- Email: [email protected]
Insulin: more lessons to be learned
EDITORIAL OPINIONS
Insulin: More Lessons to Be Learned Exactly 80 y after the first clinical use of insulin, our knowledge of this molecule continues to expand. Common understanding of the hormonal function of insulin is based on its two principal classes of action: 1) anabolic, i.e., favoring synthetic pathways by directing substrates into glycogen, protein, and lipid synthesis; and 2) anticatabolic, i.e., inhibiting catabolic processes such as glycogenolysis, proteolysis, and lipolysis. As the body’s key endocrine regulator, insulin ensures appropriate substrate supply in a highly controlled fashion. Once relative or absolute insulin deficiency occurs, this control is lost, and energy substrates flood the system, resulting in hyperglycemia, osmotic dehydration, muscle-protein wasting, and ketoacidosis. The use of combined infusions of glucose, insulin, and potassium (GIK) was introduced by Alberti in 1979 for the perioperative management of the diabetic patient.1 Subsequently, considerable attention has been given to the pharmacologic use of insulin as an anabolic agent in non-diabetic patients with the intention of ameliorating protein losses after trauma and surgery. The article by Das2 summarizes the antiinflammatory properties of insulin and reviews the potential of GIK administration as a novel therapeutic approach to inflammatory disease. Much data has accumulated showing that GIK administration can limit the ischemic myocardial damage after acute myocardial infarction as reflected in improved cardiac function and reduced morbidity and mortality. Therefore, the option of GIK treatment has been incorporated into the guidelines for the management of patients with acute myocardial infarction published by the American College of Cardiology and the American Heart Association in 1999. There is evidence that “cardiac cachexia” is associated with increased circulating levels of tumor necrosis factor-␣ (TNF-␣), mediated directly through stimulated TNF-␣ production by the failing heart or indirectly through endotoxinemia caused by increased bowel permeability, a consequence of augmented mesenteric venous pressure and intestinal edema. Because insulin inhibits TNF-␣ production in a dose-dependent manner and TNF-␣– induced myocardial depression can be ameliorated by the administration of TNF-␣ antibodies, the suppression of TNF-␣ production might be an underlying mechanism responsible for the favorable effects of insulin after acute myocardial infarction. The preserving influence of GIK infusions on the ischemic myocardium is not a new phenomenon. Originally proposed by SodiPallares in 1962, GIK administration has long been known to increase the intracellular cardiac glycogen content and enhance resistance to ischemia caused by enhanced glycolytic and anaerobic ATP production. GIK treatment also is accompanied by a decrease in circulating concentrations of free fatty acids, which per se exert deleterious effects on myocardial function and metabolism during ischemia. It is further hypothesized that the use of GIK would be effective in the treatment of a variety of other inflammatory diseases where cytokines play major pathogenic roles such as sepsis, intersititial pneumonitis, chronic inflammatory bowel disease, rheumatoid arthritis, systemic sklerosis, and Alzheimer’s disease. Further, the stimulatory effect of insulin on the synthesis of nitric oxide, a potent vasodilator and platelet antiaggregator, might be useful in the prevention of vascular thrombosis. Notwithstanding the presented evidence that insulin exhibits
Correspondence to: Thomas Schricker, MD, PhD, Department of Anesthesia, McGill University, Royal Victoria Hospital, 687 Pine Avenue West, Room S5.05, Montreal, QC, Canada H3A 1A1. E-mail: mbek@ musica.mcgill.ca Nutrition 17:419 – 425, 2001 ©Elsevier Science Inc., 2001. Printed in the United States. All rights reserved.
