1 The Wallenberg Laboratory, 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
skeletal muscle; glucose metabolism; microdialysis; muscle blood
flow
INSULIN RESISTANCE in the muscles may include the
inability of insulin to stimulate muscle glucose uptake by the glucose
transporter system as well as the oxidation and storage of glucose
(10). Accordingly, regardless of the underlying cause, in vitro
investigations have demonstrated multiple defects in muscle cells from
insulin-resistant subjects, including perturbations of the insulin
receptor signal (5) as well as the glucose transporter proteins (12)
and the glycogen synthase activity (30). In addition to these
cell-associated defects, increasing interest has recently been focused
on the putative role of the blunted vasodilatory effect of insulin
repeatedly demonstrated in peripheral tissue, i.e., skeletal muscle, in
insulin resistant-subjects (3, 4, 15). A lacking vasodilatory effect of
insulin could lead to decreased capillary delivery of insulin and
glucose to the muscle cell. In favor of such a pathogenic mechanism, a
number of studies have shown that the ability of insulin and glucose to
induce vasodilation in skeletal muscles also correlates closely to the
rate of glucose uptake (4, 15). In contrast to this theory, however, it
has been shown that glucose uptake and vasodilation induced by insulin
have different concentration-effect curves as well as time kinetics
(32). Moreover, the extent to which vasodilation contributes to glucose
uptake during pharmacological vasodilation (23, 31) or after ingestion
of food (20) or glucose (21) seems to be only minor in normal healthy
individuals. It may thus be concluded that the pathogenetic
significance of the hampered insulin-mediated vasodilation found in
insulin-resistant subjects is still not clear.
We recently employed the calibrated microdialysis technique (18) to
investigate the interstitial muscle glucose concentration (22). In that
study, it was demonstrated for the first time that the interstitial
glucose concentration in muscle is less than that in arterial plasma
after overnight fasting, indicating that the capillary wall is rate
limiting for the muscle glucose uptake (22). The finding of a
significant arterial-interstitial concentration ([a-i]) difference
then makes the calculation of the extraction fraction of glucose in the
muscle possible (17). When the interstitial muscle glucose
concentration and the extraction fraction were studied in
insulin-resistant Zucker rats, the interstitial fluid concentration of
glucose was found to be higher than normal and the a-i concentration
difference of glucose was diminished (13). To elucidate the
relationship between glucose uptake and blood flow in insulin-resistant
muscle further, we investigated a group of normal individuals and a
group of older and overweight patients with non-insulin-dependent
diabetes mellitus (NIDDM) having severe insulin resistance. The two
groups were not age matched and, naturally, did not have identical
fasting glucose levels. The two groups were studied separately, and the
data from muscle microdialysis and blood flow measurement were compared qualitatively.
Subjects
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
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.
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
Table 1.
Clinical characteristics of subjects
Study Protocol
The investigations were started at 8 AM after an overnight fast. The subjects were studied in the supine position in a room kept at 25°C. A polyethylene catheter was placed in a left forearm vein for blood sampling. The forearm was heated with electric pads (60-70°C) to arterialize the venous blood (17). Each study started with a calibration period of 180 min, followed by a euglycemic clamp performed as previously described by DeFronzo et al. (11). The clamp started with a primed infusion of insulin (Actrapid, Novo Nordisk, Copenhagen, Denmark) for 10 min followed by a constant infusion rate of 1 mU · kgMicrodialysis
In the present experimental procedures, a commercially available custom-made microdialysis catheter (16 × 0.5 mm, 20 kDa molecular weight cutoff; CMA-10, CMA, Stockholm, Sweden) was used. The inlet of the microdialysis catheter was connected to a microinjection pump (CMA 100, CMA) and perfused at a flow rate of 2.0 µl/min. Isotonic saline with addition of 2.5 mmol/l glucose and 250 µmol/l lactate was used as the perfusion fluid. Two catheters were inserted without anesthetics into the ipsilateral quadriceps femoris ~10-15 cm above the knee joint by the following procedure: the surface of the disinfected skin was punctured vertically with a 20-gauge cannula. The steel mandrel was removed and the microdialysis catheter was inserted subsequently. After 30 min equilibration, the dialysate was collected at 15-min intervals. After calibration of the microdialysis catheters (see Calibration Procedure), the euglycemic clamp was started and the glucose and lactate levels were followed for 2 h.Muscle blood flow to the calf was measured before and after 90 min of the euglycemic clamp on the contralateral leg using vein occlusion plethysmography (1).
