No differential effects of porcine and human insulin on muscle sympathetic nerve activity during euglycaemia or hypoglycaemia

Summary. On the basis of some clinical studies in diabetic patients, and experimental studies in normal humans, it has been suggested that hypoglycaemic autonomic responses are augmented with porcine (PI) compared to human insulin (HI). A difference in sensory processing has been reported following insulin-induced hypoglycaemia with PI compared to HI, and has been interpreted as different insulin effects on the central nervous system. In a double blind crossover comparison of HI and PI in nine healthy subjects, microneurographic recordings of muscle sympathetic nerve activity (MSNA) were performed, as well as measurements of cardiovascular and hormonal responses during a low dose hyperinsulinaemic euglycaemic glucose clamp (plasma insulin 60.1 ±1.9 mU ml^-1 (mean ± SEM)), followed by a period of insulin-induced hypoglycaemia. Plasma insulin and glucose were identical in the two sessions. Plasma glucose nadir during hypoglycaemia was 2.4 ± 0.2 mmol 1^-1 for HI and 2.5 ±0.1 mmol l^-1 for PI. During euglycaemia, MSNA increased from 24 ± 2 to 34 ± 3 and 23 ± 2 to 30 ± 2 burst/min (P:NS) for HI and PI, respectively, and during hypoglycaemia to 49 ± 4 and 45 ± 2 bursts min^-1 (P:NS), respectively. The maximal hypoglycaemic increments of MSNA were not different (HI 15 ± 4; PI 15 ± 2 bursts min^-1 (P: NS)) Responses of plasma noradrenaline and haemodynamic parameters did not differ either. This study does not indicate differing sympathetic responses to PI and HI in healthy humans. Evidence for a modulating effect of insulin on central sympathetic outflow was not found.     

Insulin and metabolic substrates during human sepsis

Rusavy and colleagues recently endeavoured to dissect out the metabolic effects of insulin in patients with severe sepsis, in the setting of normoglycaemia. Twenty stable patients were studied 3–7 days after admission using a euglycaemic clamp at two supraphysiological insulin levels. Increased doses of exogenous insulin caused preferential use of glucose as a metabolic substrate, while total energy expenditure remained constant. Consequently, hyperinsulinaemia reduced tissue oxygen demand and catabolism of protein in patients with sepsis; the benefits of these effects are not proven. The effects of insulin at different time points in sepsis were not examined.     

主动放松训练对肌糖原合成的影响

目的：探讨主动放松训练对于不同类型肌纤维糖原储备量的影响。方法：8位实验对象接受高强度耐力训练，训练后分组进行主动放松训练和被动放松训练。结果：主动放松训练者的血乳酸水平和DH值能更快的恢复至训练前水平，肌糖原含量在主动放松训练时保持平稳，而在被动放松训练时出现上升变化，主动放松训练对Ⅱ型肌纤维的糖原含量变化不大，而Ⅰ型肌纤维则出现肌糖原的分解，主动放松训练时血儿茶酚胺水平增高，胰岛素水平下降，该激素变化对Ⅱ型肌纤维的糖原合成过程没有影响。结论：与被动放松训练相比．主动放松训练更有利于高强度运动后的机体恢复。     

门冬胰岛素与生物合成人胰岛素治疗新诊断Ⅱ型糖尿病的对照研究

目的比较门冬胰岛素与生物合成人胰岛素治疗新诊断Ⅱ型糖尿病的临床疗效。方法将新诊断的96例Ⅱ型糖尿病患者随机均分为2组,分别为门冬胰岛素(治疗)组和生物合成人胰岛素(对照)组。患者分别在每日餐前给予皮下注射门冬胰岛素和生物合成人胰岛素,且均每晚定时皮下注射一次甘精胰岛素。比较2组患者血糖、低血糖事件、胰岛素用量的差异。结果用药后2组餐前及餐后的血糖含量均明显降低,且门冬胰岛素组餐前、餐后血糖均低于生物合成人胰岛素组;门冬胰岛素组患者低血糖发生次数低于生物合成人胰岛素组,差异有统计学意义;但2组胰岛素用量无显著差异。结论门冬胰岛素能够更好地控制Ⅱ型糖尿病的血糖,对Ⅱ型糖尿病的治疗更加有效。     

