Ischaemia and insulin, but not ischaemia and contraction, act synergistically in stimulating muscle glucose uptake in vivo in humans

Abstract

Ischaemia, like muscle contraction, has been reported to induce skeletal muscle glucose uptake in in vitro models. This stimulating effect appears independent of insulin and is probably mediated by activation of AMPK (AMP-activated protein kinase). In the present study, we hypothesized that in vivo in humans ischaemia- and insulin-induced glucose uptake are additive, and that the combined impact of ischaemia and contraction on glucose uptake is of a similar magnitude when each is applied separately. We assessed the effects of ischaemia with and without euglycaemic-hyperinsulinaemia (clamp; protocol 1) and with and without muscle contraction (protocol 2) on muscle FGU (forearm glucose uptake) in healthy subjects. Furthermore, we assessed the impact of ischaemia on FBF (forearm blood flow; plethysmography). In protocol 1, ischaemia increased FGU from 0.6+/-0.1 at baseline to 5.5+/-1.9 micromol x min(-1) x dl(-1), and insulin increased FGU to 1.6+/-0.3 micromol x min(-1) x dl(-1) (P<0.05 for both). The combination of ischaemia+insulin increased FGU to 15.5+/-2.2 micromol x min(-1) x dl(-1) (P<0.05 compared with each stimulus alone). Maximal FBF obtained after ischaemia was similar with and without hyperinsulinaemia. In protocol 2, isometric contraction increased FGU from 0.3+/-0.1 to 2.7+/-0.8 micromol x min(-1) x dl(-1) (P<0.05), but FGU was not significantly different from ischaemia compared with ischaemia+contraction. However, combined ischaemia+contraction resulted in a greater increase in FBF. In summary, ischaemia and insulin independently stimulate skeletal muscle glucose uptake in vivo in humans, whereas ischaemia and contraction do not. The observed differential effects of these stimuli on glucose uptake appear to be unrelated to changes in muscle blood flow.

Intravenous AICAR During Hyperinsulinemia Induces Systemic Hemodynamic Changes but Has No Local Metabolic Effect

“…Under these conditions, skeletal muscle glucose uptake can be further stimulated by increasing insulin or glucose concentrations 39 or by ischemia. 31 By using this dose of insulin (60 mU·m −2 ·min −1 or 360 pmol·m −2 ·min −1 ), it is not possible that the maximum stimulation of glucose uptake has already been reached. 39 In the present study, AICAR administration did not augment whole-body or local skeletal muscle glucose uptake, as reflected by similar glucose infusion rates and forearm glucose uptake during clamp conditions with AICAR administration compared with placebo.…”

“…This permitted an investigation of the glucose uptake effects of AICAR on skeletal muscle solely. Under these conditions, skeletal muscle glucose uptake can be further stimulated by increasing insulin or glucose concentrations 39 or by ischemia 31 . By using this dose of insulin (60 mU·m −2 ·min −1 or 360 pmol·m −2 ·min −1 ), it is not possible that the maximum stimulation of glucose uptake has already been reached 39 …”

“…Therefore, the combination of plasma AICAR concentrations and the infusion duration applied in the present study should have been more than sufficient to augment skeletal muscle glucose uptake. Also, the used insulin dosage is well chosen to investigate increases in FGU in healthy humans during clamp conditions, as we have previously described 31 . Interspecies differences may rather account for the differences between animal and human effects of AICAR infusion on glucose uptake (see below).…”

“…Participants underwent 2 euglycemic, hyperinsulinemic (60 mU·m −2 ·min −1 or 360 pmol·m −2 ·min −1 , 120 minutes) clamps with systemic coinfusion of AICAR or placebo (= normal saline) in a single blind, randomized order. We recently demonstrated that under such hyperinsulinemic conditions, insulin and ischemia also stimulate forearm glucose uptake (FGU) 31 . To obtain a steady state, we first infused insulin for 60 minutes, and thereafter insulin was combined with AICAR (67 mg·kg −1 ; for dose calculation, see below) or placebo infusion for an additional 60 minutes.…”

“…We recently demonstrated that under such hyperinsulinemic conditions, insulin and ischemia also stimulate forearm glucose uptake (FGU). 31 To obtain a steady state, we first infused insulin for 60 minutes, and thereafter insulin was combined with AICAR (67 mg·kg −1 ; for dose calculation, see below) or placebo infusion for an additional 60 minutes. Initially, AICAR was infused for 90 minutes in a dose of 100 mg·kg −1 .…”