Calibration Procedure
In vitro. Concentration-independent transfer rates for glucose and lactate were described in vitro in previous experiments (21). The mean in vitro recovery in the dialysate for the catheter type employed in the present study was ~60% for glucose and 81% for lactate (21).
In vivo. In vivo probe recovery was assessed in each probe according to the equilibrium (18) and internal reference calibration techniques (21, 19).
The equilibrium calibration was carried out as previously described in detail (18). Briefly, known concentrations of glucose and lactate were added to the perfusate in a nonconsecutive order, and the net increase of glucose and lactate concentration in the dialysate was measured. The linear relationship between perfusate glucose and increase in dialysate concentration was established, and the point of no net influx (indicating the interstitial glucose concentration) was estimated by means of linear regression. For internal reference calibration, 5 µCi/ml [3H]glucose and [14C]lactate were added to the perfusate, and the percentage loss over the membrane was taken as an estimate of recovery (21). The experiments according to the equilibrium method revealed a mean in vivo recovery of 0.29 ± 0.02% (n = 18) for glucose and 0.39 ± 0.02% for lactate (n = 18). The corresponding mean recovery values obtained by means of internal reference calibration were 0.27 ± 0.03 and 0.41 ± 0.02% [not significant (NS)], respectively.Analytical Methods
Glucose and lactate concentrations in plasma and in the dialysate fractions were determined enzymatically using 10-µl samples for simultaneous analyses of glucose and lactate in a YSI 2700 select biochemical analyzer (Yellow Springs Instruments, Yellow Springs, OH). Radioactivity was counted in a liquid scintillation counter using a quenched-corrected (external standards), double-isotope program (1217 Rackbeta, LKB, Uppsala, Sweden). Tissue samples were initially checked for quenching interferences using internal standards for 14C and 3H.Statistics
All statistical calculations were made on absolute values. All results are expressed as means ± SE. Significance of difference was tested with Student's t-test for paired observations and, when applicable, with analysis of variance. Linear regression analyses of the in vivo recovery experiments were performed according to the least-square method. ![]() |
RESULTS |
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Plasma Insulin and Rates of Total Glucose Disposal
The insulin values are shown in Table 2. The basal insulin values tended to be higher in the older NIDDM subjects (15.7 ± 4.8 µU/ml) than in controls (4.7 ± 0.5 µU/ml), but this difference was not significant (P < 0.06). The insulin values achieved during the glucose clamp did not differ significantly between the two groups. The glucose disposal rate in the NIDDM subjects was significantly lower than in controls (P < 0.001; Fig. 1).
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Glucose Levels Before and During the Glucose Clamp
In postabsorptive control subjects, the glucose concentration in arterial plasma and in interstitial fluid was 4.9 ± 0.2 and 4.5 ± 0.2 mmol/l, respectively, and the a-i concentration difference was significant (0.43 ± 0.16 mmol/l, P < 0.05; Table 3). In NIDDM subjects, postabsorptive hyperglycemia prevailed. The fasting glucose level in arterial plasma and interstitial fluid was 8.9 ± 0.6 and 8.4 ± 0.9 mmol/l, respectively. In this subject group, five individuals had higher glucose concentrations in plasma compared with interstitial fluid, and the a-i glucose concentration difference was not significant (0.54 ± 0.73 mmol/l, NS). Ninety minutes after the initiation of the glucose clamp, the interstitial glucose concentrations in controls were still significantly lower (4.4 ± 0.2 mmol/l) compared with the plasma concentrations (5.6 ± 0.1 mmol/l; P < 0.001), and the NIDDM subjects now also had a lower interstitial glucose concentration than that in plasma (5.6 ± 0.2 vs. 4.5 ± 0.3 mmol/l; P < 0.05; Table 4). The [a-i] differences of glucose increased gradually after 90 min of glucose clamp from the fasting state to 1.22 ± 0.25 mmol/l (P < 0.05) in controls (Fig. 2A), and in the NIDDM subjects the a-i glucose concentration difference was significant: 1.11 ± 0.27 mmol/l (P < 0.05; Fig. 2B).
