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Decreased Muscle Capillary Permeability Surface Area in Type 2 Diabetic Subjects

Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden

Address all correspondence and requests for reprints to: Soffia Gudbjörnsdóttir, Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: soffia.gudbjornsdottir{at}medic.gu.se.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Capillary recruitment in muscles, induced by insulin, has been proposed to be impaired in insulin-resistant states. To elucidate the mechanisms regulating capillary transport of insulin and glucose in type 2 diabetes, we directly calculated the permeability-surface area product (PS) for glucose and insulin in muscle.

Intramuscular microdialysis in combination with the forearm model and blood flow measurements was performed in type 2 diabetic male subjects and age- and weight-matched controls during a euglycemic-hyperinsulinemic clamp.

During steady-state hyperinsulinemia, arterial plasma glucose was 5.8 ± 0.1 and 5.9 ± 0.1 mmol/liter [not significant (NS)] in the obese and type 2 diabetic subjects, respectively. Venous glucose was significantly lower in the obese group compared with the type 2 diabetic subjects, 4.3 ± 02 vs. 4.9 ± 0.2 mmol/liter (P < 0.05). Arterial insulin was 1494 ± 90 and 1458 ± 132 pmol/liter (NS) in the obese and type 2 diabetic subjects, respectively.

The glucose infusion rate during steady-state hyperinsulinemia was 10.8 ± 0.8 and 7.2 ± 0.4 mg/kg·min in the obese and diabetic subjects, respectively (P < 0.01). Interstitial-arterial lactate difference was significantly higher in the obese subjects.

During steady-state hyperinsulinemia, PS for glucose was significantly higher in the obese subjects (1.1 ± 0.2 vs. 0.5 ± 0.1 ml/min·100 g, P < 0.05). Glucose uptake was also significantly higher in the obese subjects (3.0 ± 0.4 vs. 1.8 ± 0.3 µmol/min·100 g, P < 0.05). During steady-state hyperinsulinemia, PS for insulin was 0.4 ± 0.1 and 0.3 ± 0.1 ml/min·100 g in the obese and diabetic subjects, respectively (NS), and insulin uptake was 258 ± 54 vs. 168 ± 24, respectively (NS). When both subject groups were pooled together, a significant correlation was found between PS for glucose and glucose uptake during steady-state hyperinsulinemia. Skeletal muscle blood flow during steady-state hyperinsulinemia was 1.9 ± 0.2 and 2.3 ± 0.4 ml/100 g·min in the obese and diabetic subjects, respectively (NS). Blood flow did not increase during hyperinsulinemia in either of the two groups.

The present data clearly show that PS for glucose is subnormal during steady-state hyperinsulinemia in insulin-resistant type 2 diabetic subjects. Furthermore, there was a close correlation between glucose uptake and PS for glucose but not between blood flow and PS. We suggest that PS is a more sensitive marker for insulin resistance during hyperinsulinemia than limb flow. The lower capacity for transcapillary passage found in the type 2 diabetic subjects is suggested to further aggravate insulin resistance.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IN TYPE 2 DIABETES skeletal muscle is relatively insensitive to the effects of insulin to increase glucose uptake (1, 2) and cause vasodilation (3). The importance of the vasodilatory effect of insulin for glucose uptake was proposed because the vasodilation and an increase of glucose uptake caused by insulin correlate closely (3, 4, 5). Also, vasodilation and glucose uptake seem to be mediated by the same wortmannin-dependent pathway for insulin signaling, thereby possibly guaranteeing the access of itself and glucose to the muscle cell. However, an increase of blood flow seems not to increase glucose uptake by itself (6), and, furthermore, the vasodilatory effect of insulin seems to have a time kinetics and a dose dependence on insulin different from those for the effect on glucose uptake (7, 8). Moreover, it should be noted that increase of blood flow without recruitment of new capillaries does not automatically lead to increased transcapillary delivery of glucose (9). In the muscle, the interstitial fluid concentration of both insulin and glucose is lower than in plasma (10, 11), and, consequently, the capillary wall is rate limiting for the insulin effect (12). The more insensitive the muscle cells are to insulin and the lower the glucose uptake rate over the plasma membrane the less rate limiting the capillary wall becomes for cellular glucose uptake (13). Hence, it may not be possible to assess and quantify the importance of the blunted vasodilatory effect of insulin in insulin-insensitive muscle just by measuring vasodilation or blood flow (14, 15).

