The human skeletal muscle in vivo : the use of microdialysis to study glucose metabolism and insulin resistance

The aim of this thesis was to further develop the microdialysis technique for studies of glucose metabolism and insulin resistance in human skeletal muscle in vivo and to use this technique to explore the effect of exercise on muscle glucose metabolism and insulin action.

The first two studies were conducted to explore the possibility of using a perfusion flow rate low enough to obtain complete equilibrium between the interstitial and perfusion fluids and if the colloid included in the perfusion fluid for this purpose affected the metabolite concentrations in the dialysate.

The following three studies focus on glucose metabolism and insulin resistance by examining the extent to which insulin and/or the insulin-mimetic trace element vanadate added to the perfusion fluid exerted local effects on the glucose metabolism in healthy and in insulin-resistant human skeletal muscle, at rest and following a single bout of exercise.

It was found that to obtain complete equilibration between the perfusion fluid and the interstitial fluid in human skeletal muscle, a perfusion flow rate as low as 0.16 μl/min is necessary with the presently used catheters (Study I).

At these low perfusion flow rates a colloid needs to be included in the perfusion fluid in order to keep the fluid balance and in this thesis it was shown that the colloid dextran- 70 does not affect the metabolite concentrations in the collected dialysates (Study II).

A high cut-off microdialysis membrane can be used to infuse insulin into human skeletal muscle and to record its effect on metabolite concentrations (Study III). When the insulin-mimetic agent vanadate was infused into human skeletal muscle (Study IV), it was found to decrease the interstitial glucose concentration in a similar way as insulin, but in contrast to insulin, the effect of vanadate was not diminished in insulin-resistant skeletal muscle and was not affected by exercise (Study V).

In insulin-resistant human skeletal muscle, the effect of insulin tended to be larger following a single 2-h bout of exercise than in resting muscle (-32 % versus -20%, p<0.09) (Study V). The insulin effect in resting muscle of healthy individuals was –30 % (Study III).

In conclusion, the studies in the present thesis support the hypothesis that it will be possible in the future to measure insulin resistance in skeletal muscle with microdialysis and to use the technique to explore the effect on skeletal muscle of different therapeutic options in the treatment of type-2 diabetes. On this line, the present results indicate that a single bout of exercise normalizes the insulin effect on the interstitial glucose concentration in insulin-resistant human skeletal muscle.

List of scientific papers

I. Rosdahl H, Hamrin K, Ungerstedt U, Henriksson J (1998). Metabolite levels in human skeletal muscle and adipose tissue studied with microdialysis at low perfusion flow. Am J Physiol. 274(5 Pt 1): E936-45.
https://pubmed.ncbi.nlm.nih.gov/9612253

II. Hamrin K, Rosdahl H, Ungerstedt U, Henriksson J (2002). Microdialysis in human skeletal muscle: effects of adding a colloid to the perfusate. J Appl Physiol. 92(1): 385-93.
https://pubmed.ncbi.nlm.nih.gov/11744681

III. Rosdahl H, Hamrin K, Ungerstedt U, Henriksson J (2000). A microdialysis method for the in situ investigation of the action of large peptide molecules in human skeletal muscle: detection of local metabolic effects of insulin. Int J Biol Macromol. 28(1): 69-73.
https://pubmed.ncbi.nlm.nih.gov/11033179

IV. Hamrin K, Henriksson J (2004). Local effect of vanadate to increase glucose uptake and lactate formation in human skeletal muscle. Life Sciences. [Accepted]

V. Hamrin K, henriksson J (2004). Local effect of insulin and vanadate in insulin-resistant human skeletal muscle after one bout of one-legged exercise. [Manuscript]