Determinants of insulin-stimulated skeletal muscle glycogen metabolism in man

Abstract. To examine factors which influence skeletal muscle glycogen synthesis in man, we related insulin sensitivity measured by euglycaemic insulin clamp in 43 healthy males to muscle glycogen synthase (GS) activity, GS protein content (Western blot), glycogen concentrations and fibre composition. Insulin increased muscle glycogen content (P<0.05) and the change in glycogen content correlated with the GS protein content (r=0.90, P=0.01). GS protein concentration correlated inversely with age (r=-0.69, P=0.04). Non-oxidative glucose disposal was inversely related to per cent type 2B fibres (r=-0.52, P< 005). The influence of age on these relationships was separately studied in young (n=12, age=26 ± 2 years) and elderly (n=15, age = 56 ± 2 years) males. Insulin increased GS activity significantly only in young subjects (from 17.8 ± 30 to 25.3 ± 3.2 nmol mg protein ' min^-1; P=0.015). GS activity and non-oxidative glucose disposal correlated in young (r=0.69, P=001) but not in the elderly (r=0.064, P = 0.82) males, and this relationship was not influenced by the degree of obesity. In conclusion, muscle fibre type and GS activity are both determinants of muscle glycogen metabolism in healthy, normoglycae-mic males. The close relationship between non-oxidative glucose metabolism and GS activity in young males is altered in ageing.     

Assessment of human muscle glycogen synthesis and total glucose content by in vivo 13C MRS

BACKGROUND: Obesity is often accompanied by a decreased ability of insulin to stimulate glucose uptake and glycogenesis in skeletal muscle. The aim of this study was to investigate the rate of glycogen formation and of muscular glucose content in relation to insulin sensitivity under euglycemic conditions. MATERIALS AND METHODS: We applied a hyperinsulinemic (430 pmol m-2 min-1) euglycemic clamp with infusion of 20% glucose (30% enriched with 13C-1-glucose) to 8 subjects with a wide range of insulin sensitivities. Glycogen and glucose levels were monitored simultaneously by in vivo 13C MRS of the calf muscle on a clinical MR system at 1.5T field strength. RESULTS AND CONCLUSIONS: Glycogen synthesis rate showed a strong correlation with whole body glucose uptake during the clamp (r = 0.93, P < 0.01). With the use of 13C MRS, total muscular glucose content could be determined in vivo, and showed a positive, linear correlation with glycogen synthesis rate (r = 0.85, P < 0.01). 13C MRS provides important information regarding in vivo insulin action. Preliminary results indicate that the glycogen synthesis rate improves after treatment with troglitazone.     

Skeletal muscle metabolism and insulin resistance during endotoxin shock in the dog