Further insight into the complex relationship among vasodilation, blood flow velocity, and capillary recruitment was gained through the direct measurement of the capillary permeability-surface area product (PS) for glucose and insulin (16). This is made possible by combining blood flow measurements with recordings of the arterio-venous concentration and arterio-interstitial concentration gradients by means of concomitant arteriovenous and microdialysis measurements (16). Such measurements have yielded data suggesting that capillary recruitment and increase of the permeability surface occur before the increase of limb blood flow, supporting the earlier notion that insulin augments muscle perfusion by increasing the capillary volume and decreasing microvascular flow velocity, whereas blood flow rate in larger vessels is kept constant (14, 15).

PS for a substance describes its capacity to reach the interstitial fluid. This depends on the permeability and the capillary surface area. The surface area depends on the extent of capillary recruitment and the molecular size of the substance determines the permeability. The recent direct measurements of PS showed that the permeability surface for glucose is much lower that expected in the nonstimulated state (16). Furthermore, these measurements showed that oral glucose increases PS for glucose 2- to 3-fold, and a further similar increase is seen after prolonged infusion of insulin. Moreover, increase of PS was exerted without any concomitant change in blood flow (16). It was concluded that the insulin-mediated 2–300% increase in PS seen after oral glucose is important for the glucose uptake rate in normal muscle (13, 16). A stimulated uptake of glucose and insulin in the absence of such an increased PS would, hypothetically, lead to depletion of these substances and a lowered interstitial concentration. In insulin-resistant subjects, however, steady-state insulin and glucose concentrations in the interstitial fluid are normal despite a low blood flow rate due to the decreased rate of cellular uptake (9, 11), whereas at non-steady-state, the transcapillary transport of insulin as well as the insulin effect are delayed (17). Thus, it may be anticipated that capillary passage of insulin and glucose is hampered in insulin-resistant muscle, but direct evidence for this may not be gained by means of blood flow measurements alone and the tentative importance of such a perturbation under steady-state conditions should be evaluated further. To obtain further information, we conducted the present study, in which direct PS measurements were performed in male type 2 diabetic subjects and their age- and weight-matched controls under steady-state hyperinsulinemic-euglycemic clamping conditions.

	Subjects and Methods

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Subjects

Eight men with type 2 diabetes and their age-, sex-, and weight-matched controls were investigated as described below. All subjects were examined by a physician, and classical clinical criteria (World Health Organization) were used for diagnoses of type 2 diabetes. Patients with cardiovascular diseases were excluded. Among the type 2 diabetic patients, one had diet treatment only, four had sulfonylurea agent only, and three had both sulfonylurea and metformin. The mean diabetes duration was 4.6 yr. The subjects did not take their hypoglycemic agents on the study day. The clinical characteristics of the subjects are given in Table 1.

Study protocol

The investigations were started at 0800 h after an overnight fast. The subjects were studied in the supine position in a room kept at 25 C. Under local anesthesia, catheters were inserted into the right antecubital vein for inulin, glucose, and insulin infusions, into a deep vein in the left antecubital fossa, and into the left radial or brachial artery for blood sampling. Forearm blood flow was measured every 30 min in the right arm by venous occlusion plethysmography with a Whitney strain gauge. The hand blood circulation was occluded by inflation to 200 mm Hg of a cuff at the wrist. A bolus injection of inulin (Inutest, Kemiflor, Stockholm, Sweden) was given, and then a constant intravenous inulin infusion (24 ml/h) was given for 330 min to achieve steady-state plasma inulin levels (18). A euglycemic clamp, as previously described by DeFronzo et al. (19), was started 30 min after initiation of the inulin infusion. The clamp was started with a primed infusion of insulin (Actrapid, Novo Nordisk, Copenhagen, Denmark) for 10 min, followed by a constant infusion rate of 120 mU/m²·min for 240 min. Blood samples for glucose analyses were drawn every 5 min. The rate of glucose infusion was adjusted to maintain the blood glucose concentration at about 5.5 mM/liter. Potassium chloride (0.1 M) was infused at a rate of 10 mmol/h during the clamp to prevent hypokalemia.

