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Lundberg Laboratory for Diabetes Research (M.S., S.G., L.S., P.L.) and Wallenberg Laboratory (A.H.), Sahlgrenska University Hospital, Göteborg S-413 45, Sweden; and Department of Clinical Physiology (K.E.), Karolinska Hospital, S-17176 Stockholm, Sweden
Address all correspondence and requests for reprints to: Mikaela Sjöstrand, M.D., Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: . mikaela. sjostrand{at}medic.gu.se
Abstract
The aim of this project was to study the regulation of interstitial glycerol levels in muscle in normal subjects, and to estimate interstitial muscle glycerol in obese subjects and patients with type 2 diabetes. In healthy lean subjects, microdialysis of forearm sc and muscle tissue were combined with arterial and deep venous catheterization, as well as blood flow registrations during oral glucose ingestion. In two other separate studies, obese (n = 9) vs. lean (n = 10) subjects and type 2 diabetes patients (n = 8) vs. weight-matched control subjects (n = 8) were investigated by means of muscle microdialysis during a euglycemic hyperinsulinemic clamp. Oral glucose ingestion suppressed the interstitial sc glycerol concentration by approximately 40% (P < 0.05), whereas no significant reduction of muscle interstitial glycerol was found. In contrast to the significant muscle interstitial-arterial (I-A) glycerol difference, the venous-arterial difference was small and varying throughout the oral glucose tolerance test. At steady-state hyperinsulinemia, obese subjects’ interstitial muscle glycerol and I-A glycerol difference were both significantly higher than lean controls, whereas type 2 diabetes patient had interstitial muscle glycerol concentrations and I-A glycerol differences similar to those found in weight-matched controls. A significant and marked I-A glycerol difference exists in the absence of a significant venous-arterial difference, indicating that muscle glycerol cannot be taken as a marker of intramyocellular lipolysis because local turnover of muscle glycerol might be significant. The present data also suggest that, in contrast to sc tissue, muscle tissue lacks a clear antilipolytic effect of insulin. Moreover, the muscle interstitial glycerol concentration is elevated in obese patients but does not precipitate insulin resistance and type 2 diabetes.
THE TRIGLYCERIDE (TG) content in human skeletal muscle totals 0.2–0.5 kg, or 5–15 mmol/kg (1). In rats, a significant uptake of TG in muscle tissue has been demonstrated especially in the fasting state (2). TG is hydrolyzed to glycerol and free fatty acids. Interstitial glycerol in muscle is derived from the hydrolysis of intramyocellular as well as plasma TG. The interstitial muscle glycerol concentration in normal subjects has been reported to be 2–3 times higher than in plasma after an overnight fast (3), and after glucose ingestion (4). The enzymes involved in TG metabolism in the muscle are lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL). LPL hydrolyses plasma TG (5), and HSL catalyzes im TG lipolysis (6). Lipolysis in muscle tissue has previously been estimated by means of arterio-venous (A-V) glycerol concentration differences, as well as by im microdialysis. High physiological levels of insulin and catecholamines are reported not to affect the A-V difference of glycerol in the forearm, suggesting that muscular lipolysis is not under hormonal regulation (7). Microdialysis measurements after oral glucose ingestion demonstrated a slower and more protracted decrease of glycerol in the muscle compared with that found in plasma and adipose tissue (4, 8), further suggesting different regulations of lipolysis in fat and muscle tissue. Interestingly, inhibition of lipolysis by insulin in adipose and skeletal muscle tissue is mediated differently by separate and specific phosphodiesterase subtypes (9).
In recent years, several investigations have focused on the relationship between skeletal muscle TG and insulin resistance in nondiabetic subjects (10, 11, 13). Enlargement of the intramyocellular lipid store has also been suggested to be important in the pathogenesis of type 2 diabetes (13) through action by the glucose-fatty acid axis proposed by Randle et al. (14).
To obtain further insight into the regulation of the interstitial glycerol levels in human skeletal muscle and to validate its relevance as a marker for muscle lipolysis and insulin resistance, we have measured muscle interstitial glycerol by means of microdialysis in healthy and insulin resistant subjects. Data were compared with those obtained with the forearm A-V technique.
