1 Lundberg Laboratory for Diabetes Research and 2 Wallenberg Laboratory, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden
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ABSTRACT |
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Previous measurement of insulin in
human muscle has shown that interstitial muscle insulin and glucose
concentrations are ~30-50% lower than in plasma during
hyperinsulinemia in normal subjects. The aims of this study were to
measure interstitial muscle insulin and glucose in patients with type 2 diabetes to evaluate whether transcapillary transport is part of the
peripheral insulin resistance. Ten patients with type 2 diabetes and
ten healthy controls matched for sex, age, and body mass index were investigated. Plasma and interstitial insulin, glucose, and lactate (measured by intramuscular in situ-calibrated microdialysis) in the
medial quadriceps femoris muscle were analyzed during a
hyperinsulinemic euglycemic clamp. Blood flow in the contralateral
calf was measured by vein plethysmography. At steady-state
clamping, at 60-120 min, the interstitial insulin
concentration was significantly lower than arterial insulin in
both groups (409 ± 86 vs. 1,071 ± 99 pmol/l,
P < 0.05, in controls and 584 ± 165 vs.
1,253 ± 82 pmol/l, P < 0.05, in
diabetic subjects, respectively). Interstitial insulin concentrations did not differ significantly between diabetic
subjects and controls. Leg blood flow was significantly higher in
controls (8.1 ± 1.2 vs. 4.4 ± 0.7 ml · 100 g1 · min
1 in diabetics,
P < 0.05). Calculated glucose uptake was less in diabetic patients compared with controls (7.0 ± 1.2 vs. 10.8 ± 1.2 µmol · 100 g
1 · min
1, P < 0.05, respectively). Arterial and interstitial lactate concentrations were both higher in the control group (1.7 ± 0.1 vs. 1.2 ± 0.1, P < 0.01, and 1.8 ± 0.1 vs. 1.2 ± 0.2 mmol/l, P < 0.05, in controls and diabetics,
respectively). We conclude that, during hyperinsulinemia, muscle
interstitial insulin and glucose concentrations did not differ between
patients with type 2 diabetes and healthy controls despite a
significantly lower leg blood flow in diabetic subjects. It is
suggested that decreased glucose uptake in type 2 diabetes is caused by
insulin resistance at the cellular level rather than by a deficient
access of insulin and glucose surrounding the muscle cell.
insulin resistance; skeletal muscle; insulin uptake; glucose uptake; microdialysis
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INTRODUCTION |
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IN TYPE 2 DIABETES, the ability of insulin to stimulate glucose uptake in skeletal muscle is attenuated (10). The mechanisms behind the reduced insulin action are complex and include defects at the cellular level as well as decreased skeletal muscle perfusion. Muscle cells from non-insulin-dependent diabetes (NIDDM) subjects show insulin receptor and postreceptor defects (22) such as a diminished number of glucose transporter proteins and defective activation of tyrosine (insulin receptor) kinase (33). In addition, individuals with type 2 diabetes have a decreased capillary density in skeletal muscle (2, 28), and the insulin-mediated increase in blood flow is impaired (24). This, in turn, could theoretically result in an insufficient distribution of insulin and nutrients to the muscle cell. However, the pathophysiological importance of the decreased blood flow is not clear, and the concept has been challenged by investigators who have found that blood flow has only a minor influence on insulin-stimulated glucose uptake (32), skeletal muscle interstitial glucose (30), and insulin levels (16). To get a clearer picture of the pathophysiological relevance of the reduced blood flow in type 2 diabetes, we also need to evaluate the regulation of muscle insulin uptake and its putative dependence on the blood flow rate.
Earlier measurements of insulin in leg lymph (5, 39), as well as in the interstitial fluid in human subcutaneous tissue (19) and skeletal muscle (36), have shown that the interstitial insulin concentration is ~50% lower here than in arterial plasma. These data, together with the previously demonstrated existence of a receptor-mediated endocytosis route for insulin transport through endothelial cells, suggest an endothelial barrier for insulin transport, which could be rate limiting for the insulin-mediated glucose uptake in peripheral tissues. In a microdialysis study in rat muscle, a limited transcapillary transport of insulin was found in normal but not in insulin-resistant rats (14).
