Prolonged exercise-induced stimulation of skeletal muscle glucose uptake is due to sustained increases in tissue perfusion and fractional glucose extraction.

CONTEXT: The mechanisms behind the positive effects of physical activity on glucose metabolism in skeletal muscle and the time course of the effects need to be more elucidated. OBJECTIVE: The aim was to examine the prolonged effects of an acute bout of one-legged exercise on local skeletal muscle glucose utilization and tissue perfusion. DESIGN AND SETTING: Interstitial glucose concentration, local tissue perfusion, glucose uptake, and effects of insulin infusion were studied 12 h after an acute bout of exercise and without prior exercise. PARTICIPANTS: Ten healthy subjects, five women and five men, participated in the study. INTERVENTION: Microdialysis measurements, (133)Xe clearance, and a 2-h hyperinsulinemic euglycemic clamp were performed on two occasions. MAIN OUTCOME MEASURES: We measured interstitial glucose concentration and tissue perfusion in the quadriceps femoris muscle of both legs. RESULTS: Tissue perfusion (3.3 ± 0.6 ml × 100 g(-1) × min(-1) vs. 1.4 ± 0.2 ml × 100 g(-1) × min(-1); P = 0.007) and basal glucose uptake (2.3 ± 0.5 µmol × 100 g(-1) × min(-1) vs. 0.9 ± 0.2 µmol × 100 g(-1) × min(-1); P = 0.006) were increased in the leg that had exercised compared to the resting leg; the findings in the resting leg were comparable to those in the control experiment without prior exercise. The relative effect of insulin on fractional skeletal muscle glucose uptake was the same in all experimental settings, and insulin did not affect tissue perfusion. CONCLUSIONS: The prolonged stimulatory effect of physical exercise on skeletal muscle glucose uptake was mediated via vascular effects combined with an increase in basal glucose transport independent of enhancement of insulin responses.

Pre-operative carbohydrate loading may be used in type 2 diabetes patients.

BACKGROUND: Post-operative insulin resistance and hyperglycaemia are associated with an impaired outcome after surgery. Pre-operative oral carbohydrate loading (CHO) reduces post-operative insulin resistance with a reduced risk of hyperglycaemia during post-operative nutrition. Insulin-resistant diabetic patients have not been given CHO because the effects on pre-operative glycaemia and gastric emptying are unknown. METHODS: Twenty-five patients (45-73 years) with type 2 diabetes [glycated haemoglobin (HbA1c) 6.2 +/- 0.2%, mean +/- SEM] and 10 healthy control subjects (45-72 years) were studied. A carbohydrate-rich drink (400 ml, 12.5%) was given with paracetamol 1.5 g for determination of gastric emptying. RESULTS: Peak glucose was higher in diabetic patients than in healthy subjects (13.4 +/- 0.5 vs. 7.6 +/- 0.5 mM; P<0.01) and occurred later after intake (60 vs. 30 min; P<0.01). Glucose concentrations were back to baseline at 180 vs. 120 min in diabetic patients and healthy subjects, respectively (P<0.01). At 120 min, 10.9 +/- 0.7% and 13.3 +/- 1.2% of paracetamol remained in the stomach in diabetic patients and healthy, subjects respectively. Gastric half-emptying time (T50) occurred at 49.8 +/- 2.2 min in diabetics and at 58.6 +/- 3.7 min in healthy subjects (P<0.05). Neither peak glucose, glucose at 180 min, gastric T50, nor retention at 120 min differed between insulin (HbA1c 6.8 +/- 0.7%)- and non-insulin-treated (HbA1c 5.6 +/- 0.4%) patients. CONCLUSIONS: Type 2 diabetic patients showed no signs of delayed gastric emptying, suggesting that a carbohydrate-rich drink may be safely administrated 180 min before anaesthesia without risk of hyperglycaemia or aspiration pre-operatively.

Major differences in noradrenaline action on lipolysis and blood flow rates in skeletal muscle and adipose tissue in vivo.