Subjects and Methods
Subjects
Fifty-two subjects were investigated in three different studies (studies I–III). Study I included 17 healthy subjects who were not taking any regular medication. In study II, nine obese and 10 normal-weight subjects, who were matched for age, participated. Study III included eight men with type 2 diabetes and eight controls matched for age and body mass index (BMI). All the type 2 diabetes subjects were treated with oral hypoglycemic agents. Table 1
lists the clinical characteristics of the subjects. All subjects’ drug treatment was discontinued the night before the study. All subjects gave their informed consent, and the studies were approved by the Ethical Committee of the University of Göteborg (Stockholm, Sweden).
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Euglycemic hyperinsulinemic clamp. Studies II and III used a euglycemic hyperinsulinemic clamp. Examinations were performed as described by De Fronzo et al. (15), and modified according to the following description. A 10-min primed insulin infusion was followed by a constant insulin infusion at a rate of 240 mU·m-2·min-1 for 150 min, parallelled with glucose infusion to maintain euglycemia. Potassium chloride (0.1 mmol/liter) was infused at a rate of 10 mmol/h during the clamp to prevent hypokalemia. Arterialized blood samples were taken every 5 min for glucose and every 30 min for insulin. Each sample was immediately centrifugated at 4 C and stored at -18 C before analysis. The mean glucose infusion rate (in mg·kg-1·min-1) during the last hour of the euglycemic hyperinsulinemic clamp was used to estimate exogenous glucose disposal.
Microdialysis. The principle of microdialysis has earlier been described in detail (16, 17, 18, 19). In the present studies commercially available custom-made microdialysis catheters were used in muscle tissue (16 x 0.5 mm, 20K molecular weight cut-off in m. brachioradialis; CMA Microdialysis, Stockholm, Sweden). During the oral glucose tolerance test (OGTT) (study I) another catheter of single dialysis tubing (30 x 0.3 mm, 3K molecular weight cut-off Cuprophane; Gambro AB, Lund, Sweden) was glued to nylon tubing (standardized length of 50 mm) with cyanoacrylate and sterilized, then inserted in the abdominal per umbilical sc tissue. The inlet for the catheters was connected to a microinjection pump (CMA 100, CMA Microdialysis) and the perfusion fluid was 1.5 mmol/liter glucose and 25 µmol/liter glycerol added to isotonic saline. The flow rate was 2.5 µl/min. After an equilibration period of 60 min, the dialysates for glycerol measurements were collected at 15- to 30-min intervals continuing for 150 min after the beginning of the OGTT in study I, and during the last 60-min interval during the clamp in studies II and III (four samples).
Calibration of the microdialysis probes was performed according to the internal reference technique (17). In studies I and III, [14C] glycerol (Amersham Pharmacia Biotech, Arlington Heights, IL) was added to the perfusate, and the percentage loss of radioactivity over the microdialysis membrane was taken as an index of relative recovery (dialysate concentration/interstitial concentration). In study III, the calibration was done using urea as an internal reference (20). In the present studies, the mean in vivo recovery obtained by this technique was 18 ± 1%, 25 ± 1% and 24 ± 1% in studies I, II, and III, respectively. The mean in vivo recovery calculated for the catheters in sc adipose tissue was 25 ± 2%.
Arterial and venous catheterizations of the forearm. Using local anesthesia, catheters for blood sampling were inserted 6–8 cm in the retrograde direction into an anticubital vein that drains deep into forearm tissues (21) and into the radial artery for A-V measurements. This technique is referred to as the forearm catheter technique and was used in studies I and III.
Blood flow measurements. Blood flow in the forearm (studies I and III) and calf (study II) was measured by venous occlusion plethysmography using a Whitney strain gauge (22).
Study protocol All subjects fasted overnight and arrived at the laboratory at approximately 0800 h. The subjects rested in supine position and room temperature was kept at 25 C. Three separate studies were performed:
Study I (healthy subjects in the fasting state and during an OGTT).
Seventeen subjects were studied in the basal state, and in 8 of them, measurements were also performed after an oral glucose tolerance test. Glucose (75 mg) was dissolved in 250 ml chilled lemon-flavored water, and subjects ingested it sitting in a semisupine position.
