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A Thorell

Publications and source records attributed to A Thorell.

17 recordsLinked to original sources
PubMed1998

Extracellular-regulated protein kinase cascades are activated in response to injury in human skeletal muscle.

The mitogen-activated protein (MAP) kinase signaling pathways are believed to act as critical signal transducers between stress stimuli and transcriptional responses in mammalian cells. However, it is not known whether these signaling cascades also participate in the response to injury in human tissues. To determine whether injury to the vastus lateralis muscle activates MAP kinase signaling in human subjects, two needle biopsies or open muscle biopsies were taken from the same incision site 30-60 min apart. The muscle biopsy procedures resulted in striking increases in dual phosphorylation of the extracellular-regulated kinases (ERK1 and ERK2) and in activity of the downstream substrate, the p90 ribosomal S6 kinase. Raf-1 kinase and MAP kinase kinase, upstream activators of ERK, were also markedly stimulated in all subjects. In addition, c-Jun NH2-terminal kinase and p38 kinase, components of two parallel MAP kinase pathways, were activated following muscle injury. The stimulation of the three MAP kinase cascades was present only in the immediate vicinity of the injury, a finding consistent with a local rather than systemic activation of these signaling cascades in response to injury. These data demonstrate that muscle injury induces the stimulation of the three MAP kinase cascades in human skeletal muscle, suggesting a physiological relevance of these protein kinases in the immediate response to tissue injury and possibly in the initiation of wound healing.

Biopsy, Needle↗
PubMed1998

Perioperative insulin and glucose infusion maintains normal insulin sensitivity after surgery.

Elective surgery was performed after overnight fasting, a routine that may affect the metabolic response to surgery. We investigated the effects of insulin and glucose infusions before and during surgery on postoperative substrate utilization and insulin sensitivity. Seven patients were given insulin and glucose infusions 3 h before and during surgery (insulin group), and a control group of six patients underwent surgery after fasting overnight. Insulin sensitivity and glucose kinetics (D-[6,6-2H2]glucose) were measured before and immediately after surgery using a hyperinsulinemic, normoglycemic clamp. Glucose infusion rates and whole body glucose disposal decreased after surgery in the control group (-40 and -29%, respectively), whereas no significant change was found in the insulin group (+16 and +25%). Endogenous glucose production remained unchanged in both groups. Postoperative changes in cortisol, glucagon, fat oxidation, and free fatty acids were attenuated in the insulin group (vs. control). We conclude that perioperative insulin and glucose infusions minimize the endocrine stress response and normalize postoperative insulin sensitivity and substrate utilization.

Arthroplasty, Replacement, Hip↗
PubMed1998

Postoperative induction of insulin-like growth factor binding protein-3 proteolytic activity: relation to insulin and insulin sensitivity.

Increased serum insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) proteolytic activity (IGFBP-3-PA) has been demonstrated in a number of clinical states of insulin resistance, including severe illness, after surgery, and in noninsulin-dependent diabetes mellitus. In the present study we assessed the role of insulin sensitivity in expression of IGFBP-3-PA in serum. In 18 patients studied, a significant increase in IGFBP-3-PA (P < 0.005) was demonstrated after colo-rectal surgery. Eight patients receiving an oral glucose load before surgery demonstrated a significant greater relative increase in IGFBP-3-PA compared with 10 patients not receiving glucose (32.9 +/- 7.1% vs. 8.6 +/- 6.7%, respectively; P < 0.05). Both groups had reduced insulin sensitivity after surgery (-58 +/- 4%; P < 0.0001; n = 18), as determined by hyperinsulinemic, normoglycemic clamps; however, the group not receiving glucose displayed 18% less insulin sensitivity than the oral glucose load group (P < 0.05). Multiple regression analysis demonstrated that the relative changes in IGFBP-3-PA and C peptide levels were inversely correlated (P < 0.05), suggesting that increased IGFBP-3-PA, presumably increasing IGF bioavailability, may be associated with decreased insulin demands. Interestingly, insulin infusion during the 4-h hyperinsulinemic, normoglycemic clamp performed 24 h after surgery (post-op) resulted in a further increase in IGFBP-3-PA in both groups (P < 0.005), whereas no significant responses could be demonstrated during the pre-op clamp. The expression of increased IGFBP-3-PA was accompanied by conversion of endogenous intact 39/42-kDa IGFBP-3 into its 30-kDa fragmented form as determined by Western immunoblotting, and this conversion was virtually complete after the 4-h post-op clamp in patients displaying marked increases in IGFBP-3-PA. Characterization of the IGFBP-3-PA demonstrated that it was specific for IGFBP-3, as no degradation of IGFBP-1 and -2 was detected, and the use of various protease inhibitors demonstrated that serine proteases and possibly matrix metalloproteinases contribute to the increased IGFBP-3-PA level after surgery. We propose that IGF bioavailability may be increased by the induction of IGFBP-3-PA in insulin-resistant subjects, and that insulin regulates IGFBP-3-PA in this state.