AIMS/HYPOTHESIS: The regulation of skeletal muscle lipolysis is not fully understood. In the present study, the effects of systemic and local noradrenaline administration on lipolysis and blood flow rates in skeletal muscle and adipose tissue were studied in vivo. METHODS: First, circulating noradrenaline levels were raised tenfold by a continuous i.v. infusion (n=12). Glycerol levels (an index of lipolysis) were measured in m. gastrocnemius and in abdominal adipose tissue using microdialysis. Local blood flow was determined with the (133)Xe clearance technique and whole-body lipolysis rates assessed with a stable glycerol isotope technique ([(2)H(5)] glycerol). Second, interstitial glycerol levels in m. gastrocnemius, m. vastus and adipose tissue were measured by microdialysis during local perfusion with noradrenaline (10(-8)-10(-6) mol/l) (n=10). Local blood flow was monitored with the ethanol perfusion technique. RESULTS: With regard to systemic noradrenergic stimulation, no change in fractional release of glycerol (difference between tissue and arterial glycerol) was seen in skeletal muscle. In adipose tissue it transiently increased twofold (p<0.0001), and the rate of appearance of glycerol in plasma showed the same kinetic pattern. Blood flow was reduced by 40% in skeletal muscle (p<0.005) and increased by 50% in adipose tissue (p<0.05). After noradrenaline stimulation in situ, a discrete elevation of skeletal muscle glycerol was registered only at the highest concentration of noradrenaline (10(-6) mol/l) (p<0.05). Adipose tissue glycerol doubled already at the lowest concentration (10(-8) mol/l) (p<0.05). In skeletal muscle a decrease in blood flow was seen at the highest noradrenaline concentrations (p<0.05). CONCLUSIONS/INTERPRETATION: Lipolysis and blood flow rates are regulated differently in adipose tissue and skeletal muscle. Adipose tissue displays a high, but transient (tachyphylaxia) sensitivity to noradrenaline, leading to stimulation of both lipolysis and blood flow rates. In skeletal muscle, physiological concentrations of noradrenaline decrease blood flow but have no stimulatory effect on lipolysis rates.

Evidence for a major role of skeletal muscle lipolysis in the regulation of lipid oxidation during caloric restriction in vivo.

A lipolytic process in skeletal muscle has recently been demonstrated. However, the physiological importance of this process is unknown. We investigated the role of skeletal muscle lipolysis for lipid utilization during caloric restriction in eight obese women before and after 11 days of very low-calorie diet (VLCD) (2.2 MJ per day). Subjects were studied with indirect calorimetry and microdialysis of skeletal muscle and adipose tissue in order to analyze substrate utilization and glycerol (lipolysis index) in connection with a two-step euglycemic-hyperinsulinemic (12 and 80 mU/m(2). min) clamp. Local blood flow rates in the two tissues were determined with (133)Xe-clearance. Circulating free fatty acids and glycerol decreased to a similar extent during insulin infusion before and during VLCD, and there was a less marked insulin-induced reduction in lipid oxidation during VLCD. Adipose tissue glycerol release was hampered by insulin infusion to the same extent ( approximately 40%) before and during VLCD. Skeletal muscle glycerol release was not influenced by insulin before VLCD. However, during VLCD insulin caused a marked (fivefold) (P < 0.01) increase in skeletal muscle glycerol release. The effect was accompanied by a fourfold stimulation of skeletal muscle blood flow (P < 0.01). We propose that, during short-term caloric restriction, the reduced ability of insulin to inhibit lipids, despite a preserved antilipolytic effect of the hormone in adipose tissue, is caused by an augmented mobilization of fat from skeletal muscle, and that a physiological role of muscle lipolysis provides a local source of fatty acids.

Action of glucagon and glucagon-like peptide-1-(7-36) amide on lipolysis in human subcutaneous adipose tissue and skeletal muscle in vivo.

In vitro and animal studies have shown that glucagon and glucagon-like peptide-1 (GLP-1)-(7-36) amide may participate in the regulation of lipolysis. However, results on human subjects in vivo are inconclusive. To avoid confounding effects, such as changes in insulin secretion when perfusing hormones iv, we used the in situ microdialysis to analyze the impact of human glucagon and GLP-1 on lipolysis rates and local blood flow. Nine healthy volunteers were given an 80-min local perfusion of each hormone (10(-6) mol/L), both in skeletal muscle (gastrocnemius) and in sc abdominal adipose tissue, after a basal period with perfusion of Ringer's solution. Variations in the lipolysis rate and blood flow, respectively, were assessed by measuring of the dialysate glycerol content and the ethanol ratio (outgoing-to-ingoing ethanol concentration). The in vitro relative recovery of the microdialysis probes was 5.2 +/- 1.2%. No significant effects of either GLP-1 or glucagon on either lipolysis rate or blood flow were detected in muscle or adipose tissue. Isoprenaline (10(-6) mol/L), which was perfused after glucagon or GLP-1 in the same catheters, significantly increased the lipolysis rate (a 249% increase of dialysate glycerol in adipose tissue and a 72% increase in skeletal muscle). Furthermore, isoprenaline, but not glucagon or GLP-1, stimulated lipolysis in vitro in isolated human sc adipose tissue. We conclude that neither glucagon nor GLP-1 affect the lipolysis rate of human sc adipose tissue or skeletal muscle.