The effect of locally infused endotoxin on gracilis muscle glucose uptake was determined in anesthetized mongrel dogs. The effects of infusion of small amounts of Escherichia coli endotoxin into the arteries of isolated, innervated, constant flow perfused gracilis muscles on glucose uptake and other metabolic variables were determined. Locally infused endotoxin consistently caused a significant and substantial increase in skeletal muscle glucose uptake with no alterations in muscle arteriovenous difference of insulin, oxygen, carbon dioxode, or pH, or in venous blood hematocrit or temperature. These data demonstrate that endotoxin can act locally to increase glucose uptake by skeletal muscle, independent of the action of insulin or other metabolic factors. During natural (free flow) conditions, glucose uptake by the muscle increased markedly during six hours of shock. Increased glucose uptake occurred concomitantly with muscle ischemia and hypoxia. However, when muscle blood flow was held constant, thereby preventing local muscle ischemia and hypoxia, glucose uptake by the gracilis muscle did not change during shock. These results implicate local muscle ischemia and/or hypoxia as the mediator(s) of the increased muscle glucose uptake during shock. Further studies demonstrated that local muscle hypoxia was the stimulus for increased glucose uptake by skeletal muscle during endotoxin shock, and muscle ischemia per se did not after muscle glucose uptake. Since approximately 50% of body mass is composed of skeletal muscle, the contribution of this organ system to the hypoglycemia of endotoxin shock in the dog may be substantial. The ability of insulin to promote glucose diffusion into skeletal muscle before and during gram-negative endotoxin shock was studied in mongrel dogs anesthetized with sodium pentobarbital. The in vivo, isolated, innervated, constant flow perfused gracilis muscle preparation was used. Prior to shock induction, close intra-arterial insulin infusion resulted in a 320% increase in muscle glucose uptake. However, at one, two, and three hours of endotoxin shock, gracilis muscle glucose uptake was unaltered by insulin infusion. This loss of responsiveness to insulin occurred with no alteration in gracilis muscle oxygen uptake, muscle venous P_O2, or muscle blood flow. During control experiments, however, the muscle response to intra-arterial infusion of insulin (increased glucose uptake) was unaltered during the three-hour control period. These data demonstrate that skeletal muscle insulin resistance develops early and is maintained during three hours of endotoxin shock in the dog.     

Regulation of glycogen synthase and phosphorylase activities by glucose and insulin in human skeletal muscle.

We examined the insulin dose-response characteristics of human muscle glycogen synthase and phosphorylase activation. We also determined whether increasing the rate of glucose disposal by hyperglycemia at a fixed insulin concentration activates glycogen synthase. Physiological increments in plasma insulin but not glucose increased the fractional activity of glycogen synthase. The ED50: s for insulin stimulation of whole body and forearm glucose disposal were similar and unaffected by glycemia. Glycogen synthase activation was exponentially related to the insulin-mediated component of whole body and forearm glucose disposal at each glucose concentration. Neither insulin nor glucose changed glycogen phosphorylase activity. These results suggest that insulin but not the rate of glucose disposal per se regulates glycogen synthesis by a mechanism that involves dephosphorylation of glycogen synthase but not phosphorylase. This implies that the low glycogen synthase activities found in insulin-resistant states are a consequence of impaired insulin action rather than reduced glucose disposal.     

Availability of glycogen and plasma FFA for substrate utilization in leg muscle of man during exercise

Summary. Six men performed two-legged cycle ergometer exercise at loads demanding 2–4 and 3–4 litres O₂ min^-1 (62 and 84% of Vo₂ max) for 20 min each or to exhaustion twice with 1 h rest between. An initial glycogen difference of 28 mmol glucose units kg^-1 of thigh muscle between the two legs was produced by one-legged exercise on a previous day followed by the consumption of a low carbohydrate diet. During the 1 h rest nicotinic acid (NA) was administered to inhibit lipolysis. Total body Fo₂ was unchanged by the NA administration. Work done by each leg, indicated by force on the pedals, was equal. RQ indicated a larger oxidation of fat in the leg with low glycogen. Muscle glycogen was 15 and 10 mmol kg^-1 in the normal and low glycogen leg at the end of the first exercise bouts and 3–8 mmol kg^-1 in both legs at exhaustion. The low glycogen leg extracted lactate from the blood whereas the normal leg released lactate and the uptake of glucose from the blood was greater by the low glycogen leg. These differences between the low glycogen and control legs did not persist during the NA condition when muscle glycogen content was equal in both legs. Further, the leg glucose uptake in the control and the NA conditions was positively related to the percentage of glycogen-empty muscle fibres and inversely to the glucose-6-P0₄ concentration. Thus the magnitude of the local glycogen stores of muscle influences the uptake and use of blood-borne substrates as well as determining endurance capacity during moderate to high intensity exercise.     