Administration, Oral↗
PubMed1997

Site of insulin resistance after surgery: the contribution of hypocaloric nutrition and bed rest.

1. Insulin resistance after surgery has been shown to be related to several important derangements in protein and fat metabolism. However, mechanisms of impaired glucose tolerance after surgery remain ill-defined. 2. Insulin sensitivity and glucose kinetics (6,6(2)H2-glucose) were studied in seven patients before and after elective surgery (surgery group), by two step-hyperinsulinaemic (0.3 and 0.8 munits kg-1 min-1), normoglycaemic (4.5 mmol/l) clamps. Six healthy subjects were studied, using the same protocol, before and after a similar period of bed rest and hypocaloric nutrition (fast/bed rest group) to delineate the effects of surgery per se. 3. Basal endogenous glucose production and whole-body glucose disposal was higher after surgery (P < 0.001), whereas no change was found after fast/bed rest. During glucose clamps, the glucose infusion rates required to maintain normoglycaemia and whole-body glucose disposal decreased (P < 0.001) after surgery, while endogenous glucose production increased (P < 0.001). In the control subjects, levels of endogenous glucose production remained unchanged after fast/bed rest. In contrast, glucose infusion rates and whole-body glucose disposal during glucose clamps also decreased after fast/bed rest (P < 0.01). However, the relative decrease in both these parameters was greater after surgery compared with after fast/bed rest (P < 0.01). 4. After surgery, energy expenditure and fat oxidation increased (P < 0.001), whereas glucose oxidation decreased (P < 0.05). No significant change was found in glucose utilization postoperatively. After fast/bed rest, no change was found in energy expenditure. However, fat oxidation increased (P < 0.01), whereas glucose oxidation and glucose utilization decreased (P < 0.05). 5. In conclusion, impaired glucose tolerance develops after surgery as a result of decreased insulin-stimulated whole-body glucose disposal as well as increased endogenous glucose release. Despite the increase in endogenous glucose production, the reduction in endogenous glucose production with each elevation of insulin was unaffected by surgery. Perioperative bed rest and/or hypocaloric nutrition contribute to the decrease in insulin-stimulated whole-body glucose disposal in the post-operative state, whereas these factors have no effects on endogenous glucose production.

Adult↗
PubMed1997

Vitamin A concentration in the liver decreases with age in patients with cystic fibrosis.