Rates of skeletal muscle and adipose tissue glycerol release in nonobese and obese subjects.

Skeletal muscle and adipose tissue lipolysis rates were quantitatively compared in 12 healthy nonobese and 14 insulin-resistant obese subjects for 3.5 h after an oral glucose load using microdialysis measurements of interstitial glycerol concentrations and determinations of local blood flow with 133Xe clearance in the gastrocnemius muscle and in abdominal subcutaneous adipose tissue. Together with measurements of arterialized venous plasma glycerol, the absolute rates of glycerol mobilization were estimated. In the basal state, skeletal muscle and adipose tissue glycerol levels were 50% higher (P < 0.05-0.01) and adipose tissue blood flow (ATBF) and muscle blood flow (MBF) rates were 30-40% lower (P < 0.02-0.05) in obese versus nonobese subjects. After glucose ingestion, adipose tissue glycerol levels were rapidly and transiently reduced, whereas in muscle, a progressive and less pronounced fall in glycerol levels was evident. MBF remained unchanged in both study groups, whereas ATBF increased more markedly (P < 0.01) in the nonobese versus obese subjects after the oral glucose load. The fasting rates of glycerol release per unit of tissue weight from skeletal muscle were between 20 and 25% of that from adipose tissue in both groups. After glucose ingestion, the rates of glycerol release from skeletal muscle and from adipose tissue were almost identical in nonobese and obese subjects. However, the kinetic patterns differed markedly between tissues; in adipose tissue, the rate of glycerol mobilization was suppressed by 25-30% (P < 0.05) after glucose ingestion, whereas no significant reduction was registered in skeletal muscle. We conclude that significant amounts of glycerol are released from skeletal muscle, which suggests that muscle lipolysis provides an important endogenous energy source in humans. In response to glucose ingestion, the regulation of skeletal muscle glycerol release differs from that in adipose tissue; although the rate of glycerol release from adipose tissue is clearly suppressed, the rate of glycerol mobilization from skeletal muscle remains unaltered. In quantitative terms, the rate of glycerol release per unit of tissue weight in adipose tissue and in skeletal muscle is similar in nonobese and obese subjects in both the postabsorptive state and after glucose ingestion.

beta-Adrenergic regulation of lipolysis and blood flow in human skeletal muscle in vivo.

Little is known about the regulation of catecholamine-stimulated lipolysis in human skeletal muscle. Therefore, beta-adrenergic regulation of lipolysis and blood flow was investigated in healthy subjects in vivo by use of microdialysis of the gastrocnemius muscle. First, during a hypoglycemic, hyperinsulinemic clamp, which induces a lipolytic response in skeletal muscle tissue, the muscle was locally perfused with beta-adrenoceptor blocking agents. Perfusion with nonselective (propranolol) and beta2-selective (ICI-118551) blocking agents counteracted the hypoglycemia-induced lipolysis (P < 0.01), but perfusion with metoprolol (beta1-blocker) did not affect the glycerol response. Second, selective beta-adrenoceptor agonists were perfused in situ into skeletal muscle during resting conditions. beta2-Adrenoceptor stimulation with terbutaline induced a concentration-dependent increase in skeletal muscle glycerol levels and in tissue blood flow, whereas perfusion with beta1- or beta3-adrenoceptor agonists (dobutamine or CGP-12177) did not influence the glycerol concentration or blood flow. In conclusion, in skeletal muscle tissue, only the beta2-subtype is of importance among beta-adrenoceptors for regulation of lipolysis and blood flow. This is in contrast to adipose tissue, where beta1- and beta3-adrenoceptors are also involved.

Lipolytic response during spontaneous hypoglycaemia in insulin-dependent diabetic subjects.