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|
|
Lactate Levels Before and During the Glucose Clamp
The mean interstitial concentration of lactate in the postabsorptive state, estimated by regression analysis, was 0.73 ± 0.04 mmol/l for controls and 0.95 ± 0.06 mmol/l for NIDDM subjects. In controls, this concentration was significantly higher than that in arterial plasma (0.60 ± 0.03 mmol/l, P < 0.05). In the NIDDM subjects, plasma lactate was higher than in interstitial fluid (1.11 ± 0.27 mmol/l), but the concentration differences did not reach statistical significance (Table 3). After 90 min of the glucose clamp, the interstitial lactate concentrations increased to 1.38 ± 0.10 mmol/l compared with the plasma concentrations (1.13 ± 0.10 mmol/l; P < 0.05) in controls, whereas in the NIDDM subjects there was still no significant difference between plasma concentrations (1.09 ± 0.09 mmol/l) and the interstitial concentrations (1.15 ± 0.09 mmol/l; Table 4).The [a-i] differences of lactate in the postabsorptive
state were 0.13 ± 0.05 mmol/l, and, after 90 min of glucose
ingestion (
0.25 ± 0.10 mmol/l) in controls (Fig.
3A) and
in the NIDDM subjects, these differences decreased significantly from
0.17 ± 0.15 to
0.06 ± 0.12 mmol/l
(P < 0.05; Fig.
3B).
|
Leg Blood Flow Measurements
In controls, mean leg blood flow was 6.4 ± 1.0 ml · 100 g ![]() |
DISCUSSION |
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The present results clearly show that insulin-resistant muscle has qualitatively different interstitial glucose kinetic characteristics compared with muscle from normal insulin-sensitive subjects. The regulation of the interstitial glucose and lactate levels was different in the two subject groups both in the postabsorptive state and during insulin infusion. The results also suggest that the blunted vasodilatory effect of insulin in the older NIDDM subjects does not explain the markedly reduced glucose uptake during insulin clamping. The results do not permit conclusions as to the mechanism behind the insulin resistance or what mechanisms regulate insulin kinetics and action in NIDDM. The aim of the study was to compare qualitatively the kinetics of glucose and lactate in insulin-resistant muscle, regardless of the underlying mechanisms, with those in normals. Therefore, an extremely insulin-resistant subject group of NIDDM overweight patients were compared with younger lean controls.
Postabsorptive State
In the younger lean control group, it was confirmed (21) that the interstitial muscle glucose concentration was less than that in arterial plasma after an overnight fast. Given the blood flow, in this study estimated indirectly by assessment of leg blood flow, the extraction of glucose can be estimated by the formula: [a-i] · (1In insulin-resistant muscle, no significant a-i difference of glucose was demonstrated despite the fact that the leg blood flow rate in the fasting state was not different from that in normals. In these subjects, capillary delivery of glucose is thus not rate limiting for glucose uptake during fasting hyperglycemia. Glucose is taken up predominantly by passive diffusion in this situation, in agreement with the concept that non-insulin-dependent glucose uptake is increased during fasting hyperglycemia (2, 11). Furthermore, the finding that the capillary wall is not rate limiting for glucose delivery in these subjects convincingly demonstrates the pathogenic significance of an intracellular defect behind the insulin resistance. Thus, in fasting hyperglycemic NIDDM subjects, muscle blood flow does not regulate glucose uptake. In harmony with this, lactate diffuses passively over the capillary wall despite the increased plasma lactate concentration in these subjects. Because the a-i concentration difference of lactate was not significant, in contrast to what was registered in the normal subjects, the lactate release could not be estimated by microdialysis measurements. However, earlier studies have demonstrated an increased rate of nonoxidative glucose metabolism in fasting NIDDM subjects (7, 8). Thus, despite a putative increase of lactate formation by muscle cells in insulin-resistant subjects having a normal blood flow rate in the leg, lactate equilibrates over the capillary wall. The tissue lactate release is limited by cellular production in this situation and is not restricted by the endothelial barrier.