BACKGROUND: Vitamin A deficiency is a common manifestation in cystic fibrosis (CF), but high levels of vitamin A in the liver have also been described. High levels of vitamin A in the liver are toxic, while normal levels might be protective against liver damage. In order to investigate whether liver damage in patients with CF is related to vitamin A content of the liver, vitamin A status was investigated in 15 patients with CF aged 8 to 34 years. METHODS: Liver biopsy was performed on clinical indication and the vitamin A concentration in the liver was determined as retinylpalmitate. Serum levels of retinol and retinol-binding protein were investigated on the morning of the biopsy. Eight patients had morphologic signs of cirrhosis. Eight patients had been on treatment with ursodeoxycholic acid for 1 to 3 years. All but three patients had been on vitamin A supplementation for years. RESULTS: Five patients had serum concentrations of retinol below the reference range and seven patients had decreased serum levels of retinol-binding protein. There was a strong correlation between serum levels of retinol and retinol-binding protein (rs = 0.90, p = 0.01), but no correlations with age, Shwachamn score, or genotype. Six of the patients had vitamin A concentrations in the liver < 40 micrograms/g wet weight, and the concentrations decreased significantly with age (rs = 0.77, p = 0.01), without correlation to clinical score or liver disease. There was no indication of hypervitaminosis, although younger patients had been or were being treated with vitamin A in fat-water emulsion. CONCLUSIONS: Our results indicate that the risk of vitamin a deficiency in cystic fibrosis increases with age. The data do not support the view that patients are at risk for hypervitaminosis by long-term supplementation with vitamin A. No correlation was found between the severity of liver disease and the vitamin A content in the liver.

Adolescent↗
PubMed1996

The effect of preoperative carbohydrate loading on hormonal changes, hepatic glycogen, and glucoregulatory enzymes during abdominal surgery.

The effect of preoperative glucose infusion on preoperative alterations in hepatic glycogen content, the activity of key hepatic glucoregulatory enzymes (fructose 1,6-diphosphatase [FDPase]), pyruvate kinase (PK), hormonal developments, and plasma levels of free fatty acids (FFA) were investigated in 16 patients undergoing open cholecystectomy. Patients were randomized to receive (group G) or not receive (group C) overnight glucose infusion (5 mg.kg-1.d-1) preoperatively. Infusion of glucose overnight resulted in preoperative elevations of insulin and c-peptide (P < 0.05) and lower plasma levels of FFA, while the same glucose levels were found in both groups, 4.6 mmol/L. During and after surgery, only minor changes in the plasma levels of insulin, c-peptide, catecholamines, glucagon, cortisol, growth hormone, and FFA were found, with minimal differences between groups. The hepatic glycogen content was 65% higher in group G and a significant reduction was confirmed only in this group of patients during surgery. The higher glycogen content was associated with a higher FDPase activity ratio (P < 0.05), which remained unchanged during surgery. In contrast, a significant (P < 0.05) increase in the activity of this enzyme was found in group C. The PK activity ratio did not differ between groups and remained unchanged during surgery. The finding of enhanced FDPase activity suggests that the indirect route (via gluconeogenesis) represents an important contributor to the increased glycogen formation during glucose infusion. Additionally, surgery in the overnight fasted patient induces enzymatic changes favoring gluconeogenesis. Lastly, preoperative high-dose glucose infusion has only minor effects on the endocrine response, plasma levels of FFA, and glycogen depletion during elective open cholecystectomy.

Adult↗
PubMed1996

Determination of protein synthesis in lymphocytes in vivo after surgery.

1. The stimulation and depression of peripheral blood lymphocytes has previously been studied in vitro, showing an immune depression postoperatively; however, it is difficult to interpret these in vitro findings. Therefore, an in vivo technique has been established for determination of the fractional protein synthesis rate, as an index of metabolic activity in human peripheral blood lymphocytes, by using a stable isotope technique. 2. The rate of protein synthesis was calculated from the increase in enrichment of L-[2H5]phenylalanine in protein of a mixed population of mononuclear leucocytes, isolated by density gradient, after an intravenous flooding dose of L-[2H5]phenylalanine. A linear time course of isotopic incorporation into the cells was demonstrated. 3. The fractional rate of protein synthesis of a mixed population of mononuclear leucocytes was studied in relation to surgical interventions and to potential modifiers of the response. The fractional synthesis rate increased 24 h after open and laparoscopic cholecystectomy (49 +/- 19% and 40 +/- 14% respectively, P < 0.02), irrespective of postoperative total parenteral nutrition or preoperative glucose infusion. In contrast to surgery, insulin did not stimulate protein synthesis in peripheral mononuclear leucocytes.

Adult↗
PubMed1996

The metabolic response to cholecystectomy: insulin resistance after open compared with laparoscopic operation.