The adipose tissue lipolytic response to spontaneous, non-experimental hypoglycaemic episodes was investigated in patients with IDDM during ordinary life conditions. The absolute concentration of glucose and glycerol in subcutaneous adipose tissue was monitored in mobile patients with microdialysis in 16 IDDM subjects. The absolute glycerol level in adipose tissue was about five times as high as in venous plasma, whereas the glucose concentration was almost the same in the two compartments. Fourteen hypoglycaemic episodes (glucose < 3.5 mmol/l) were recorded. Adipose tissue glycerol increased markedly by 75 % in response to hypoglycaemia and remained increased during at least 4 hours following glucose nadir (F = 3.70, p = 0.003). The circulating levels of free fatty acids increased about three-fold in parallel to the in situ lipolytic response (F = 2.98, p = 0.025). The same lipolytic response was observed whether or not the hypoglycaemic event was perceived by the patient. A rapid decrease in glucose concentration above hypoglycaemic levels did not affect the adipose tissue dialysate glycerol. It is concluded that spontaneous hypoglycaemia elicits a long-term lipolytic response in adipose tissue as evidenced by increased levels of glycerol in adipose tissue with a parallel increase in serum free fatty acids. However, lipolysis is not activated by a rapid glucose decrease per se. The microdialysis method can be used to characterise the lipolytic response to hypoglycaemic episodes in every day life of IDDM patients.

Various phosphodiesterase subtypes mediate the in vivo antilipolytic effect of insulin on adipose tissue and skeletal muscle in man.

The antilipolytic effect of insulin on human abdominal subcutaneous adipose tissue and skeletal muscle during local inhibition of cAMP-phosphodiesterases (PDEs) was investigated in vivo, by combining microdialysis with a euglycaemic, hyperinsulinaemic clamp. During hyperinsulinaemia, the glycerol concentration decreased by 40% in fat and by 33% in muscle. Addition of the selective PDE3-inhibitor amrinone abolished the insulin-induced decrease in adipose glycerol concentration, but did not influence the glycerol concentration in skeletal muscle. Nor did the PDE4-selective inhibitor rolipram or the PDE5-selective inhibitor dipyridamole influence the insulin-induced decrease in muscle tissue glycerol. However, the non-selective PDE-inhibitor theophylline counteracted the antilipolytic action of insulin at both sites. The specific activity of PDEs was also determined in both tissues. PDE3-activity was 36.8+/-6.4 pmol x min(-1) x mg(-1) in adipose tissue and 3.9+/-0.5 pmol x min(-1) x mg(-1) in muscle. PDE4-activity in skeletal muscle was high, i.e., 60.7+/-10.2 pmol x min(-1) x mg(-1) but 8.5 pmol x min(-1) x mg(-1) or less in adipose tissue. In conclusion, insulin inhibits lipolysis in adipose tissue and skeletal muscle by activation of different PDEs, suggesting a unique metabolic role of muscle lipolysis.

Importance of phosphodiesterase 3 for the lipolytic response in adipose tissue during insulin-induced hypoglycemia in normal man.

The present investigation aimed to clarify the role of phosphodiesterase (PDE) type 3 for in vivo lipolysis in human adipose tissue during simultaneous insulin and catecholamine stimulation. Therefore, ten healthy subjects were investigated during insulin-induced hypoglycemia. Microdialysis probes were implanted in the subcutaneous adipose tissue and perfused by solvents with or without addition of the specific PDE 3 antagonist amrinone. Furthermore, changes in the local blood flow surrounding the dialysis probes were assessed by the ethanol escape technique. During the 60 min period before the start of the insulin infusion, adipose tissue glycerol levels (lipolysis index) increased significantly when amrinone was added to the perfusate (p = 0.0006, one-factor ANOVA). The antilipolytic response to the early phase of insulin infusion decreased (delta glycerol 9.0+/-3.5 vs. 29.9+/-6.0 micromol/l, p = 0.04) and the lipolytic response after hypoglycemia increased (AUC 122.4+/-18.0 vs. 13.4+/-16.3 micromol x l(-1) x h, p = 0.0001) comparing the experiments with or without amrinone, respectively. When amrinone was excluded from the perfusate, there was an increase in the nutritive blood flow during hypoglycemia, whereas there were no significant changes in the local blood flow surrounding the probe when amrinone was added to the perfusate. In conclusion, during insulin-induced hypoglycemia, PDE 3 activation clearly counteracts the lipolytic effect of catecholamines. When PDE 3 is specifically blocked, lipolysis increases greatly. Thus, PDE 3 is important for the in vivo regulation of the antilipolytic and lipolytic responses to hormones in human adipose tissue.