antiinflammatory properties, several issues raised in the article by Das deserve further comment, in particular the modifying role of glucose as an obligatory part of the GIK regimen, the effects of GIK infusions on stress-induced insulin resistance, and some practical aspects. Because insulin has to be administered with glucose to avoid hypoglycemia, it is difficult to discern the independent effects of insulin and feeding. Considering the significant interdependence between the body’s nutritional and immunologic statuses, this concern applies in particular to conclusions obtained from longterm investigations in diabetic and non-diabetic individuals. Although the improvement of myocardial function during experimental endotoxic shock by GIK treatment was unrelated to the prevailing plasma glucose levels, one must not forget the fact that there is a strong relationship between acute changes in plasma glucose homeostasis and the immune system. Acute hyperglycemia has been demonstrated to limit the phagocytic capacity of polymorphonuclear neutrophil leukocytes, impair granulocyte chemotaxis, and adversely affect the complement system. However, dysfunction of polymorphonuclear neutrophil leukocytes as seen in diabetic patients undergoing cardiac surgery can be partly reversed by aggressive glucose control.3 The clinical relevance of these findings is underscored by the observation that maintaining perioperative normoglycemia decreases the incidence of infectious complications in diabetic patients after cardiac surgery.4 Hyperglycemia, stimulated gluconeogenesis, and impaired glucose utilization and tolerance are typical, well-described features of the metabolic response to sepsis and tissue trauma. Traditionally, these abnormalities in glucose metabolism have been ascribed to the overproduction of the counterregulatory hormones cortisol, epinephrine, and norepinephrine. All of these hormones alter glucose homeostasis, directly or indirectly, by counteracting the action of insulin, leading to the impairment of tissue insulin sensitivity. More recently, attention has focused on various biochemical mediators (TNF-␣ and interleukines) that are released during the acute inflammatory response to stress. Considering the metabolic complexity of sepsis or septic syndromes, it is not surprising that the results of studies assessing the impact of cytokines on carbohydrate metabolism are not consistent. TNF-␣, for example, has been reported to induce hypoglycemia and hyperglycemia or exert no effect at all.5 Marked insulin resistance is present after routine surgical procedures, even without sepsis or other complications, and can persist up to 20 d thereafter. The entity, sites, and mechanisms of such insulin resistance have been widely investigated but still are the subject of controversy. For example, insulinmediated glucose disposal in injured patients has been demonstrated to be impaired only at maximally stimulating insulin concentrations, suggesting that responsiveness, i.e., maximal response, rather than sensitivity to the hormone is reduced.6 In contrast, other investigators have reported that postoperative glucose utilization and oxidation can be normalized provided that large-enough loads of glucose and insulin are administered.7 In septic patients, peripheral glucose uptake has been shown to be insensitive to insulin clamped at physiologic, plasma insulin levels. Insulin administration resulting in supraphysiologic plasma concentrations increased but did not normalize whole-body glucose disposal.8 Thus, whether insulin action can be restored to normalcy during sepsis by exogenous infusion of insulin is not known. Further, it is not known which insulin plasma levels are required to overcome insulin resistance and, more importantly, produce clinically significant effects during inflammatory disease. The GIK solution suggested by Das comprises 30% glucose with 50 U/L of insulin and 80 mmol/L of potassium infused at a rate faster than 1.5 mL/kg per hour, which is equivalent to an 0899-9007/01/$20.00
420
Editorial Opinions
Nutrition Volume 17, Number 5, 2001
insulin infusion rate of at least 5 U/h. The rationale of this “high-dose” insulin infusion presumably is based on the results of meta-analyses showing that the benefit of GIK therapy after myocardial infarction is largely attributable to trials using the higher dosage. However, does this “high-dose” therapy recommended for use in medical patients also apply to the patient after trauma and during sepsis? Under physiologic conditions, plasma insulin concentrations rarely increase above 100 mU/L except transiently after a very high carbohydrate load. Low-dose insulin infusions at 2.6 U/h have been shown to produce insulin concentrations between 30 and 50 mU/L, whereas with insulin infusions at 10.6 U/h insulin plasma concentrations might exceed 200 mU/L.9 Thus, by infusing insulin at an hourly rate between 5 and 10 U, one would expect plasma insulin levels to remain below 200 mU/L, especially during states of increased insulin clearance, as seen during sepsis and after injury.10 According to the results of recent studies in surgical patients, therapeutical