Two microdialysis catheters were inserted into the brachioradialis muscle in the forearm. The subjects who participated in the OGTT had an additional catheter inserted in the abdominal periumbilical sc tissue. Microdialysate sampling for glycerol measurements were done at 15-min intervals for 90 min in the postabsorptive state and continued after the start of the OGTT for 150 min. Forearm blood flow measurements, arterial and deep venous blood samples for glycerol, glucose and insulin were taken every 15 min during the OGTT.
Study II (obese and lean subjects during a euglycemic hyperinsulinemic clamp).
Nine obese subjects and 10 lean controls were studied during a euglycemic hyperinsulinemic clamp. The forearm was heated with electric pads to arterialize the venous blood (23), and a polyethylene catheter was placed in a forearm vein for blood sampling. Arterialized blood samples were taken every 5 min for glucose and every 30 min for glycerol and insulin. Two microdialysis catheters were inserted into the quadriceps femoris muscle, and dialysates for glycerol measurements were collected at 15-min intervals during the last 60 min of the clamp (four samples). Leg blood flow measurements, were made two times during the last hour of the clamp.
Study III (type 2 diabetes patients and healthy subjects during an euglycemic hyperinsulinemic clamp).
Eight subjects with type 2 diabetes and eight controls, matched for age and BMI, were investigated during an euglycemic hyperinsulinemic clamp. Arterial and deep venous catheterizations were performed and arterial blood samples were taken every 5 min for glucose. Arterial and venous blood samples were taken every 30 min for glycerol and insulin. Two microdialysis catheters were inserted into the brachioradialis muscle in the forearm, and dialysates for glycerol measurements were collected at 15-min intervals during the last 60 min of the clamp (four samples). Forearm blood flow measurements were made two times during the last hour of the clamp.
Analytical methods Plasma glycerol and dialysate glycerol concentrations were determined with enzymatic fluorometric methods, using a tissue sample analyzer (CMA/600, CMA Microdialysis). Radioactivity was counted in a liquid scintillation counter using a quenched-corrected (external standards), double isotope program (1900 CA, TRI-CARB, Packard Instrument, Meriden, CA). Glucose concentrations in plasma were determined enzymatically using 10-µl samples for analysis on a YSI, Inc. 2700 select biochemical analyzer (Yellow Springs Instrument Co. Inc., Yellow Springs, OH). Plasma insulin, in studies I and II, was determined with a double-antibody RIA (Amersham Pharmacia Biotech, Uppsala, Sweden), and with an enzymatic immunoassay (DAKO Corp. Diagnostics, Cambridge, UK) in study III.
Statistics The mean of four interstitial concentrations during 0–60 min were used in the basal state in study I, and during the last 60 min of the clamp in studies II and III. The dialysates sampling interval was 15 min during the OGTT in study I and during steady-state hyperinsulinemia at 210–270 min in studies II and III. The results are expressed as means ± SE. Significance of difference was tested with Wilcoxon Signed Rank test for paired observations when comparing data from different compartments (arterial, venous, interstitial muscle, and sc), and time points within groups. For comparison of unpaired data the nonparametric Mann-Whitney test was applied. The StatView version 4.0 program for the Macintosh system was used for all analyses.
Results
Study I (fasting subjects and subjects during an OGTT)
In healthy subjects, after one night’s fasting, muscle interstitial glycerol was significantly higher than plasma glycerol (80 ± 15 vs. 45 ± 5 µmol/liter, n = 17, P < 0.01). In the OGTT group, basal interstitial glycerol in sc adipose tissue (186 ± 24 µmol/liter, n = 8) was higher than in both muscle (67 ± 15 µmol/liter) and plasma (44 ± 7 µmol/liter), P < 0.05 (Fig. 1). Arterial (44 ± 7 µmol/liter) and venous (46 ± 7 µmol/liter) glycerol concentrations were similar (n = 8, NS) (Fig. 1). The venous glycerol concentration was significantly higher than the arterial during the OGTT, P < 0.05 (Table 2). Arterial and venous glycerol decreased significantly, when compared with basal, P < 0.05 (Table 2 and Fig. 1). The venous-arterial (V-A) difference of glycerol tended to increase during the OGTT from 2.6 ± 2.9 to 6.9 ± 2.2 µmol/liter after 105 min, (NS). The basal muscle interstitial glycerol concentration was 67 ± 15 µmol/liter, compared with 44 ± 5 µmol/liter 105 min after the start of the oral glucose load (NS, Table 2). The difference of the interstitial muscle and arterial glycerol concentrations was constant during the OGTT (NS, Table 2). The interstitial sc glycerol level was significantly reduced during the OGTT, (P < 0.05), as was the difference of interstitial sc and arterial glycerol concentration, (P < 0.05) (Table 2). The forearm blood flow was unchanged during the OGTT (2.0 ± 0.2 ml·100 g -·min-1, at the end of the study compared with base line levels, 2.2 ± 0.2 ml·100 g -·min-1, NS).