The principle of muscle microdialysis has been described in detail previously (10, 20, 21). Microdialysis catheters were inserted without anesthetics into the left brachioradialis muscle 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. Two commercially available custom-made microdialysis catheters (16 x 0.5 mm, 20-kD molecular mass cutoff, CMA-10, and 12 x 0.5 mm, 100-kD molecular mass cutoff, CMA-10, CMA, Stockholm, Sweden) were used. The inlet of the microdialysis catheter was connected to a microinjection pump (CMA 100, CMA) and perfused with isotonic saline, with the addition of 1.5 mmol/liter glucose and 1% human albumin for insulin and inulin measurements and the addition of 1.5 mmol/liter glucose and ³H-labeled glucose, 0.25 mmol/liter lactate, and ¹⁴C-labeled lactate for glucose and lactate measurements. The flow rate was 1.0 µl/min. for insulin-inulin measurements and 2.5 µl/min for glucose measurements. Microdialysates were collected at 30-minute intervals for insulin-inulin and at 15-minute intervals for glucose and lactate.

Measurements of interstitial insulin were taken according to the external reference calibration technique (10) at steady state. This technique is based on the fact that the relationship between the relative recoveries of two substances in vitro is the same as the relationship between the recoveries for the same two substances in vivo. Inulin was used as a reference substance because its molecular size is similar to that of insulin. The relation between recovery of inulin and insulin in vitro was 2.3. The mean relative recovery of inulin (dialysate inulin/plasma inulin) in vivo was 11.1 ± 1.1. The in vivo recovery of insulin was calculated for each subject. The mean calculated in vivo recovery of insulin was 4.8 ± 0.5. The in vivo recovery factor was used for recalculating steady-state dialysate insulin contents to interstitial insulin concentrations. For calibration of the catheters measuring glucose and lactate, the internal reference technique (22) was applied. Radioactively labeled substances were included in the perfusate, and the loss of radioactivity over the microdialysis membrane was used to calculate relative recovery.

The PS was estimated according to the equation:

where V is the venous plasma concentration, I is the interstitial concentration, A is the arterial plasma concentration, and Q is the plasma flow rate (23, 24, 25). To calculate the plasma flow rate from the blood flow rate, we are assuming a reasonable hematocrit and multiplying blood flow rate by 0.6.

Glucose and insulin uptake were estimated by Fick’s principle:

The A-V or extraction fraction can also be calculated according to the formula:

PS for a substance may then be calculated, using the formula for extraction fraction, when flow, arterial, venous, and interstitial concentrations of the substance of interest are known.

The equation has been validated in a previous study where microdialysis measurements of muscle glucose uptake were done simultaneously with positron emission tomography scan measurements of deoxyglucose uptake (26).

Analytical methods

Glucose and lactate concentrations in plasma and microdialysates were determined enzymatically with 10-µl samples on a YSI 2700 select biochemical analyzer (Yellow Springs Instrument Co., Inc., Yellow Springs, OH).

Insulin was measured with an ELISA in both plasma and microdialysates (Dako Diagnostics Ltd., Cambridgeshire, UK).

Inulin concentrations in plasma and dialysate fractions were determined photometrically, according to the method described by Waugh (27).

Statistics

The results are expressed as means ± SE of the mean. Significance was tested with Student’s t test. Simple linear regression was used to analyze correlations between two variables.

Statistical calculations of mean insulin, inulin, and glucose levels as well as blood flow were made on absolute values obtained during the last 60 min at steady state (insulin and glucose 180–240 min, inulin 300–360 min).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Fasting state

After an overnight fast, plasma glucose was 5.2 ± 0.05 and 10.3 ± 0.8 mmol/liter in the obese and type 2 diabetic subjects, respectively (P < 0.0001); fasting arterial insulin was 29.6 ± 4 and 46.2 ± 6 pmol/liter, respectively (P < 0.05) (Table 1).

Steady-state hyperinsulinemia: glucose, insulin, lactate, and glucose infusion rate (Table 2)

During steady-state hyperinsulinemia, during the last 30 min of the clamp, arterial plasma glucose was 5.8 ± 0.1 and 5.9 ± 0.1 mmol/liter (NS) in the obese and type 2 diabetic subjects, respectively. Venous glucose was significantly lower in the obese group compared with the type 2 diabetic subjects, 4.3 ± 02 vs. 4.9 ± 0.2 mmol/liter (P < 0.05). Arterial insulin was 1494 ± 90 and 1458 ± 132 pmol/liter (NS) in the obese and type 2 diabetic subjects, respectively.