Regional differences and effect of weight reduction on human fat cell metabolism

Abstract. The metabolism of adipocytes from severely obese patients was investigated before and after weight was reduced by jejuno-ileal by-pass. After weight reduction lipolysis and glucose incorporation into triglycerides were decreased as was the cell size. The effect of submaximal concentrations of insulin on glucose incorporation increased with weight reduction implying increased cellular insulin sensitivity.
The rate of glucose incorporation and basal lipolysis in the adipocytes correlated directly with the fasting plasma insulin level before weight reduction. After weight reduction there was a positive correlation between the decrease in glucose metabolism and the reduction in the plasma insulin level. These data support the concept that plasma insulin may be important for the long-term regulation of glucose metabolism and lipolysis in fat cells.
In other patients with normal body weight, studies on regional differences in adipocyte metabolism showed that fat cells from the subcutaneous abdominal region responded better to both noradrenaline and insulin than femoral fat cells. The differences between these sites were less pronounced during incubation with isopropylnoradrenaline, suggesting there was increased α-receptor activity in the femoral region.
Adipocytes in the abdominal subcutaneous region are thus metabolically much more active than those in the femoral region. This might explain why several blood parameters such as arterial free fatty acid and glycerol levels correlate with lipolysis of abdominal but not femoral cells and why plasma insulin and triglyceride levels correlate with abdominal but not femoral fat cell size. Also, the responsiveness of adipocytes in the abdominal region may explain why cells in this region decreased more in size than those in the femoral region during weight reduction.     

运动对糖、脂代谢的影响

本文通过对运动营养研究中有关运动中碳水化合物补给与脂肪动员氧化等热点问题的概述,分别介绍了运动对糖、脂代谢影响研究中的新观点与运动中糖脂代谢的相互影响。     

Synthesis of muscle glycogen during recovery after prolonged severe exercise in diabetic and non-diabetic subjects.

Glycogen synthesis rate in skeletal muscle studied in six juvenile diabetic and six non-diabetic males ingesting a carbohydrate rich diet during 12 h of resting recovery after exhaustive bicycle exercise. The diabetic subjects took their regular insulin. Blood samples and muscle biopsies were obtained at rest prior to exercise, immediately after cessation of exercise and after 2,4,6.9 and 12 h of recovery. A marked decrease in muscle glycogn content was observed in response to exercise in both groups of subjects. Mean glycogen utilization rate was the same in the two groups. Glycogen synthesis rate during the first 4 h or recovery was 6.4 +/- 0.6 mmol glucosyl units/kg w.w./h in the diabetic subjects and 7.2 +/- 0.7 mmol glycosyl units/kg w.w./h in the non-diabetic subjects. During the next 8 h glycogen synthesis rate was approximately 1/3 of that being 2.0 +/- 0.3 and 2.4 +/- 0.5 mmol glucosyl units/kg w.w./h in the two groups respectively. Glycogen synthetase I-activity increased markedly in response to exercise in both groups of subjects. However, no differences were observed between the groups. No significant differences in muscle glucose 6-phosphate concentrations were observed between the two groups. Plasma glucose levels were significantly higher in the diabetic than in the non-diabetic subjects. It is concluded that glycogen synthesis during recovery following prolonged severe exercise can proceed at the same rate in diabetic subjects taking their regular insulin as in non-diabetic subjects.     

Continuous monitoring of oxygen tension in human gastrocnemius muscle during exercise

Summary. A technique for continuous monitoring of the intramuscular oxygen tension (i.m. PO₂) in human skeletal muscle at rest and during exercise was evaluated. A commercially available oxygen transducer mounted in the tip of a flexible catheter was slightly modified and its characteristics in terms of linearity, response time etc. were investigated in vitro. The oxygen probe was introduced through a cannula into the gastrocnemius muscle often normal subjects and ten patients with peripheral arterial insufficiency. The i.m. PO₂ was continuously monitored at rest as well as during fatiguing leg exercise performed on a foot ergometer. The resting i.m. PO₂ was 3.83 ± 0.45 kPa in normal subjects and 3.67 ±0.53 kPa in patients with peripheral arterial insufficiency. During exercise a decrease in the i.m. Po₂ was found in both patients and normal subjects. At a work load of 8 kg normal subjects exercised for 8.1 ±0.6 min and the i.m. PO₂ decreased to 2.45±0.39 kPa. At the same work load (8 kg) the i.m. PO₂ decreased to I -22±0–4 kPa in the patients although their exercise time was considerably shorter (2.5 ±0.3 min) because of the development of claudication pain. An increase of the work load to 12 kg in the normals reduced the exercise time to 2.2 ± 0.1 min and provoked a more pronounced decrease in the i.m. PO₂ (0.99 ±0.01 kPa). The limitations and advantages of the present technique are discussed in relation to other techniques. The results demonstrate that this technique is suitable for measurements of i.m. PO₂ in human skeletal muscle tissue during exercise.     