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The obese subjects had a significantly reduced glucose infusion rate (P < 0.001) during steady-state hyperinsulinemic euglycemic clamping, and their plasma insulin levels reached significantly higher levels (P < 0.01) than in age matched controls (Table 3). The leg blood flow during hyperinsulinemia did not differ between the groups (Table 3). Arterial, muscle interstitial, and I-A (interstitial-arterial) glycerol difference concentrations were all higher in the obese group when compared with controls, P < 0.05 (Table 4). In both groups, the muscle interstitial glycerol was higher than the plasma glycerol, P < 0.05 (Table 4).
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At steady-state clamping conditions, the mean glucose infusion rate was significantly lower in patients with type 2 diabetes than in age and weight matched control subjects, whereas the arm blood flow was similar in both groups (Table 3
). During hyperinsulinemia, diabetic subjects had significantly higher venous glycerol levels (39 ± 6 vs. 18 ± 4 µmol/liter, P < 0.01), and tended to have higher arterial glycerol (32 ± 7 vs. 17 ± 3 µmol/liter, NS) than controls. The V-A glycerol concentration difference was 7.1 ± 2.4 µmol/liter (P < 0.05) in the type 2 diabetes group vs. 1.2 ± 0.2 µmol/liter (NS) in controls. The mean I-A glycerol concentration difference of all subjects was 22 ± 6 µmol/liter, n = 16, P < 0.01. Neither the arterial, the interstitial nor the I-A difference of glycerol concentrations differed significantly between diabetic subjects and controls (Table 4).
Discussion
The present data confirm earlier findings that interstitial muscle glycerol levels are higher than those found in plasma, both in the postabsorptive state and during hyperinsulinemia. In contrast to the significant muscle-plasma gradient of glycerol, the V-A difference was small and varying, suggesting an ongoing lipid metabolism in the muscle tissue, not reflected by the V-A difference of glycerol. The antilipolytic effect of insulin, as investigated by means of an oral glucose load, was demonstrated in adipose tissue by a significant decline in both interstitial glycerol and I-A glycerol concentration difference. Because hyperglycemia per se does not seem to have an independent antilipolytic effect in adipose tissue (24), the decline presently observed may be considered as an effect of the insulin. In contrast, such a suppressing effect after carbohydrate ingestion was not demonstrated either in the interstitial muscle glycerol level, or in the gradient of glycerol between muscle tissue and plasma.
We also found higher interstitial muscle glycerol levels in insulin-resistant obese subjects when compared with lean controls during a euglycemic hyperinsulinemic clamp, whereas no such difference was detected between type 2 diabetic subjects and controls, matched for age and BMI.
Muscle glycerol before and after oral glucose
In the present study, there was no significant difference between arterial and venous glycerol concentrations in the forearm of healthy subjects after fasting overnight. This supports the previous notion from an earlier examination of 37 studies of A-V balances of glycerol in the forearm after an overnight fast, where 40% of the subjects demonstrated a significant forearm glycerol uptake (25). Thus, it may be concluded that glycerol release from the forearm, in contrast to the adipose tissue, cannot be taken as an indicator of the total muscle lipolysis rate. This is also in harmony with an isotope study, which measured the forearm A-V difference of glycerol, where the enrichment of glycerol in deep venous blood was about half of that observed in arterialized blood not reflected by the net exchange of glycerol (26).