To our knowledge, insulin measurements in the interstitial fluid in skeletal muscle in type 2 diabetic subjects have not been performed previously. The aim of the present study was to combine blood flow measurements with microdialysis to further investigate the relation between blood flow and leg muscle interstitial insulin, glucose, and lactate levels in type 2 diabetes. These parameters give us the opportunity to estimate and compare the apparent insulin and glucose uptake in skeletal muscle in non-insulin-dependent diabetes mellitus (NIDDM) patients and controls.
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RESEARCH DESIGN AND METHODS |
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Subjects.
Ten volunteers with NIDDM (five males and five females) and 10 group-matched control subjects who did not take any regular medication
were investigated. The clinical characteristics of the participants are
listed in Table 1. Among the NIDDM
patients, one was being treated with insulin, eight had oral
hypoglycemic agents, and one had a combination of insulin and oral
medication. They did not take their insulin or oral hypoglycemic agents
on the morning of the investigation. All subjects gave their informed consent, and the study was approved by the Ethical Committee of the
University of Göteborg.
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Study protocol.
The investigations started at 0800 after an overnight fast. The
subjects were rested in the supine position in a room kept at 25°C.
The forearm was heated with electrical pads to arterialize the venous
blood (3). A polyethylene catheter was placed in a forearm
vein for blood sampling. Fasting plasma glucose, plasma lactate, and
plasma insulin were taken. Inulin (Inutest; Kemiflor, Stockholm, Sweden) was given as a intravenous bolus injection, followed
by a constant infusion (24 ml/h) for 360 min to reach steady-state
plasma inulin after 240 min (35). Thirty minutes after the
inulin infusion was initiated, a euglycemic hyperinsulinemic clamp
was started as described previously (12). The insulin infusion started with a primed infusion for 10 min, followed by a
constant infusion rate of 120 mU · m2 · min
1 for 120 min
paralleled with glucose infusion to maintain euglycemia. Potassium
chloride (0.1 mmol/l) was infused at a rate of 10 mmol/h during the
clamp procedure to prevent hypokalemia. Arterial blood samples were
taken every 5 min for glucose and every 30 min for lactate, inulin, and
insulin. Each sample was immediately centrifuged at 4°C and stored at
18°C before analysis.
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Estimation of glucose uptake, lactate release, and insulin
uptake.
Fick's principle was used to estimate the regional rate of glucose
uptake and microdialysis for estimation of the apparent extraction
fraction (EF). The EF was calculated according to the formula
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Analytical methods. Glucose and lactate concentrations in plasma and in the dialysate fractions were determined enzymatically using 10-µl samples for simultaneous analysis of glucose and lactate on 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 (1900 CA, TRI-CARB; Packard Instruments, Meriden, CT). Plasma insulin was measured with a double-antibody radioimmunoassay (Pharmacia, Uppsala, Sweden).The concentration of insulin in the microdialysates was determined with an enzymatic immunoassay (DAKO Diagnostics, Cambridge, UK). Inulin concentrations in plasma and dialysates were determined photometrically using 20-µl samples (38).
Statistics. Statistical calculations of the means of the four collected microdialysates with lactate and glucose, the microdialysates (one sample) with inulin and insulin, and the two LBF measurements were made using absolute values obtained during the last 60 min of the clamp (steady state). The results are expressed as means ± SE. StatView statistics software for the Macintosh was used for all statistical calculations. Significance of difference was tested with Student's t-test for paired and unpaired observations when appropriate. For unpaired comparison of the insulin data, the nonparametric Mann-Whitney test was used, and for paired insulin data the Wilcoxon Signed Rank test was applied. A value of P < 0.05 was considered statistically significant. Correlations were calculated according to the linear regression method.
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RESULTS |
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During steady-state hyperinsulinemic euglycemic clamping
conditions, the mean glucose infusion rate and the LBF were
significantly lower in patients with type 2 diabetes than in normal
subjects (Table 2). LBF and glucose
infusion rate (GIR) tended to correlate without reaching statistical
significance (r2 = 0.20, p < 0.07).