Effects of swim training on body weight,carbohydrate metabolism,lipid and lipoprotein profile

The beneficial effects of regularexercise are primarily based on data using land-based exercise. Currently, no data exist thatdemonstrate the efficacy of swimming exercise for the treatment of obesity and cardiovascularrisk factors, despite the fact that swimming is a widely recommended exercise mode. Eighteenpreviously sedentary obese individuals were divided into a swim-training group and a non-exercising control group. The training group swam at 60% of maximal heart rate reservefor 45 min per day for 3 days per week for 10 weeks, whereas the control group remainedsedentary. The swim-training programme produced significant cardiovascular training effects,as evidenced by reductions (P<0·05) in resting and submaximal heartrate values in the training group. Significant reductions (P<0·05) werealso observed in the rating of perceived exertion and blood lactate concentrations during fixedsubmaximal exercise on an arm cycle ergometer. Caloric and macronutrient intake estimatedfrom the dietary records stayed constant before and after training. Body mass, body fatpercentage (36±2% vs. 35±2%) and body mass index, as well asregional adiposity, showed no statistically significant changes. Neither the training nor thecontrol groups experienced significant changes in fasting serum glucose and insulinconcentrations and glucose–insulin ratio during the study. Total, high-densitylipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol did not change significantlyin either group. It was concluded that swim training of the duration, frequency and intensityused in the present study failed to elicit favourable modifications in these traditionalcardiovascular risk factors.     

Plasma volume changes during hypoglycaemia: the effect of autonomic blockade

To investigate the role of the autonomic nervous system in changes in blood volume and composition induced by acute hypoglycaemia in man, seven healthy subjects participated in three experiments on separate days: insulin-induced hypoglycaemia with concomitant alpha-adrenoceptor blockade; insulin-induced hypoglycaemia with total autonomic blockade (alpha-adrenoceptor blockade combined with beta-adrenoceptor blockade and atropine); and insulin-induced hypoglycaemia without any autonomic blockade. In the experiments without autonomic blockade the peripheral venous hematocrit increased, plasma volume decreased, intravascular albumin content decreased and the transcapillary escape rate of albumin increased. In both experiments with autonomic blockade the increase in venous haematocrit was abolished, yet plasma volume decreased, intravascular albumin content decreased and the transcapillary escape rate of albumin increased in these experiments. Thus, the changes in plasma volume and composition in response to hypoglycaemia are due to the combined actions of adrenaline and of insulin.     

Effects of interferon alpha on insulin binding and glucose transport in human adipocytes