OBJECTIVE: To study the changes in insulin sensitivity and plasma concentrations of interleukin-6 (IL-6) after open compared with laparoscopic cholecystectomy. DESIGN: Prospective open study. SETTING: University hospital, Sweden. SUBJECTS: 12 otherwise healthy patients undergoing either open (n = 6) or laparoscopic (n = 6) cholecystectomy. MAIN OUTCOME MEASURE: Relative insulin sensitivity (compared with preoperative) on the day after operation. Changes in IL-6 concentrations postoperatively. RESULTS: The mean (SEM) relative reduction in insulin sensitivity was significantly smaller after laparoscopic (18 (5)%) compared with the open operation, (58 (4)%) (p < 0.01). There was a significant increase in plasma concentrations of IL-6 postoperatively, but there was no difference between the groups. CONCLUSION: Insulin sensitivity is less affected 24 hours after laparoscopic than after open cholecystectomy, which in this study was not accompanied by a simultaneous difference in the IL-6 response. The small postoperative reduction of insulin sensitivity may be a contributing factor to the clinical benefit of improved wellbeing observed after laparoscopic surgery.

Adult↗
PubMed1995

Laparoscopic cholecystectomy does not prevent the postoperative protein catabolic response in muscle.

OBJECTIVE: The authors determined the effect of laparoscopic cholecystectomy on protein synthesis in skeletal muscle. In addition to a decrease in muscle protein synthesis, after open cholecystectomy, the authors previously demonstrated a decrease in insulin sensitivity. This study on patients undergoing laparoscopic and open surgery, therefore, included simultaneous measurements of protein synthesis and insulin sensitivity. SUMMARY BACKGROUND DATA: Laparoscopy has become a routine technique for several operations because of postoperative benefits that allow rapid recovery. However, its effect on postoperative protein catabolism has not been characterized. Conventional laparotomy induces a drop in muscle protein synthesis, whereas degradation is unaffected. METHODS: Patients were randomized to laparoscopic or open cholecystectomy, and the rate of protein synthesis in skeletal muscle was determined 24 hours postoperatively by the flooding technique using L-(2H5)phenylalanine, during a hyperinsulinemic normoglycemic clamp to assess insulin sensitivity. RESULTS: The protein synthesis rate decreased by 28% (1.77 +/- 0.11%/day vs. 1.26 +/- 0.08%/day, p < 0.01) in the laparoscopic group and by 20% (1.97 +/- 0.15%/day vs. 1.57 +/- 0.15%/day, p < 0.01) in the open cholecystectomy group. In contrast, the fall in insulin sensitivity after surgery was lower with laparoscopic (22 +/- 2%) compared with open surgery (49 +/- 5%). CONCLUSIONS: Laparoscopic cholecystectomy did not avoid a substantial decline in muscle protein synthesis, despite improved insulin sensitivity. The change in the two parameters occurred independently, indicating different mechanisms controlling insulin sensitivity and muscle protein synthesis.

Adult↗
PubMed1995

Preoperative gastric emptying. Effects of anxiety and oral carbohydrate administration.

BACKGROUND: Overnight fasting is routine before elective surgery. This may not be the optimal way to prepare for surgical stress, however, because intravenous carbohydrate supplementation instead of fasting has recently been shown to reduce postoperative insulin resistance. In the current study, gastric emptying of a carbohydrate-rich drink was investigated before elective surgery and in a control situation. METHODS: Twelve patients scheduled for elective surgery were randomly given 400 mL of either a carbohydrate-rich drink (285 mOsm/kg, 12.0% carbohydrates, n = 6) or water 4 hours before being anesthetized. Gastric emptying was measured (gamma camera, 99Tcm). Each patient repeated the protocol postoperatively as a control. All values were presented as the mean +/- SEM by means of a nonparametric statistical evaluation. RESULTS: Despite the increased anxiety experienced by patients before surgery (p < 0.005), gastric emptying did not differ between the experimental and control situations. Initially, water emptied more rapidly than carbohydrate. However, after 90 minutes, the stomach was emptied regardless of the solution administered (3.2 +/- 1.1% [mean +/- SEM] remaining in the stomach in the carbohydrate group versus 2.3 +/- 1.2% remaining in the stomach in the water group). CONCLUSIONS: Preoperative anxiety does not prolong gastric emptying. The stomach had been emptied 90 minutes after ingestion of both the carbohydrate-rick drink and water, thereby indicating the possibility of allowing an intake of iso-osmolar carbohydrate-rich fluids before surgery.