Insulin Infusion
In lean control subjects the insulin infusion caused a threefold increase in a-i glucose concentration difference and, concomitantly, leg blood flow increased ~50%. It may thus be concluded that the insulin-mediated increase in muscle blood flow does not compensate for the enhanced glucose utilization in muscle by preventing the decrease in interstitial glucose concentration. Again, because the increase in leg blood flow is representative of the vasodilation taking place in muscle (15), the glucose extraction can be assessed. It should be noted that increased blood flow could be mediated by both increased velocity of the capillary bloodstream and recruitment of new capillaries and that both these processes have been demonstrated after insulin (25). This means that the extraction of glucose will be enhanced by increase of both PS for glucose (~7 ml · minIn NIDDM subjects, insulin infusion was introduced during fasting hyperglycemia and the glucose infusion was balanced to reach the same level as that received in the normal group. During normoglycemia, the NIDDM subjects appeared to be severely insulin resistant, as indicated by the low glucose infusion rate (60% lower than in the normal group) despite the considerably higher plasma insulin values. It is also notable that in insulin-resistant muscles insulin infusion induced a gradual increase in the glucose a-i concentration difference, which reached the same amplitude as in normals after 90 min. During the same period, no increase of leg blood flow was registered, confirming a blunted vasodilatory effect of insulin (4).
Interestingly, the late appearance of a significant a-i glucose concentration difference in NIDDM subjects indicates a delayed onset of the insulin effect, as recently discussed by others (26). Moreover, it implies a shift in a rate-limiting step(s) for muscle glucose uptake, in which the capillary wall becomes rate limiting as normoglycemia is reached (Fig. 2B). Also, this suggests that the glucose transport protein, which evidently is less rate limiting for glucose uptake during hyperglycemia (33), may become rate limiting again during normoglycemia maintained by insulin.
When the glucose uptake rate is assessed (~6
µmol · min1 · 100 g
1) during normoglycemia
in the insulin-resistant muscles, it appears that the reduction in
assessed muscle glucose uptake corresponds to a significant reduction
in glucose infusion rate (35 and 60% reduction, respectively). The
severe reduction in insulin sensitivity and glucose uptake is further
demonstrated by the i-a concentration difference for lactate, which did
not reach statistical significance during the insulin infusion,
indicating reduced conversion of glucose to lactate (Fig.
3B).
The present data also make it possible to evaluate the putative role of the lacking vasodilatory effect of insulin in the occurrence of insulin resistance in the subjects presently investigated. It might be argued that, because a-i glucose concentration differences were similar during insulin infusion in the two subject groups, the only factor that differentiated the insulin effect is the blood flow. However, the present and previous data (21) from normal individuals show that vasodilation induced by insulin and glucose is not critical for the increase in muscle glucose uptake. Furthermore, if limited access to glucose was the regulating factor behind the reduced glucose uptake in insulin-resistant subjects, the a-i concentration difference of glucose demonstrated here would have been increased and not nonexistent (fasting hyperglycemia) or normal (normoglycemic insulin clamp conditions). By contrast, it may be considered that, despite the low rate of glucose uptake in insulin-resistant muscle cells during insulin infusion, the a-i concentration difference of glucose appears to be normal, whereas muscle blood flow is reduced. We hypothesize that the a-i concentration difference is autoregulated in normal subjects by regulation of the blood flow through vasodilatory glucose metabolites such as lactate and CO2 (29) and that this "autoregulation" is diminished in severe insulin resistance.