Protracted glucose fall in subcutaneous adipose tissue and skeletal muscle compared with blood during insulin-induced hypoglycaemia.

The absolute glucose concentrations in subcutaneous adipose tissue and skeletal muscle were determined with microdialysis in 10 normal-weight, healthy subjects during a standardized hyperinsulinaemic hypoglycaemic clamp. The concentration of tissue dialysate glucose was measured in 15-min fractions and compared with that in arterialized venous plasma. Insulin (0.15 U x kg(-1) x h[-1]) was infused i.v. to lower the plasma glucose level to 2.5 mmol/l over 30 min. This level was maintained for 30 min by using a variable glucose infusion. Thereafter, the insulin infusion was stopped and the plasma glucose level was gradually increased to baseline levels over 120 min. During a 60-min basal period, the glucose levels in muscle were 0.6 mmol/l lower than those in plasma (p = 0.002), whereas the levels in adipose tissue and plasma were similar. The glucose nadirs in muscle (1.6 +/- 0.1 mmol/l) and adipose tissue (2.0 +/- 0.1 mmol/l) were significantly lower than that in plasma (2.4 +/- 0.1 mmol/l) (p = 0.001 and 0.02, respectively), and the time-to-nadir was substantially longer in muscle (69 +/- 5 min) and adipose tissue (57 +/- 2 min) than in plasma (39 +/- 3 min) (p = 0.0004). When the insulin infusion was stopped, the increases in adipose tissue and muscle glucose concentrations were delayed by approximately 25 and 45 min, respectively, as compared to the increase in plasma glucose. Thus, it seems that glucose measurements in adipose tissue and muscle more adequately reflect overall tissue homeostasis than do measurements in blood and that clinically relevant tissue glucopenia may be overlooked by conventional blood glucose measurements.

Detection of hypoglycaemia by microdialysis measurements of glucose in subcutaneous adipose tissue.

The aim of the present investigation was to study how various fractional sampling times affect the detection of hypoglycaemia, using microdialysis of the adipose tissue. We therefore studied eight healthy subjects during a standardized hyperinsulinaemic hypoglycaemic clamp. The glucose concentration in the adipose tissue dialysate was determined in timed fractions of 15 min, 30 min and 60 min and compared to those in arterialized venous plasma. Before and after hypoglycaemia, the plasma and adipose tissue glucose concentrations were similar. However, during hypoglycaemia, the adipose tissue glucose nadir, as measured in 15-min fractions of the tissue dialysate, was significantly lower than that in plasma (2.1 +/- 0.1 vs. 2.4 +/- 0.1 mmol/l, p = 0.05) and during the increase in plasma glucose, the corresponding increase in adipose tissue glucose was delayed by approximately 20 min (p = 0.004). When the microdialysate was sampled over 30 or 60 min periods, there was a close agreement between the plasma and adipose tissue glucose nadirs. We conclude that there is a protracted fall in subcutaneous adipose tissue glucose levels in response to insulin-induced hypoglycaemia. While shorter microdialysis sampling periods improve the resolution of the hypoglycaemic event, 30-min fractions seem sufficient to detect hypoglycaemia in a clinically relevant way.

Absolute concentrations of glycerol and lactate in human skeletal muscle, adipose tissue, and blood.

The absolute concentrations of glycerol and lactate were studied with microdialysis of adipose tissue and skeletal muscle in normal-weight subjects. The basal interstitial glycerol concentration was 232 +/- 33, 96 +/- 8, and 59 +/- 6 mumol/l in fat, muscle, and arterialized plasma, respectively (P = 0.0002). This relationship was maintained during both euglycemic hyperinsulinemia, when glycerol decreased in all three compartments, and hypoglycemia, when glycerol first decreased and then increased in fat, muscle, and blood (P = 0.0001 for both). Basal interstitial lactate concentrations were similar in adipose tissue (1.1 +/- 0.2 mmol/l) and skeletal muscle (1.9 +/- 0.4 mmol/l) and higher than in arterialized blood (0.6 +/- 0.1 mmol/l, P = 0.002). During hyperinsulinemia and hypoglycemia, lactate increased (P = 0.0001) and the tissue-blood relationship was maintained (P = 0.04). In conclusion, adipose tissue and skeletal muscle mobilize glycerol and lactate at rest. Glycerol and lactate production are influenced by hyperinsulinemia and hypoglycemia in both tissues. Adipose tissue appears to be the major site of glycerol production, whereas skeletal muscle and fat may be equally important for lactate production.