Interstitial lactate was significantly higher than arterial lactate in the obese group (1670 ± 171 vs. 1139 ± 54 µmol/liter, P < 0.05) but not in the diabetic group (1339 ± 216 vs. 1169 ± 59 µmol/liter, NS).

Permeability surface area and tissue uptake (Table 2 and Fig. 1)

During steady-state hyperinsulinemia the PS for glucose was significantly higher in the obese subjects (1.1 ± 0.2 vs. 0.5 ± 0.1 ml/min·100 g, P < 0.05). Glucose uptake was also significantly higher in the obese subjects (3.0 ± 0.4 vs. 1.8 ± 0.3 µmol/min·100 g, P < 0.05). During steady-state hyperinsulinemia, PS for insulin was 0.4 ± 0.1 and 0.3 ± 0.1 ml/min·100 g in the obese and diabetic subjects, respectively (NS), and insulin uptake was 258 ± 54 and 168 ± 24 fmol/min·100 g, respectively (NS).

View larger version (15K): [in this window] [in a new window]   FIG. 1. Correlation between PS for glucose and glucose uptake rate during steady-state hyperinsulinemia, P < 0.05. Open circles, Control subjects. Filled circles, Type 2 diabetes subjects.

Skeletal muscle blood flow (Table 2)

Skeletal muscle blood flow during steady-state hyperinsulinemia was 1.9 ± 0.2 and 2.3 ± 0.4 ml/100 g·min in the obese and diabetic subjects, respectively (NS) (Table 2). Blood flow did not increase during hyperinsulinemia in either of the two groups.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A recent investigation employing direct measurements of muscle capillary permeability showed that PS for glucose increased after an oral glucose load, and a further increase was demonstrated during an insulin infusion (16). Thus, the data suggest that insulin and glucose, indeed, may increase the access of itself to the muscle cell, as previously proposed (28). The present data obtained from the same kind of measurements in muscle clearly show that PS for glucose is subnormal under steady-state insulin clamp conditions in insulin-resistant type 2 diabetic subjects. Furthermore, a close and positive correlation was demonstrated between the rate of muscle glucose uptake and PS for glucose. However, no such correlation was demonstrated between blood flow and either glucose uptake or PS for glucose. The data suggest that PS measurement is a better discriminator than blood flow of the insulin resistance residing in skeletal muscle, supporting earlier studies of insulin sensitivity and capillary recruitment (13, 29, 30). It may be presumed that the recruitment of capillaries normally resulting in an increased PS during insulin stimulation is altered in the type 2 diabetic subjects because the low PS for glucose presently registered is similar to the PS value seen in normal subjects under fasting conditions (16). The previously noted low capillary density in muscles from type 2 diabetic subjects (31) should, however, also alter the capillary recruitment. Hence, it cannot be concluded from the present data as to whether the low PS in type 2 diabetic subjects is due to a blunted recruitment signal or to a low number of recruitable capillaries.

It should be noted that, at steady state, the interstitial muscle insulin and glucose concentrations were normal in the type 2 diabetes group. As previously reported (9, 11), the insulin resistance residing in the muscle cell in itself leading to a subnormal glucose uptake rate balances the low transcapillary transport rate of glucose and insulin so that the interstitial fluid concentrations stay normal. The importance of the perturbed capillary recruitment for the reduction in glucose uptake is, however, evident because a normal increase in PS in type 2 diabetes muscle would lead to supernormal interstitial concentrations (32). Because both insulin binding and glucose transport are concentration-dependent processes, this, in turn, would result in an increased insulin response and increased glucose transport through mass action. Consequently, the blunted capillary recruitment and increase of permeability surface are a prerequisite for the relative resistance to the effect of insulin to increase glucose uptake in these cells. Also, because this evidently is a regulated process, prevented event, it may also be questioned as to whether the correlation between glucose uptake and PS for glucose describes a reduction of PS necessary for or secondary to the reduction of glucose uptake and metabolism. As previously demonstrated in rat quadriceps muscle, reduction of glucose transport leads to decreased interstitial fluid concentrations of lactate and reduction of muscle blood flow (33). Also, insulin-resistant humans demonstrate low interstitial concentrations of lactate and reduced blood flow in muscle during insulin stimulation (11). In addition to the ability of insulin to increase NO synthesis and cause vasodilation (34), capillary recruitment could hypothetically be caused by lactate (11, 33). In harmony with this hypothesis, the insulin-resistant type 2 diabetic subjects in the present study showed no significant increase compared with their controls either in PS for glucose or in lactate production during insulin infusion.