Adult↗
PubMed1994

Insulin resistance after abdominal surgery.

A study was carried out to determine the time course and degree of postoperative insulin resistance in patients undergoing elective abdominal surgery. Mean(s.e.m.) insulin sensitivity was determined before and on the first (n = 10), fifth, ninth and 20th (n = 5) days after elective open cholecystectomy using the normoglycaemic (4.7(0.1) mmol/l), hyperinsulinaemic (402(12)pmol/l) glucose clamp technique. Preoperative insulin sensitivity expressed as the M value varied from 2.3 to 8.2 mg per kg per min. The relative reduction in insulin sensitivity was most pronounced on the first day after surgery, at a mean(s.e.m.) of 54(2) per cent. Thereafter, a large variation between individuals was found during the course of recovery, and insulin sensitivity returned to normal 20 days after operation. On the first day after surgery, plasma concentrations of glucose, C peptide, noradrenaline and glucagon were slightly but significantly higher than before operation (P < 0.05), whereas insulin, growth hormone, cortisol and adrenaline levels were unaltered. Marked insulin resistance thus develops after elective upper abdominal surgery and persists for at least 5 days after operation. Factors other than simultaneous changes in levels of the hormones studied seem to regulate the maintenance of postoperative insulin resistance.

Adult↗
PubMed1994

Response of protein synthesis in human skeletal muscle to insulin: an investigation with L-[2H5]phenylalanine.

The role of insulin in the regulation of muscle protein synthesis in adult humans has been investigated with intravenous infusion of insulin at levels comparable with those observed after normal feeding. Glucose was also infused to maintain euglycemia. Muscle protein synthesis was measured in six healthy subjects before and during insulin and glucose infusion from the incorporation of L-[2H5]phenylalanine into the protein of vastus lateralis sampled by percutaneous biopsy. L-[2H5]phenylalanine was given as a single injection of a flooding amount (45 mg/kg). The relatively low levels of enrichment of phenylalanine in protein (0.005 atom%) were measured by modified gas chromatography-mass spectrometry and verified by comparison with incorporation of L-[2,6-3H]phenylalanine. Similarity of enrichment in tissue-free and plasma pools (flooding) and linear incorporation over the period of measurement were also verified. The fractional rate of muscle protein synthesis in the group of postabsorptive subjects was 1.65 +/- 0.11% (SE)/day. The rate was unaltered by insulin and glucose infusion, 1.66 +/- 0.16%/day.

Adult↗
PubMed1994

Glucose infusion instead of preoperative fasting reduces postoperative insulin resistance.

In severe catabolic states, such as burn injury, sepsis and accidental injury, a state of marked insulin resistance is encountered. Insulin resistance is also present after elective surgical treatment, more pronounced with increasingly greater magnitude of operation performed. Results of recent animal experiments have shown that even short periods of food deprivation, reducing carbohydrate reserves, alter responses to stress. This notion resulted in our questioning the rationale of carbohydrate depletion associated with overnight preoperative fasting. Twelve patients undergoing elective open cholecystectomy were randomly given no infusion (control group) or 5 milligrams per kilogram per minute of glucose infusion (glucose group) during preoperative overnight fasting. Insulin sensitivity (M value, milligram per kilogram per minute) was determined using the hyperinsulinemic normoglycemic clamp (plasma insulin level, 65 microunits per milliliter and blood glucose level, 4.5 millimoles per liter) before and the first postoperative day. Preoperative insulin sensitivity was similar in the two groups. Postoperatively, M values decreased by 55 +/- 3 percent (control group) and by 32 +/- 4 percent (glucose group) (p < 0.01). Plasma levels of insulin, c-peptide, glucagon, growth hormone, catecholamines and cortisol in connection with clamps were similar in both groups preoperatively and postoperatively. The present results indicate that active preoperative carbohydrate preservation may improve postoperative metabolism because postoperative occurrence of insulin resistance was reduced with preoperative glucose infusion.