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During the euglycemic hyperinsulinemic clamp, the interstitial insulin
concentration was significantly lower than arterial insulin in both
groups (409 ± 86 vs. 1,071 ± 99 pmol/l, P < 0.01, in controls and 584 ± 165 vs. 1,253 ± 82 pmol/l,
P < 0.05, in diabetic subjects, respectively). Neither
the interstitial insulin nor the arterial-interstitial insulin
concentration differences differed significantly between diabetic
subjects and controls. Also, the estimated muscle insulin uptake was
similar in both groups (Fig. 1).
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The arterial-interstitial glucose concentration differences were similar in the two groups. In both groups, the mean arterial glucose concentration was significantly higher than the muscle interstitial fluid concentration of glucose. The calculated glucose uptake rate in diabetic patients was lower than in controls (Table 2). The estimated glucose uptake rate and the GIR tended to have a positive correlation without reaching statistical significance (r2 = 0.18, P < 0.09). Estimated glucose uptake rate correlated significantly with blood flow (r2 = 0.55, P < 0.01), whereas there was no correlation between interstitial muscle glucose level and blood flow (r2 = 0.008, not significant).
During steady-state clamping, the mean arterial and interstitial lactate concentrations were higher in the control group. The arterial-interstitial lactate concentration differences were insignificant and similar in both groups (Table 2).
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DISCUSSION |
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The data in this study demonstrate that, despite a significantly lower LBF in type 2 diabetic subjects (with a significantly reduced glucose infusion rate), the distribution of insulin to the interstitial muscle fluid is similar to that in healthy controls during hyperinsulinemia. Furthermore, it is confirmed that insulin-mediated glucose uptake is impaired in insulin-resistant type 2 diabetic patients. The present data also show significantly lower levels of lactate in plasma and muscle interstitial fluid in the diabetic group compared with controls during the hyperinsulinemic euglycemic clamp.
Estimation of insulin uptake. The interstitial concentrations of insulin in muscle tissue in the present study were ~50% of the level of insulin in plasma, which is in accord with previous studies in lymph (39) as well as in adipose tissue (19) and human skeletal muscle (36). Lower lymph insulin than arterial plasma insulin has also been demonstrated in insulin-resistant obese men during euglycemic hyperinsulinemic clamp, but the lymph insulin in obese subjects was higher than in lean controls, indicating that the transcapillary transport of insulin was not insufficient in insulin-resistant humans (5). Similar findings of higher-than-normal insulin levels in lymph (1) and muscle interstitial fluid (14) in insulin-resistant animals support the view that a defect in insulin penetration to the interstitial fluid is not the cause of insulin resistance.
The muscle interstitial insulin concentrations in this study were obtained during clamping conditions with high plasma insulin levels. Because the microdialysis technique and analytical methods do not allow measurements of interstitial insulin at lower physiological plasma insulin levels, the insulin transport remains unclear under these circumstances. Because the recovery of insulin in the dialysate is low, the method used for calibrating the microdialysis catheters, called the external reference technique, has been validated in Ref. 36. The decreased blood flow during hyperinsulinemia in the diabetic group in this study is in accord with earlier clamp studies, where an impaired insulin-mediated vasodilatation was found in obese (23) and NIDDM subjects (24). Even though the type 2 diabetic subjects had 40% lower LBF during hyperinsulinemia, the interstitial insulin levels were similar in both groups. The estimated insulin uptake did not differ between type 2 diabetics and controls. It should be noted that the calculated insulin uptake depends on the blood flow as well as on the PS; therefore, it is of major importance which value of PS is used in the formula described above. In human skin, PS was found to be higher in the diabetic subjects at rest, but after exercise they had the same PS as controls (21). In rat muscle, PS did not differ between insulin-resistant and normal rats (C. Holmäng, M. Niklasson, B. Rippe, and P. Lönnroth, unpublished observations). PS for small molecules increases with blood flow, whereas PS for larger molecules like inulin/insulin is less dependent on the blood flow rate (9). In a recent microdialysis study, we found that PS for insulin in human skeletal muscle was unchanged when the blood flow increased by 40% (13). Hence, when calculating the insulin uptake, we used the same PS (0.6) in both diabetic subjects and controls. The finding of a similar insulin uptake in diabetic subjects and controls despite a significantly impaired blood flow in the insulin-resistant state suggests that the insulin uptake in human skeletal muscle during steady-state hyperinsulinemia is not regulated by blood flow. However, the possible existence of a delayed transcapillary insulin transport in type 2 diabetes still remains to be elucidated in direct studies during non-steady-state conditions.Glucose metabolism and estimation of glucose uptake. Previous studies have shown that insulin's ability to stimulate glucose uptake is reduced in insulin-resistant rats (31) and in legs in NIDDM subjects (11). In accord with those previous results, the estimated glucose uptake in this study was significantly lower in insulin-resistant type 2 diabetic subjects than in controls.