A circadian rhythm in lipid mobilization which is altered in IDDM.

It is not clear how circadian lipolysis and circulating concentrations of non-esterified fatty acids (NEFA) are altered in intensively treated insulin-dependent diabetic (IDDM) patients. Ten IDDM patients on an intensive insulin regimen and eight healthy control subjects were investigated under ordinary living conditions for 27 h by microdialysis of subcutaneous adipose tissue. The true tissue glycerol concentration and adipose blood flow changes were monitored as an index of lipolysis. A circadian pattern in adipose tissue lipolysis was observed in both groups, decreasing during the day and increasing during evening-night. The daytime decrease was normal, but the evening-night rise was elevated in IDDM (p = 0.03). Circulating NEFA decreased during the day and increased at night. The latter increase was enhanced threefold in IDDM (p = 0.003) and correlated with fasting glucose levels (r = 0.77). Nocturnal growth hormone (GH) was increased fivefold in IDDM and correlated to nocturnal lipolysis (r = 0.83). Adipose tissue blood flow increased during the night in a similar fashion in both groups. Near-normalization of glucose for 24 h in IDDM did not affect the nocturnal increases in NEFA, GH and lipolysis. In conclusion, a circadian rhythm in lipolysis was found. Increased lipolytic rates during evening-night may at least in part raise nocturnal circulating NEFA. Nocturnal NEFA and lipolysis are further enhanced in IDDM, maybe due to elevated GH, but not to insulinopenia or hyperglycaemia.

Lipolytic catecholamine resistance linked to alpha 2-adrenoceptor sensitivity--a metabolic predictor of weight loss in obese subjects.

OBJECTIVE: The weight loss achieved during treatment with very-low-calorie diets (VLCD) varies between individuals. The aim of this study was to investigate whether interindividual variations in catecholamine-induced lipolysis are of importance for the rate of weight loss during VLCD. DESIGN: Prospective study. SUBJECTS: Twenty-eight obese, but otherwise healthy and drug-free women aged 20-57 y with BMI 33.3-47.5 kg/m2 were investigated before entering a four week weight reduction program with a calorie-restricted diet. MEASUREMENTS: A subcutaneous adipose tissue biopsy was obtained from the abdominal area. Isolated fat cells were prepared and incubated in vitro with agents acting on lipolysis at defined steps in the lipolytic cascade. Glycerol release was measured and used as a lipolytic index. Following the biopsy, the subjects underwent a four week VLCD treatment. RESULTS: The decrease in body weight in the whole group ranged between 4.8 and 13.5 kg. Dietary compliance was ascertained by daily measurements of urine-ketones and regular interviews and was satisfactory in all subjects throughout the study. Based on percent body weight reduction, the material was divided into two equally sized groups, classified as rapid or slow weight losers. The rapid weight losers were 10-fold more sensitive to the lipolytic effect of noradrenaline (P = 0.04) and 10-fold less sensitive (P = 0.002) to the antilipolytic effect induced by the alpha 2-adrenoceptor agonist clonidine than the slow weight losers. In the whole material, weight loss was significantly correlated (adjusted r2 = 0.25) with alpha 2-adrenoceptor sensitivity. CONCLUSION: Rapid weight loss during VLCD is associated with increased adipocyte lipolytic sensitivity to catecholamines due to decreased alpha 2-adrenoceptor sensitivity, which in turn may promote lipid mobilization. It appears that variations in alpha 2-adrenoceptor sensitivity in adipocytes may be predictive of weight loss during VLCD.

Self-monitoring of blood glucose in type I diabetic patients: comparison with continuous microdialysis measurements of glucose in subcutaneous adipose tissue during ordinary life conditions.