We have previously demonstrated that interferon administration impairs glucose tolerance and causes insulin resistance in healthy man. Whether this is a direct effect of interferon is not known. The present study was undertaken to examine directly the effect of interferon alpha on insulin binding and action on glucose transport in isolated human adipocytes. Different concentrations of interferon alpha (range 10(-3)-10(5) IU ml-1) and different incubation times (0-5-24 h) with interferon were employed. Acute and 5-h and 24-h exposure of human adipocytes to 10(-2)-10 IU ml-1 of interferon increased the high affinity binding of 125I-insulin (P less than 0.05). In contrast, human interferon alpha had no effect on insulin binding in rat adipocytes. In short-term studies interferon had no effect on 14C-glucose transport clearance. 24-h preincubation of human adipocytes with 10(-2), 10, 10(4) IU ml-1 interferon increased maximally-insulin stimulated 14C-glucose transport clearance (P less than 0.05) and glucose transport responsiveness to insulin was enhanced by 24% (P less than 0.05) in cells exposed to 10(-2) IU ml-1 interferon. After 5 and 24-h preincubations with interferon we observed modest changes in glucose transport sensitivity to moderate concentrations of insulin (50-100 pM) with upregulation in the presence of 10(-2)-10 IU ml-1 interferon and downregulation in the presence of 10(4)-10(5) IUm ml-1 interferon (P less than 0.05). The insulin sensitivity index (ED50) did not change.(ABSTRACT TRUNCATED AT 250 WORDS)     

ATP and IMP in single human muscle fibres after high intensity exercise

Summary. Within a muscle there is large variation in the activity of various enzymes among single fibres. It is reasonable, therefore, to expect a corresponding variation in their metabolic response to exercise. This was examined by obtaining muscle biopsies from five men at rest and after intense short-term exercise consisting of three bouts of 30 knee extensions each and intervened by 60 s rest. Freeze-dried dissected single fibres identified as type 1 or type 2 were analysed for ATP and IMP contents by liquid chromatography. Rest. Average ATP tended to be higher in type 2 than in type 1 fibres. The ATP range was 14–30 and 14–32 mmol × kg^-1 dry muscle (dm) in type 1 and 2 fibres, respectively. IMP was less than 1 mmol × kg^-1 dm in most fibres and similar in types 1 and 2. Exercise. Muscle force decreased 70% during exercise. The average decrease in ATP content was significant for both fibre types with somewhat larger response for type 2 (20%) than type 1 (10%) fibres. The ATP range was 10–28 and 10–30 mmol × kg^-1 dm in type 1 and 2 fibres, respectively. Average IMP content increased substantially in both fibre types, more so for type 2, and the range for individual fibres was 0–13 (type 1) and 0–21 (type 2) mmol × kg^-1 dm. Conclusion. After exhaustive short-term exercise, a large variation in ATP and IMP contents was evident among single type 1 and type 2 fibres. None of the fibres, however, showed an ATP content lower than 10 mmol × kg^-1 dm. It is suggested that the muscle force loss, demonstrated in the present study, is not attributed to a lowered ATP content per se.     

Blood flow variation in human muscle during electrically stimulated exercise bouts

OBJECTIVES: To evaluate, with a high spatial resolution, the blood flow variations in human skeletal muscle during neuromuscular electric stimulation (NMES) and hence to gain better understanding of the mechanisms of muscle spatial recruitment during NMES. DESIGN: One thigh was submitted to 3 stimulation bouts of different durations (S1=4min, S2=8min, S3=12min) with a workload corresponding to 10% of quadriceps maximal isometric voluntary torque. SETTING: A cyclotron research center at a Belgian university. PARTICIPANTS: Ten healthy male volunteers. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were studied with positron emission tomography and H(2)(15)O. Tissue blood flow was evaluated during the last 4 minutes of each stimulation bout in multiple regions of interest (ROIs) selected in the transverse section of the stimulated thigh. RESULTS: Mean tissue blood flow was significantly lower during S1 (5.9+/-1.3mL. min(-1). 100g(-1)) than during S2 (10.6+/-3.4mL. min(-1). 100g(-1)) and S3 (11.6+/-3.7mL. min(-1). 100g(-1)) (P<.05). For each ROI, an arbitrary tissue blood flow activation level of 5mLmin(-1)100g(-1) was fixed. The mean percentage of activated ROIs reached 42.4%, 62.7%, and 63.6% during S1, S2, and S3, respectively. Between S1 and S3, the newly recruited ROIs were preferentially located far from the electrode. CONCLUSION: During NMES, new muscular regions situated far from the stimulation site are recruited. These recruitment mechanisms are particular and contrast with the recruitment of motor units seen during voluntary contraction.