When estimating the glucose uptake, we adopted a PS value of 4 ml · 100 gRegulation of blood flow in insulin-resistant muscle. The finding that insulin-resistant muscle has a reduced capillary density (2, 28) in combination with a decreased insulin-mediated vasodilatory response has formed the basis for the hypothesis that an insufficient distribution of insulin and glucose to the muscle tissue might be the cause of insulin resistance. However, the hypothetical role of reduced blood flow as a causal factor behind insulin-resistant muscle glucose uptake has been debated. Insulin-stimulated vasodilation and glucose uptake in muscle correlate positively in conscious rats (18) as well as in humans (23). Vasodilatation during hyperinsulinemia also seems to be accompanied by capillary recruitment in the limb (4). These findings have raised the hypotheses that blood flow (and tissue recruitment) is regulating the glucose uptake in muscle and that the vasodilatory effect of insulin is of major importance for the glucose uptake. However, there seems to be a delay in the effect of insulin on blood flow in relation to its direct effect on glucose uptake (41). In addition, no increase in femoral glucose uptake was found in a study where LBF was doubled by infusing bradykinin (32). Also, microdialysis studies of glucose (30) and insulin (14) in muscle interstitial fluid have not provided evidence that the interstitial concentrations of glucose or insulin are regulated by the blood flow rate, indicating that blood flow is only a minor determinant for insulin-mediated glucose uptake. Interestingly, insulin resistance and reduced muscle glucose uptake in glucosamine-infused rats decrease muscle lactate production and blood flow (16). This is in accord with the data in the present study and with the view that glucose nonoxidative metabolism may regulate the blood flow. Hence, instead of a causal relationship between blood flow and muscle glucose uptake, we believe that the lower interstitial fluid concentrations of lactate may play a role in the diminished blood flow in insulin-resistant muscle. The suggested mechanisms behind the vasodilatory action of insulin may include both the direct effect to increase endothelium-derived nitric oxide (37) and a secondary effect to enhance lactate production through nonoxidative glucose metabolism (6).
In summary, the data in this study show that, during hyperinsulinemia, muscle interstitial insulin and glucose concentrations did not differ between patients with type 2 diabetes and healthy controls despite significantly lower leg blood flow rates in diabetic subjects. Thus it may be suggested that the apparently decreased glucose uptake in type 2 diabetes is caused by insulin resistance at the cellular level and not by deficient access by insulin and glucose surrounding the muscle cell. Furthermore, lactate levels in plasma and muscle interstitial fluid were decreased in NIDDM subjects, which might play a role in the impaired insulin-mediated vasodilatory response. ![]() |
ACKNOWLEDGEMENTS |
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We are grateful to Britt-Mari Larsson and Margareta Landén for technical assistance and to Gudrun Jonson for secretarial aid.
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FOOTNOTES |
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This study was supported by grants from the Swedish Research Council (Project Nos. 10864, 11330, and 12206), the Swedish Diabetes Association, Nordisk Insulinfond, Novo Nordisk Pharma AB, the Inga-Britt and Arne Lundberg Foundation, and Göteborgs Läkarsällskap.
Address for reprint requests and other correspondence: M. Sjöstrand, Lundberg Laboratory for Diabetes Research, Sahlgrenska Univ. Hospital, S-413 45 Göteborg, Sweden (E-mail: mikaela.sjostrand{at}medic.gu.se).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 22 December 1999; accepted in final form 21 June 2000.
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