OBJECTIVE: To evaluate whether frequent self-monitoring of blood glucose (SMBG) sufficiently reflects the true diurnal glucose control during ordinary daily life in type I diabetic patients. RESEARCH DESIGN AND METHODS: By using a microdialysis technique, continuous monitoring of adipose tissue glucose was performed in 24 type I diabetic patients during ambulatory conditions. A microdialysis probe was implanted subcutaneously and perfused by a portable microinfusion pump. Dialysate fractions were collected in 1- to 2-h samples during 3 consecutive days. The diurnal microdialysis glucose profiles were compared with those obtained by SMBG recordings performed seven times a day. RESULTS: In seven patients, the SMBG profiles showed marked aberrations as compared to the continuous microdialysis glucose recordings; during the 3-day study period, 5-6 inconsistencies were registered. In only 4 patients (17%) did SMBG provide a valid reflection (0-2 inconsistencies) of the diurnal glucose profile, whereas in 13 patients the SMBG recordings paralleled the diurnal adipose tissue glucose profiles in an intermediate way (3-4 major inconsistencies). The inaccuracy of the SMBG data was due more often to the fact that wide glucose swings remained unrecognized, rather than to erroneous testing techniques (P < 0.05), and it was more evident during the night (P < 0.05). CONCLUSIONS: In many type I diabetic patients, the true diurnal variability in glycemia is too great to be accurately reflected even by frequent self-monitoring of blood glucose.

Gender differences in adrenergic regulation of lipid mobilization during exercise.

Gender differences in adrenergic regulation of glycerol levels in subcutaneous, abdominal adipose tissue were investigated during submaximal exercise in non-obese, healthy men and women, using microdialysis. During exercise, glycerol levels in venous plasma and venous serum concentrations of free fatty acids increased more in women and reached about two-fold higher values than in men (p < 0.005 or less). Plasma noradrenaline and insulin did not differ between the sexes, whereas plasma adrenaline was two-fold higher in men than in women during exercise (p < 0.01). The glycerol levels in adipose tissue increased during exercise and decreased in the post-exercise period in either sex. When the non-selective beta adrenoceptor blocking agent propranolol was added to the microdialysis perfusate before exercise was initiated, the subsequent increase in dialysate glycerol was significantly diminished in both sexes (p < 0.05). A similar addition of the alpha adrenoceptor blocking agent phentolamine, however, caused a significant further rise in tissue glycerol in men (p < 0.05), whereas the exercise induced increase in glycerol levels remained unaffected by phentolamine in women. Adipose tissue blood flow did not change during exercise in either men or women. In either sex, dialysate lactate levels increased during exercise. This increase was not altered if alpha- or beta-blocking agents were added to the perfusate. In summary, during short term submaximal work, women have a higher increase in circulating lipid than men. This appears, at least in part, to be due to a sex difference in the adrenergic regulation of lipid mobilization during exercise. In men exercise activates beta- as well as alpha-adrenergic receptors in adipose tissue, whereas only beta receptors are activated in adipose tissue of women. Finally, methodological investigations indicate that microdialysis is a valid method for short-term exercise experiments.

Role of phosphodiesterase III in the antilipolytic effect of insulin in vivo.

The effect of three types of phosphodiesterase (PDE) inhibitors on in vivo antilipolysis was investigated in healthy subjects using a 2-h euglycemic, hyperinsulinemic (40 mU.m-2.min) clamp together with microdialysis of abdominal subcutaneous adipose tissue. During hyperinsulinemia (approximately 330 pmol/l), the circulating glycerol concentration was reduced to approximately 50% of the basal level of 53.2 +/- 3.6 mumol/l, indicating an antilipolytic effect. The decrease in adipose tissue dialysate glycerol, which mirrors the change in interstitial glycerol concentration, was about 40% during hyperinsulinemia when Ringer's solution alone was perfused. Local perfusion with a selective PDE IV inhibitor, rolipram (10(-4) mol/l), did not influence the insulin-induced decrease in dialysate glycerol (F = 0.8 vs. perfusion with Ringer's solution by two-factor analysis of variance [ANOVA]), although rolipram increased the dialysate glycerol level by 144 +/- 7% of the baseline value. However, local perfusion with a selective PDE III inhibitor, amrinone (10(-3) mol/l), or a nonselective PDE inhibitor, theophylline (10(-2) mol/l), abolished the ability of insulin to lower dialysate glycerol (F = 16.5, P < 0.01 and F = 8.5, P < 0.01, respectively, as compared with perfusion with Ringer's solution). The findings could not be explained by changes in the local blood flow (as measured by a microdialysis--ethanol escape technique), which was not affected by hyperinsulinemia in the presence or the absence of PDE inhibitors in the dialysis solvent. We conclude that PDEs play an important role in mediating the antilipolytic effect of insulin in vivo and that PDE III is the dominant isoenzyme modulating this effect.