effects of insulin can be obtained only with insulin plasma levels higher than 200 mU/L. Seven days of insulin infusion (between 25 and 49 U/h), aiming at an average plasma insulin concentration of 600 mU/L, significantly reduced the mean donor-site healing time in severely burned patients.11 Administration of insulin producing plasma levels of 900 mU/L increased muscle and fractional wound protein synthesis after burn injury.12 Insulin therapy with measured plasma insulin concentrations above 200 mU/L has been demonstrated to blunt the catabolic response to injury.13 These findings lend support to the hypothesis that insulin requirements in critically ill patients are much higher than those in non-surgical subjects. This concept of high-dose insulin administration during critical illness raises metabolic concerns because the provision of excessive amounts of glucose given simultaneously to maintain normoglycemia has been shown to cause fatty infiltration of the liver and stimulate carbon-dioxide production. Another reason to avoid high plasma insulin concentrations was the observation that rising insulin plasma levels above 6000 mU/L increased intraoperative norepinephrine plasma concentrations, indicating a stimulated sympathoadrenal response to surgery.14 In addition, increased insulin plasma concentrations have been found to promote the formation of small hormone– antibody complexes that easily disintegrate and serve as insulin depots with the risk of late, uncontrolled hypoglycemia. Hypophosphatemia causing a shift in the oxygen dissociation curve, a decrease in the red-cell ATP content, and even hemolysis is another adverse effect of high-dose GIK treatment.15 Although there is convincing evidence that patients with myocardial infarction can benefit from GIK therapy, the role of GIK infusions in the treatment of inflammatory disease needs to be better defined. Mere correlations between the magnitude of insulin resistance or plasma substrate concentrations and indices of severity of illness should be interpreted carefully. At present, they certainly do not justify the hypothesis that GIK treatment by increasing insulin sensitivity improves the survival of septic patients, which, despite numerous efforts, have remained unchanged during the past 20 y. As long as the practical issues of GIK therapy in surgical and critically ill patients, including dose, duration, and target insulin plasma concentration, are not resolved, it might be worthwhile to explore alternative approaches to ameliorate the body’s sensitivity to endogenous insulin such as avoidance of long preoperative fasting periods,16 early postoperative mobilization,17 and optimal pain control.18
Thomas Schricker, MD, PhD Ralph Lattermann, MD Department of Anesthesia McGill University Montreal, Quebec, Canada
REFERENCES 1. Alberti KGMM, Thomas DJB. The management of diabetes during surgery. Br J Anaesth 1979;51:693 2. Das UN. Is insulin an antiinflammatory molecule? Nutrition 2001;17:385 3. Rassias AJ, Marrin CAS, Arruda J, et al. Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Anesth Analg 1999;88:1011 4. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999;67:352 5. Pomposelli JJ, Flores EA, Bistrian BR. Role of biochemical mediators in clinical nutrition and surgical metabolism. J Parent Enteral Nutr 1988;12:212 6. Black PR, Brooks DC, Bessey PQ, Wolfe RR, Wilmore DW. Mechanisms of insulin resistance following injury. Ann Surg 1982;196:420 7. Brandi LS, Frediani M, Oleggini M, et. al. Insulin resistance after surgery: normalization by insulin treatment. Clin Sci 1990;79:443 8. Shangraw RE, Jahoor F, Mioyoshi H, et. al. Differentiation between septic and postburn insulin resistance. Metab Clin Exp 1989;38:983 9. Sonksen P, Sonksen J. Insulin: understanding its action in health and disease. Br J Anaesth 2000;85:69 10. Dahn MS, Lange P, Mitchell RA, Lobdell K, Wilson R. Insulin production following injury and sepsis. J Trauma 1987;27:1031 11. Pierre EJ, Barrow RE, Hawkins HK. Effects of insulin on wound healing. J Trauma 1998;44:342 12. Sakurai M, Aarsland A, Herndon DN, et al. Stimulation of muscle protein synthesis by long-term insulin infusion in severely burned patients. Ann Surg 1995;222:283 13. Woolfson AMJ, Heatley RV, Allison SP. Insulin to inhibit protein catabolism after surgery. N Engl J Med 1979;300:14 14. Boldt J, Knothe C, Zickmann B, et al. Influence of different glucose–insulin– potassium regimes on glucose homeostasis and hormonal response in cardiac surgery patients. Anesth Analg 1993;76:233 15. Swaminathan R, Morgan DB, Ionescu M, Hill GL. Hypophosphatemia and its consequences in patients following open heart surgery. Anaesthesia 1978;33:601 16. Nygren J, Thorell A, Soop M. Perioperative insulin and glucose infusion maintains normal insulin sensitivity after surgery. Am J Physiol 1998;275:E140 17. Galassetti P, Coker RH, Lacy DB, Cherrington AD, Wasserman DH. Prior exercise increase hepatic glucose uptake during a glucose load. Am J Physiol 1999;276:E1022 18. Schricker T, Wykes L, Carli F. Epidural blockade improves substrate utilization after surgery. Am J Physiol 2000;279:E646
PII S0899-9007(01)00511-1