Animals↗
PubMedDate not supplied

Short-term hypocaloric nutrition but not bed rest decrease insulin sensitivity and IGF-I bioavailability in healthy subjects: the importance of glucagon.

Hyperinsulinemic, normoglycemic clamps were performed before and after 24 h of either hypocaloric nutrition or bed rest in healthy subjects. Decreased insulin sensitivity and insulin-like growth factor-I (IGF-I) bioavalibility, as measured by the serum IGF-I/insulin-like growth factor binding protein-1 (IGFBP-1) ratio, was found after fasting, whereas no metabolic changes were found after bed rest. Glucagon seems to be a key regulator of IGFBP-1 after brief hypocaloric nutrition. Hypocaloric nutrition and immobilization may add to the catabolic response to surgery and other trauma. Presently, six healthy subjects were studied before and after a 24-h period of hypocaloric nutrition (200 kcal/24 h, fast) or immobilization (bed rest) using the hyperinsulinemic (0.8 mU.kg-1.min-1), normoglycemic (4.5 mmol/L) clamp, indirect calorimetry, and circulating levels of substrates and hormones. After fast, body weight decreased (P < 0.05), and nitrogen balance was negative (-10 +/- 1 g urea nitrogen/24 h). Basal levels of free fatty acids, glucagon, and IGFBP-1 increased (P < 0.05), whereas c-peptide levels and the IGF-I/IGFBP-1 ratio decreased (P < 0.05). However, no change was found in basal levels of IGF-1 or substrate oxidation. Furthermore, changes (%) in basal levels of glucagon after fast correlated to IGFBP-1 (r = 1.0, P < 0.05), whereas the suppressibility of IGFBP-1 by insulin was maintained at normal levels. During clamps, glucose infusion rates (GIR) decreased after fast (-43 +/- 13%, mean +/- SEM, P < 0.001). Although not significantly, clamp levels of fat oxidation tended to increase and glucose oxidation tended to decrease. Levels of IGFBP-1 during clamps were higher as compared with the control clamp (P < 0.05). No adverse metabolic changes were seen after bed rest, and no change in GIR during clamps were seen as compared with the control measurement (0 +/- 14%). After brief hypocaloric nutrition, insulin sensitivity is reduced, whereas IGF-I bioavalibility is reduced by an increase in levels of IGFBP-1. Glucagon seems to contribute to the increase in IGFBP-1 during these conditions.

Adult↗
PubMedDate not supplied

Development of postoperative insulin resistance is associated with the magnitude of operation.

OBJECTIVE: To study the development of insulin resistance and changes in stress hormone concentrations in patients undergoing elective operations of different magnitude. DESIGN: Prospective open study. SETTING: University hospital, Sweden. SUBJECTS: 12 otherwise healthy patients, undergoing elective surgery for cholecystectomy (n = 6) and inguinal hernia repair (n = 6). INTERVENTIONS: Insulin sensitivity was measured by the normoglycaemic, hyperinsulinaemic glucose clamp technique before operation (control) and on the first postoperative day. MAIN OUTCOME MEASURE: Relative insulin sensitivity (compared with preoperative) on the day after each operation. Changes in stress hormone concentrations in relation to the relative change in insulin sensitivity. RESULTS: After hernia repair, mean (SEM) insulin sensitivity was reduced by 32 (4)%, p < 0.05 compared with baseline, and after open cholecystectomy by 56 (3)%, (p < 0.05). The difference between the two groups was highly significant (p < 0.01). The changes in concentrations of catecholamines, glucagon, cortisol and growth hormone after operation were only small, and did not correlate with the relative changes in insulin sensitivity. CONCLUSIONS: Insulin resistance develops even after a minor elective operation, (inguinal hernia repair). The degree of postoperative insulin resistance was more pronounced after open cholecystectomy. The alteration in insulin sensitivity could not be related to simultaneous changes in the hormones studied.

Catecholamines↗