It should be noted in this context that the finding of a low permeability surface in muscle at steady state also may have relevance for the understanding of insulin and glucose metabolism at non-steady state. Recent investigation has shown that insulin-resistant subjects have a delayed transcapillary transport of insulin to the interstitial fluid (17), and the onset of the insulin effect to stimulate glucose uptake is equally delayed (17, 35). In harmony with this concept, during muscle contraction capillary recruitment leads to elimination of arterial interstitial concentration gradients, in turn leading to glucose uptake rates markedly higher than those seen in the presence of nonphysiologically high levels of insulin (36).

It is interesting that muscle (forearm) blood flow was similar in the two groups, whereas PS for glucose differed markedly. It is notable that both subject groups were moderately but definitely overweight; hence, the control subjects should also have been insulin-resistant and been found to have a reduced PS for glucose. However, it is also clear that changes in PS do not necessarily parallel changes in blood flow, especially at low rates (14, 15, 16). In fact, oral glucose may lead to increased muscle perfusion through capillary recruitment, whereas the muscle blood flow is kept constant through a decreased capillary perfusion velocity. Also, in previous studies muscle blood flow has been found to be decreased in some (3, 4, 11) but not all (37, 38) insulin-resistant subject groups. In a recent study in our laboratory, postabsorptive obese subjects with a normal muscle blood flow showed a blunted increase in PS for glucose after oral glucose (our unpublished data). Altogether, previous observations and the present data suggest that a blunted increase in PS is a more sensitive marker for insulin resistance than an absent vasodilatory effect as revealed by blood flow measurements.

There has been a lively debate on the tentative importance of the established relationship among limb blood flow, vasodilation exerted by insulin, and muscle glucose uptake. Some (3, 4) but not all (7, 39, 40) studies verify this relationship; moreover, in insulin-resistant subjects, vasodilation was not accompanied by increased glucose uptake rates (6, 39). In harmony with the finding of normal interstitial concentrations of glucose and insulin (11), it has also been shown that the importance of blood flow for glucose uptake is reduced in insulin-resistant muscle (9). We suggest that the present finding of a reduction in PS as an estimate of capillary permeability surface may give some explanation for the contrasting data available in the literature in this matter. Moreover, we also hypothesize that pharmacological vasodilation may increase glucose uptake by increasing the interstitial concentration, as long as glucose transport through facilitated diffusion is rate limiting for cellular glucose uptake. Absence of a tentative effect of vasodilation in type 2 diabetes would predict the presence of additional rate-limiting steps to the glucose transporter. Possible such steps were suggested by the finding of significant concentrations of glucose in the cytosol. Consequently, a possible therapeutic approach to be evaluated further in insulin-resistant subjects would be the combination of insulin sensitizers and vasodilators.

One limitation in this study is that the low PS for glucose among the type 2 diabetes subjects was not paralleled by a proportional decrease in PS for insulin. Because transcapillary transport of glucose and insulin follows the same principles of passive diffusion and also travels through the same pores, a parallel reduction in PS for insulin would have been expected. However, the low precision in microdialysis measurements of insulin as well as blood flow measurements together with the limited number of subjects investigated may have influenced the results. As a consequence, we could only demonstrate a tendency toward such a reduction of passage and uptake of insulin. Altogether, previous observations and the present data suggest that a blunted increase in PS is a more sensitive marker for insulin resistance than blood flow measurements.

In summary, insulin-resistant type 2 diabetic subjects demonstrate reduced muscle capillary recruitment and low permeability surface for glucose during an insulin infusion. The resulting low capacity for transcapillary passage of insulin and glucose should further aggravate the insulin resistance and might delay the onset of the insulin effect.

	Acknowledgments

 
This study was supported by grants from the Swedish Research Council (Projects 10864, 11330, and 12206), by the Swedish Diabetes Association, by the Novo Nordisk Foundation, by the Inga-Britt and Arne Lundbergs Foundation, by the Knut och Alice Wallenberg Foundation, and by the Magnus Bergvalls Foundation.

	Footnotes

 
First Published Online November 9, 2004

Abbreviations: NS, Not significant; PS, permeability-surface area product.

Received May 19, 2004.

Accepted October 28, 2004.

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