Glycerol measured by microdialysis in muscle tissue may theoretically be produced by the hydrolysis of triglycerides from myocytes, plasma lipoproteins, and adipocytes, located between the muscle sheets. There may also be local glycerol metabolism in the muscle, even when the amounts of glycerokinase are small (27). In rat skeletal muscle, blood glycerol was found to be the precursor of muscle TG synthesis (especially in oxidative muscle during the fasting state), indicating functionally important amounts of glycerokinase in muscle (28).
In the present study, the fasting muscle interstitial glycerol levels were approximately two times higher than in plasma in accordance with previous reports (3, 29). The glycerol levels in arterial and venous blood, as well as in interstitial adipose tissue, declined significantly during the oral glucose tolerance test but just tended to decline in muscle tissue. Similar results have been reported from another microdialysis studies after glucose ingestion (4, 8) and during euglycemic hyperinsulinemic clamp (9, 30, 31). In the above studies, the decline in interstitial glycerol was interpreted as an antilipolytic effect of insulin (4, 8, 9, 30, 31). However, a significant reduction in the I-A glycerol concentration difference should be a better marker for a tentative antilipolytic effect than a decline in interstitial glycerol. The present results show an unchanged I-A difference of glycerol concentration after glucose ingestion and, thus, for the first time, challenge the view that insulin has a clear antilipolytic effect in muscle tissue.
There are several reports on potential differences regarding the regulation of lipolysis in adipose tissue and muscle. In human adipose tissue, the cytosolic HSL was primarily activated by ß-adrenergic stimuli and cAMP and insulin exerts an antilipolytic effect (1), whereas LPL was activated by insulin (32). During glucose/insulin infusion in normal subjects the LPL activity in adipose tissue biopsies was reported to be enhanced, whereas LPL activity in muscle biopsies declined (33). This could favor lipid storage in adipose tissue during hyperinsulinemia. It has also been demonstrated that lipolysis stimulated by catecholamines is mediated by other ß-adrenoceptor subtypes in human adipose tissue than those found in skeletal muscle (34). In summary, lipolysis in fat and muscle tissue seems to be differently regulated. Furthermore, because microdialysis in muscle gave results that were markedly different from those found in the adipose, microdialysis seems to be a valid method for sampling interstitial muscle glycerol without major interference from interfascial adipose tissue.
LPL-derived fatty acid uptake into human skeletal muscle (forearm) has been reported to be efficient even without an increase of the insulin levels (35). Thus, there seems to be a flux of glycerol and fatty acids, in both directions, i.e. between the circulation and the muscle cell and the balance seems not to be entirely insulin dependent. Consequently, the interstitial muscle glycerol level may reflect the net balance between transport of glycerol and FFA from plasma in to the muscle cell, and the flux of glycerol in the opposite direction (from intramyocellular TG). Interstitial glycerol levels in muscle can neither be taken as an indicator of interstitial FFA levels, nor as a marker of muscle cell lipolysis.
Muscle glycerol during hyperinsulinemic euglycemic clamp in obese and lean subjects
The results from study II show that the arterial and interstitial muscle concentrations of glycerol, as well as the I-A difference, were higher in obese subjects than in controls under circumstances where a full antilipolytic effect of insulin should be expected. It, seems, therefore, that obesity is associated with higher muscle interstitial glycerol levels in the thigh, even at high plasma insulin concentrations. During steady-state hyperinsulinemia, leg blood flow was similar in obese and normal subjects, as has also been observed previously at high insulin concentrations (36).
Plasma insulin levels were 60% higher in obese subjects than in lean controls during the euglycemic hyperinsulinemic clamp. Comparisons with the obese subjects are weakened due to this difference and, when discussing the results from study II, the discrepancy in plasma insulin levels between the groups should be taken into account. The higher plasma insulin in obese subjects during hyperinsulinemia is probably due to the fact that the amount of insulin infused was based on body surface area rather than lean body mass. Glucose infusion rate have been shown to be more accurately measured if adjusted for fat free mass instead of body weight (37). Moreover, insulin clearance has been reported to be lower in obese subjects (38) and the distribution volume for insulin is lower in adipose tissue when compared with muscle. However, the plasma insulin levels presently employed should be expected to exert a maximal antilipolytic effect in adipose tissue (39) and, hence, the group differences in glycerol results may not have been overinterpreted. In support, the glucose infusion rate was significantly reduced in the obese group despite the higher plasma insulin levels, confirming the well established association between obesity and insulin resistance (40, 41).