Because reduction of cellular glucose uptake and not failing delivery
of glucose is the factor determining the interstitial concentration, it
may be presumed that pharmacological increase of the blood flow rate in
insulin-resistant muscle would increase the interstitial glucose
concentration and hence decrease the a-i concentration difference.
Interestingly, we recently reported high interstitial glucose
concentrations in normoglycemic insulin-resistant Zucker rats (13). In
further support of the importance of cellular uptake of glucose for the
interstitial concentration, we were recently able to demonstrate acute
rapid reduction of muscular glucose uptake and concomitant increase of
interstitial muscle glucose by -adrenergic stimulation in the rat
(unpublished observation).
Although blood flow does not seem to regulate glucose uptake during steady-state insulin clamp conditions, it may be noted that the time course of onset of the insulin effect appeared to be severely delayed in the NIDDM subjects. It may be considered in this context that interstitial insulin levels are lower than in plasma (6) and that capillary delivery of insulin may thus be restricted and saturable (13, 27). A tentative reduction of muscle blood flow rate due to subnormal capillarization and vasodilatory response to insulin may thus delay the insulin effect. In support of this concept, we recently demonstrated a delayed distribution of insulin in femoral muscle of insulin-resistant testosterone-treated rats (24). These rats demonstrate a reduced muscular capillarization, which is normalized after long-term physical exercise (14). Physical exercise also normalizes the interstitial distribution time of insulin in these animals (24).
In summary, the capillary wall is rate limiting for glucose uptake and lactate release in normal muscle during euglycemic conditions but not in hyperglycemic elderly and overweight NIDDM subjects. The vasodilatory effect of insulin mediates only a small increase of glucose uptake in muscles, and a blunted vasodilation cannot explain the reduced glucose uptake. The putative role of vasodilation in the insulin distribution in the interstitial fluid must be further explored.
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ACKNOWLEDGEMENTS |
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The laboratory assistance provided by Lena Strindberg is gratefully acknowledged.
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FOOTNOTES |
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This study was supported by grants from the Swedish Research Council (project no. 10864, 11330, and 12206), the Inga-Britt and Arne Lundberg Foundation, the Swedish Diabetes Association, and the Nordisk Insulin Fond.
Address for reprint requests: A. Holmäng, Wallenberg Laboratory, Göteborg Univ., S-413 45 Göteborg, Sweden.
Received 14 July 1997; accepted in final form 12 November 1997.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Andersson, O. K.,
L. Hansson,
and
R. Sivertsson.
Primary hypertension refractory to triple drug treatment. A study on central and peripheral hemodynamics.
Circulation
58:
615-621,
1978[Medline].
2.
Baron, A. D.,
O. G. Kolterman,
J. Bell,
J. L. Mandarino,
and
J. M. Olefsky.
Rates of non-insulin mediated glucose uptake are elevated in type II diabetic subjects.
J. Clin. Invest.
76:
1782-1788,
1985[Medline].
3.
Baron, A. D.,
M. Laakso,
G. Brechtel,
and
S. V. Edelman.
Mechanism of insulin resistance in non-insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow.
J. Clin. Endocrinol. Metab.
73:
637-643,
1991[Abstract].
4.
Baron, A. D.,
H. Steinberg,
G. Brechtel,
and
A. Johnson.
Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake.
Am. J. Physiol.
266 (Endocrinol. Metab. 29):
E248-E253,
1994
5.
Caro, J. F.,
M. K. Sinha,
S. M. Raju,
O. Ittoop,
W.-J. Pories,
E. G. Flickinger,
D. Meelheim,
and
G. L. Dohm.
Insulin receptor kinase in human skeletal muscle from obese subjects with and without non-insulin dependent diabetes.
J. Clin. Invest.
79:
1330-1337,
1987[Medline].
6.
Castillo, C.,
C. Bogardus,
R. Bergman,
P. Thuillez,
and
S. Lillioja.
Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men.