On the Delayed Effects of Exercise on Leptin: More Questions Than Answers Over the past two decades, the U.S. population has been experiencing an increase in the incidence of obesity and a decrease in daily physical activity. A concern to many in the health care field has been the accumulating evidence that lower levels of physical activity and physical fitness have been associated with increased risk of certain chronic diseases and premature death.1 A group of experts brought together by the Centers for Disease Control and Prevention formulated specific exercise recommendations for North Americans: “Every U.S. adult should accumulate 30 min or more of moderate intensity physical activity on most, preferably all, days of the week.”2 A year before, the ob gene product leptin was discovered,3 and several reports since have demonstrated a positive relationship between leptin and adipose-tissue mass.4 Little is known about the interactions of exercise and leptin, with almost no data available on the exercise effects on leptin in obesity and diabetes. Thus, future information obtained from exercise
Correspondence to: Marc C. Torjman, PhD, Department of Anesthesiology, Jefferson Medical College, Thomas Jefferson University, 111 S. 11th Street, Suite G-8490, Philadelphia, PA 19107, USA. E-mail: marc. [email protected]
Insulin: More Lessons to Be Learned Exactly 80 y after the first clinical use of insulin, our knowledge of this molecule continues to expand. Common understanding of the hormonal function of insulin is based on its two principal classes of action: 1) anabolic, i.e., favoring synthetic pathways by directing substrates into glycogen, protein, and lipid synthesis; and 2) anticatabolic, i.e., inhibiting catabolic processes such as glycogenolysis, proteolysis, and lipolysis. As the body’s key endocrine regulator, insulin ensures appropriate substrate supply in a highly controlled fashion. Once relative or absolute insulin deficiency occurs, this control is lost, and energy substrates flood the system, resulting in hyperglycemia, osmotic dehydration, muscle-protein wasting, and ketoacidosis. The use of combined infusions of glucose, insulin, and potassium (GIK) was introduced by Alberti in 1979 for the perioperative management of the diabetic patient.1 Subsequently, considerable attention has been given to the pharmacologic use of insulin as an anabolic agent in non-diabetic patients with the intention of ameliorating protein losses after trauma and surgery. The article by Das2 summarizes the antiinflammatory properties of insulin and reviews the potential of GIK administration as a novel therapeutic approach to inflammatory disease. Much data has accumulated showing that GIK administration can limit the ischemic myocardial damage after acute myocardial infarction as reflected in improved cardiac function and reduced morbidity and mortality. Therefore, the option of GIK treatment has been incorporated into the guidelines for the management of patients with acute myocardial infarction published by the American College of Cardiology and the American Heart Association in 1999. There is evidence that “cardiac cachexia” is associated with increased circulating levels of tumor necrosis factor-␣ (TNF-␣), mediated directly through stimulated TNF-␣ production by the failing heart or indirectly through endotoxinemia caused by increased bowel permeability, a consequence of augmented mesenteric venous pressure and intestinal edema. Because insulin inhibits TNF-␣ production in a dose-dependent manner and TNF-␣– induced myocardial depression can be ameliorated by the administration of TNF-␣ antibodies, the suppression of TNF-␣ production might be an underlying mechanism responsible for the favorable effects of insulin after acute myocardial infarction. The preserving influence of GIK infusions on the ischemic myocardium is not a new phenomenon. Originally proposed by SodiPallares in 1962, GIK administration has long been known to increase the intracellular cardiac glycogen content and enhance resistance to ischemia caused by enhanced glycolytic and anaerobic ATP production. GIK treatment also is accompanied by a decrease in circulating concentrations of free fatty acids, which per se exert deleterious effects on myocardial function and metabolism during ischemia. It is further hypothesized that the use of GIK would be effective in the treatment of a variety of other inflammatory diseases where cytokines play major pathogenic roles such as sepsis, intersititial pneumonitis, chronic inflammatory bowel disease, rheumatoid arthritis, systemic sklerosis, and Alzheimer’s disease. Further, the stimulatory effect of insulin on the synthesis of nitric oxide, a potent vasodilator and platelet antiaggregator, might be useful in the prevention of vascular thrombosis. Notwithstanding the presented evidence that insulin exhibits
Correspondence to: Thomas Schricker, MD, PhD, Department of Anesthesia, McGill University, Royal Victoria Hospital, 687 Pine Avenue West, Room S5.05, Montreal, QC, Canada H3A 1A1. E-mail: mbek@ musica.mcgill.ca Nutrition 17:419 – 425, 2001 ©Elsevier Science Inc., 2001. Printed in the United States. All rights reserved.