A possible source of the interstitial glycerol could be the enlarged TG stores in muscle cells as previously demonstrated in muscle biopsies from obese type 2 diabetic subjects (42). Hypertriglyceridemia as well as large intermyocellular TG stores may also be putative contributors to the high interstitial muscle glycerol levels found in the obese group. Adipose tissue infiltrating muscle groups in the thigh was recently reported to be associated with insulin resistance (43). It is notable that the interstitial glycerol in adipose and muscle tissue is regulated differently by both insulin (4, 8, 9) and ß-adrenergic stimulation (34). Also a clear antilipolytic effect is seen in adipose tissue at considerably lower plasma concentrations than presented in this study. Therefore, it may be ruled out that glycerol from inter or intrafascial adipose cells influences the present difference between obese and lean subjects.
Muscle glycerol during hyperinsulinemic euglycemic clamp in type 2 diabetes
As expected (44), the glucose infusion rate was approximately 25% lower in diabetic subjects than in controls matched for age and BMI. Forearm blood flow rate did not differ between the groups at hyperinsulinemia. The venous plasma glycerol was significantly higher and both the arterial, as well as the interstitial muscle glycerol levels tended to be higher in the diabetic group when compared with controls. It is important to note in this context that the interstitial glycerol level is influenced by the circulating glycerol concentrations produced through resistance to the antilipolytic effect of insulin in adipose cells (45). Interestingly, as a marker of the net balance of glycerol, the muscle interstitial-arterial differences of glycerol were similar in both groups.
Recent investigations have shown the existence of a relationship between increased intracellular triglycerides in muscle and insulin resistance (12). In addition, an increased intramyocellular lipid content, measured by magnetic resonance spectroscopy, has also been shown to be related with insulin resistance (13) and might be of importance for the development of type 2 diabetes. In contrast to im triglycerides, the interstitial glycerol level seems to be a poor marker for insulin resistance because the I-A concentration differences of glycerol were similar in type 2 diabetic subjects and controls. When estimating the glycerol production on the basis of the V-A glycerol differences by Ficks principle (glycerol production = V-A · plasma flow) the result is close to zero in both subject groups. However, when using the I-A difference for calculating a tentative glycerol production rate (18, 46) the production is markedly higher. This discrepancy in glycerol production when estimated from I-A vs. V-A glycerol concentrations suggests that there is a local turnover of glycerol in the muscle tissue, even in the presence of high plasma levels of insulin.
It should be kept in mind that data from study II and III are from different muscle groups. Still, no comparisons are done between data from different limbs, only with respective control group within the two studies.
In summary, the present data confirm that glycerol uptake is significant in the muscle and, regardless of the source of interstitial glycerol, the glycerol measured by muscle microdialysis reflects the net result of TG and glycerol metabolism in muscle tissue. A higher glycerol level surrounding the muscle cell may reflect an increased intramyocellular TG store and enhanced overall lipolysis rates (47) which, in turn, could impair glucose utilization in the skeletal muscle in accordance with Randle’s glucose fatty acid axis theory (14). The data from studies II and III do not support the association between elevated interstitial muscle glycerol levels and insulin resistance in type II diabetes, but rather between muscle glycerol and obesity.
Acknowledgments
We are grateful to Margareta Landén for technical assistance and to Gerd Nilsen for secretarial aid.
Footnotes
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, Inga-Britt and Arne Lundberg Foundation and Göteborgs Läkaresällskap.
Abbreviations: A-V, Arterio-venous; BMI, body mass index; HSL, hormone-sensitive lipase; I-A; interstitial-arterial; LPL, lipoprotein lipase; OGTT, oral glucose teolerance test; TG, triglyceride; V-A, venous-arterial.
Received October 18, 2001.
Accepted January 31, 2002.
References
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