J. Clin. Invest.
93:
10-16,
1994[Medline].
7.
Consoli, A.,
N. Nurjhan,
F. Capani,
and
J. Gerich.
Predominate role of gluconeogenesis in increased hepatic glucose production in NIDDM.
Diabetes
38:
550-557,
1989[Abstract].
8.
Consoli, A.,
N. Nurjhan,
J. Reilly, Jr.,
D. Bier,
and
J. Gerich.
Mechanism of increased gluconeogenesis in non-insulin dependent diabetes mellitusrole of alterations in systemic hepatic and muscle lactate and alanine metabolism.
J. Clin. Invest.
86:
2038-2040,
1990[Medline].
9.
Crone, C.,
and
D. G. Levitt.
Capillary permeability to small solutes.
In: Handbook of Physiology. The Cardiovascular System. Microcirculation. Bethesda, MD: Am. Physiol. Soc., 1984, sect. 2, vol. IV, pt. 1, chapt. 10, p. 411-466.
10.
DeFronzo, R. A.
Lilly lecture. The triumvirate: -cell, muscle, liver. A collusion responsible for NIDDM.
Diabetes
37:
667-687,
1988[Medline].
11.
DeFronzo, R. A.,
R. Gunnarsson,
O. Björkman,
M. Olsson,
and
J. Wahren.
Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent (type 2) diabetes mellitus.
J. Clin. Invest.
76:
149-155,
1985[Medline].
12.
Dohm, G. L.,
E. B. Tapscott,
W. J. Pories,
D. J. Dabbs,
E. G. Flickinger,
D. Meelheim,
T. Fushiki,
S. M. Atkinson,
C. W. Elton,
and
J. F. Laro.
An in vitro human skeletal muscle preparation suitable for metabolic study. Decreased insulin stimulation of glucose transport in muscle from morbidity obese and diabetic subjects.
J. Clin. Invest.
82:
486-494,
1988[Medline].
13.
Holmäng, A.,
K. Mimura,
P. Björntorp,
and
P. Lönnroth.
Interstitial muscle insulin and glucose levels in normal and insulin resistant Zucker rats.
Diabetes
46:
1799-1804,
1997[Abstract].
14.
Holmäng, A.,
J. Svedberg,
E. Jennische,
and
P. Björntorp.
Effects of testosterone on muscle insulin sensitivity and morphology in female rats.
Am. J. Physiol.
259 (Endocrinol. Metab. 22):
E555-E560,
1990
15.
James, D. E.,
K. M. Burleigh,
L. H. Storlien,
S. P. Bennett,
and
E. W. Kraegen.
Heterogeneity of insulin action in muscle: influence of blood flow.
Am. J. Physiol.
251 (Endocrinol. Metab. 14):
E422-E430,
1986
16.
Jansson, P. A.,
J. Fowelin,
H. von Schenck,
U. Smith,
and
P. Lönnroth.
Measurement by microdialysis of the insulin concentration in subcutaneous interstitial fluid.
Diabetes
42:
1469-1473,
1993[Abstract].
17.
Jansson, P. A.,
A. Larsson,
U. Smith,
and
P. Lönnroth.
Glycerol production in subcutaneous adipose tissue in lean and obese man.
J. Clin. Invest.
89:
1610-1617,
1992[Medline].
18.
Lönnroth, P.,
P. A. Jansson,
and
U. Smith.
A microdialysis method allowing characterization of intercellular water space in humans.
Am. J. Physiol.
253 (Endocrinol. Metab. 16):
E228-E231,
1987
19.
Lönnroth, P.,
and
L. Strindberg.
Validation of the internal reference technique for calibrating microdialysis in situ.
Acta Physiol. Scand.
153:
375-380,
1995[Medline].
20.
Mijares, A.,
and
M. Jensen.
Contribution of blood flow to leg glucose uptake during a mixed meal.
Diabetes
44:
1165-1169,
1995[Abstract].
21.
