 min) over the course of the lipid/glycerol infusion.

Fig. 2.

GIR during a 6-h hyperinsulinemic-euglycemic clamp with concurrent lipid or glycerol infusion. The GIR required for maintenance of euglycemia during the 6-h clamp was higher in the glycerol group compared with the lipid group in both the sedentary (A) and trained (B) subjects. C, Lipid infusion produced a greater decline in the GIR AUC during the entire clamp (0–360 min) in the trained group than the sedentary group. Values shown are mean ± se. *, Significant (P < 0.05) difference for the lipid vs. glycerol comparison within an activity group. White circle, Sedentary glycerol group (n = 7); black circle, sedentary lipid group (n = 7); white square, trained glycerol group (n = 7); black square, trained lipid group (n = 7).

Fig. 3.

Alterations in insulin signaling during the 6-h hyperinsulinemic-euglycemic clamp. Insulin signaling was measured by Ser 636/639-pIRS1/IRS1 (A and C) and Ser 473-pAKT/AKT (B and D) at biopsy 1 (0 min) and biopsy 3 (360 min). A and B, Representative Western blots. C and D, Sedentary glycerol (SG; n = 7), sedentary lipid (SL; n = 7), trained glycerol (TG; n = 7), and trained lipid (TL; n = 7) groups are shown. #, P < 0.05 for the paired comparison with biopsy 1 within each group.

Fig. 4.

Mitochondrial mRNA alterations during the 6-h hyperinsulinemic-euglycemic clamp. The mitochondrial mRNA response to hyperinsulinemia differed between the groups. A, Sedentary glycerol (n = 7); B, sedentary lipid (n = 7); C, trained glycerol (n = 7); D, trained lipid (n = 7). All mRNA was quantitated as arbitrary units (AU) normalized to 28S ribosomal RNA. Values are shown as means ± se. †, P < 0.05 for the paired comparison between trained and sedentary groups with the same infusion. #, P < 0.05 for the paired comparison with biopsy 1 within each group.