We raised and lowered arterial pressures with stepwise intravenous infusions of phenylephrine and nitroprusside in ten healthy young men and measured changes of R-R intervals, post-ganglionic peroneal nerve muscle sympathetic activity, and antecubital vein plasma noradrenaline and neuropeptide Y concentrations. Respiratory peak-valley R-R interval changes declined with arterial pressure reductions, but did not rise with pressure elevations. Sympathetic activity was modulated by respiration over the entire range of pressures and, at each pressure, was more prominent in expiration than inspiration. Levels of muscle sympathetic nerve activity were low during supine rest, were suppressed almost completely during small increases of pressure, and were increased proportionally during pressure reductions. Over a range of average diastolic pressures from 69 to 89 mmHg, antecubital vein plasma noradrenaline levels were related linearly (r = 0.86, P = 0.0001) to muscle sympathetic nerve activity. Neuropeptide Y levels increased proportionally with muscle sympathetic nerve activity during pressure reductions, but did not decline during pressure elevations. Our results suggest that in man, muscle sympathetic outflow is modulated finely by small changes of baroreceptor input, and that during pharmacologically induced changes of arterial pressure, changes of antecubital vein plasma noradrenaline concentrations provide excellent estimates of changes of sympathetic nerve traffic to skeletal muscle.

To study the relationship between blood flow rate and muscle metabolism, muscle microdialysis was performed in nine human subjects (5 females and 4 males) after an oral glucose load (75 g). Two microdialysis probes were inserted into the medial femoral muscle for estimation of glucose and lactate concentrations in the interstitial fluid, and the muscle blood flow was measured concomitantly with strain-gauge plethysmography. After subjects fasted overnight, their glucose concentration in arterial plasma and interstitial fluid was 4.6 +/- 0.13 vs. 3.8 +/- 0.23 mmol/l (P < 0.05), and the corresponding lactate concentrations were 0.60 +/- 0.07 vs. 0.83 +/- 0.07 mmol/l (P < 0.05). Muscle blood flow was 5.2 +/- 0.7 and 7.5 +/- 1.4 ml.100 g-1.min-1 (P < 0.05) at 0 and 90 min after oral glucose, respectively. The arterial-interstitial concentration differences of glucose increased after oral glucose [at 0 min 0.73 +/- 0.24 vs. 2.19 +/- 0.60 mmol/l at 90 min (P < 0.001)]. The corresponding values for lactate were -0.23 +/- 0.10 at 0 min vs.-0.26 +/- 0.18 mmol/l at 90 min (not significant). The data show that 1) the capillary wall is partly rate limiting for glucose uptake, and 2) after oral glucose, the glucose concentration gradient over the capillary wall increases despite a limited increase in blood flow rate, which then mediates approximately 10-20% of total enhancement of glucose uptake in muscle.

To study the regulation of the interstitial glucose concentration in skeletal muscle, nine control subjects and nine older and overweight non-insulin-dependent diabetes mellitus (NIDDM) subjects with extreme insulin resistance were investigated with microdialysis in the medial femoral muscle before and during a euglycemic insulin clamp. After an overnight fast, arterial plasma glucose concentration was 4.9 ± 0.1 and 8.5 ± 0.6 mmol/l ( P < 0.001), respectively. The arterial-interstitial concentration ([a-i]) differences of glucose and lactate were 0.43 ± 0.16 ( P < 0.05) and −0.13 ± 0.05 mmol/l, respectively, in normal subjects. In NIDDM subjects, [a-i] differences for glucose and lactate were nonsignificant. Muscle blood flow was similar in controls and NIDDM subjects. During the glucose clamp, the glucose [a-i] differences increased and the lactate [a-i] differences decreased significantly in both groups. The glucose 170 infusion rate was 8.0 ± 0.77 vs. 3.2 ± 0.51 mg ⋅ kg−1 ⋅ min−1( P < 0.001), and blood flow was 9.9 ± 1.6 vs. 6.7 ± 0.9 ml ⋅ 100 g−1 ⋅ min−1( P < 0.05) in controls and NIDDM subjects, respectively. These results show that 1) the capillary wall is rate limiting for muscle glucose uptake and lactate release in control subjects but not in postabsorptive hyperglycemic insulin-resistant subjects, 2) vasodilation during insulin infusion does not prevent the increase in [a-i] difference of glucose in normal subjects, and 3) in severely insulin-resistant muscle, the [a-i] difference of glucose is not extended despite lack of vasodilation.

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In this open study, postabsorptive net lactate release in abdominal subcutaneous adipose tissue was clearly increased in NIDDM patients after metformin treatment. Basal ATBF as well as MBF was improved after metformin treatment. Whether this reflects enhanced metabolic control or is a drug-specific effect remains to be established.