Objective: It has been proposed that the microcirculation contributes to insulin-stimulated muscle glucose uptake (MGU) by recruiting capillaries and thus enhancing the dispersion of insulin from capillaries into interstitium. This theory contrasts with intravital microscopy (IVM) measurements showing near-complete capillary recruitment at baseline, and it does not address the possibility that dispersion of glucose, rather than insulin, could limit MGU. This study tests the hypotheses that perfusion effects on MGU are 1) capillary recruitment-independent and 2) critical more so for the interstitial dispersion of glucose, rather than insulin.
Methods: In one experiment, microvascular perfusion was measured using IVM before and after intravenous insulin injections. In a second experiment, mice were treated with vasoactive drugs. Microvascular perfusion, dispersion of fluorophores approximating insulin size (10 kDa dextran) and glucose (2-NBDG), and muscle accumulation of a radioactive glucose analogue (phospho-2[14C]DG) were measured.
Results: The first experiment showed ∼95% recruitment of capillaries before insulin with no recruitment following insulin. In the second experiment, perfusion-limited delivery indices (calculated from capillary blood flow and its distribution) and 2-NBDG dispersion, but not diffusion-limited delivery indices (calculated from perfused surface area and permeability) or 10 kDa dextran dispersion, predicted phospho-2[14C]DG accumulation.
Conclusions: These findings show that the role of perfusion in insulin-stimulated MGU is mediated by blood flow rather than capillary recruitment, and that the rate of glucose dispersion into the interstitium overrides insulin dispersion as a determinant of muscle insulin sensitivity in vivo.
P.M. McClatchey: None. I.M. Williams: None. N.A. Mignemi: None. C.C. Hughey: None. O.P. McGuinness: None. J.A. Beckman: Consultant; Self; AstraZeneca, Bristol-Myers Squibb Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; Bayer AG, Novartis AG. D. Wasserman: None.
National Institutes of Health (DK059637, DK054902, DK050277, T32DK101003, F32DK120104, P30DK020593); American Heart Association