Müller, M.,
A. Holmäng,
O. K. Andersson,
H. G. Eichler,
and
P. Lönnroth.
Measurement of interstitial muscle glucose and lactate concentrations during an oral glucose tolerance test.
Am. J. Physiol.
271 (Endocrinol. Metab. 34):
E1003-E1007,
1996
22.
Müller, M.,
R. Schmid,
M. Nieszpaur-Los,
A. Iassolt,
P. Lönnroth,
P. Fasching,
and
H.-G. Eichler.
Key metabolic kinetics in human skeletal muscle during ischaemia and reperfusion: measurement by microdialysis.
Eur. J. Clin. Invest.
25:
601-607,
1995[Medline].
23.
Natali, A.,
R. Bonadonna,
and
D. Santoro.
Insulin resistance and vasodilation in essential hypertension. Studies with adenosine.
J. Clin. Invest.
94:
1570-1576,
1994[Medline].
24.
Niklasson, M., P. Daneryd, P. Lönnroth, and A. Holmäng. The effect of testosterone and exercise on insulin
kinetics in rat (Abstract). Int. J. Obes. 20, Suppl. 4: 78, 1996.
25.
Raitakari, M.,
P. Nuutila,
V. Ruotsalainen,
H. Laine,
M. Teras,
H. Iida,
S. Makimathla,
T. Vtrainer,
V. Oihonen,
H. Sipila,
M. Haaparanta,
O. Sohn,
V. Wegehus,
J. Knuuh,
and
H. Yki-Järvinen.
Evidence for dissociation of insulin stimulation of blood flow and glucose uptake in human skeletal muscle: studies using [15O]H2O, [18F]fluoro-2-deoxy-D-glucose, and positron emission tomography.
Diabetes
45:
1471-1477,
1996[Abstract].
26.
Prager, R.,
P. Wallace,
and
J. M. Olefsky.
In vivo kinetics of insulin action on peripheral glucose disposal and hepatic glucose output in normal and obese subjects.
J. Clin. Invest.
78:
472-481,
1986[Medline].
27.
Prigeon, R. L.,
M. E. Roder,
D. Porte,
and
S. E. Kahn.
The effect of insulin dose on the measurement of insulin sensitivity by the minimal model technique. Evidence for saturable insulin transport in humans.
J. Clin. Invest.
97:
501-507,
1996
28.
Renkin, E.
Control of microcirculation and blood-tissue exchange.
In: Handbook of Physiology. The Cardiovascular System. Microcirculation. Bethesda, MD: Am. Physiol. Soc., 1984, sect. 2, vol. IV, pt. 2, chapt. 14, p. 627-688.
29.
Saltin, B.,
and
P. D. Gollnick.
Skeletal muscle adaptability: significance for metabolism and performance.
In: Handbook of Physiology. Skeletal Muscle. Bethesda, MD: Am. Physiol. Soc., 1983, sect. 10, chapt. 19, p. 555-632.
30.
Shulman, D.,
D. Rothman,
T. Jue,
P. Stein,
R. A. DeFronzo,
and
R. Schulman.
Quantification of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C-nuclear magnetic resonance spectroscopy.
N. Engl. J. Med.
322:
223-228,
1990[Abstract].
31.
Yki-Järvinen, H.
Action of insulin on glucose metabolism in vivo.
J. Clin. Endocrinol. Metab.
7:
903-927,
1993.
32.
Yki-Järvinen, H.,
A. A. Young,
C. Lamkin,
and
J. E. Foley.
Kinetics of glucose disposal in whole body and across the forearm in man.
J. Clin. Invest.
79:
1713-1719,
1987[Medline].
33.
Zierath, J. R.,
D. Galuska,
L. A. Nolte,
J. Smedegaard-Kristensen,
and
H. Wallberg-Henriksson.
Effects of glycaemia on glucose transport in isolated skeletal muscle from patients with NIDDM: in vitro reversal of muscular insulin resistance.
Diabetologia
37:
270-277,
1994[Medline].