antiinflammatory properties, several issues raised in the article by Das deserve further comment, in particular the modifying role of glucose as an obligatory part of the GIK regimen, the effects of GIK infusions on stress-induced insulin resistance, and some practical aspects. Because insulin has to be administered with glucose to avoid hypoglycemia, it is difficult to discern the independent effects of insulin and feeding. Considering the significant interdependence between the body’s nutritional and immunologic statuses, this concern applies in particular to conclusions obtained from longterm investigations in diabetic and non-diabetic individuals. Although the improvement of myocardial function during experimental endotoxic shock by GIK treatment was unrelated to the prevailing plasma glucose levels, one must not forget the fact that there is a strong relationship between acute changes in plasma glucose homeostasis and the immune system. Acute hyperglycemia has been demonstrated to limit the phagocytic capacity of polymorphonuclear neutrophil leukocytes, impair granulocyte chemotaxis, and adversely affect the complement system. However, dysfunction of polymorphonuclear neutrophil leukocytes as seen in diabetic patients undergoing cardiac surgery can be partly reversed by aggressive glucose control.3 The clinical relevance of these findings is underscored by the observation that maintaining perioperative normoglycemia decreases the incidence of infectious complications in diabetic patients after cardiac surgery.4 Hyperglycemia, stimulated gluconeogenesis, and impaired glucose utilization and tolerance are typical, well-described features of the metabolic response to sepsis and tissue trauma. Traditionally, these abnormalities in glucose metabolism have been ascribed to the overproduction of the counterregulatory hormones cortisol, epinephrine, and norepinephrine. All of these hormones alter glucose homeostasis, directly or indirectly, by counteracting the action of insulin, leading to the impairment of tissue insulin sensitivity. More recently, attention has focused on various biochemical mediators (TNF-␣ and interleukines) that are released during the acute inflammatory response to stress. Considering the metabolic complexity of sepsis or septic syndromes, it is not surprising that the results of studies assessing the impact of cytokines on carbohydrate metabolism are not consistent. TNF-␣, for example, has been reported to induce hypoglycemia and hyperglycemia or exert no effect at all.5 Marked insulin resistance is present after routine surgical procedures, even without sepsis or other complications, and can persist up to 20 d thereafter. The entity, sites, and mechanisms of such insulin resistance have been widely investigated but still are the subject of controversy. For example, insulinmediated glucose disposal in injured patients has been demonstrated to be impaired only at maximally stimulating insulin concentrations, suggesting that responsiveness, i.e., maximal response, rather than sensitivity to the hormone is reduced.6 In contrast, other investigators have reported that postoperative glucose utilization and oxidation can be normalized provided that large-enough loads of glucose and insulin are administered.7 In septic patients, peripheral glucose uptake has been shown to be insensitive to insulin clamped at physiologic, plasma insulin levels. Insulin administration resulting in supraphysiologic plasma concentrations increased but did not normalize whole-body glucose disposal.8 Thus, whether insulin action can be restored to normalcy during sepsis by exogenous infusion of insulin is not known. Further, it is not known which insulin plasma levels are required to overcome insulin resistance and, more importantly, produce clinically significant effects during inflammatory disease. The GIK solution suggested by Das comprises 30% glucose with 50 U/L of insulin and 80 mmol/L of potassium infused at a rate faster than 1.5 mL/kg per hour, which is equivalent to an 0899-9007/01/$20.00
420
Editorial Opinions
Nutrition Volume 17, Number 5, 2001
insulin infusion rate of at least 5 U/h. The rationale of this “high-dose” insulin infusion presumably is based on the results of meta-analyses showing that the benefit of GIK therapy after myocardial infarction is largely attributable to trials using the higher dosage. However, does this “high-dose” therapy recommended for use in medical patients also apply to the patient after trauma and during sepsis? Under physiologic conditions, plasma insulin concentrations rarely increase above 100 mU/L except transiently after a very high carbohydrate load. Low-dose insulin infusions at 2.6 U/h have been shown to produce insulin concentrations between 30 and 50 mU/L, whereas with insulin infusions at 10.6 U/h insulin plasma concentrations might exceed 200 mU/L.9 Thus, by infusing insulin at an hourly rate between 5 and 10 U, one would expect plasma insulin levels to remain below 200 mU/L, especially during states of increased insulin clearance, as seen during sepsis and after injury.10 According to the results of recent studies in surgical patients, therapeutical effects of insulin can be obtained only with insulin plasma levels higher than 200 mU/L. Seven days of insulin infusion (between 25 and 49 U/h), aiming at an average plasma insulin concentration of 600 mU/L, significantly reduced the mean donor-site healing time in severely burned patients.11 Administration of insulin producing plasma levels of 900 mU/L increased muscle and fractional wound protein synthesis after burn injury.12 Insulin therapy with measured plasma insulin concentrations above 200 mU/L has been demonstrated to blunt the catabolic response to injury.13 These findings lend support to the hypothesis that insulin requirements in critically ill patients are much higher than those in non-surgical subjects. This concept of high-dose insulin administration during critical illness raises metabolic concerns because the provision of excessive amounts of glucose given simultaneously to maintain normoglycemia has been shown to cause fatty infiltration of the liver and stimulate carbon-dioxide production. Another reason to avoid high plasma insulin concentrations was the observation that rising insulin plasma levels above 6000 mU/L increased intraoperative norepinephrine plasma concentrations, indicating a stimulated sympathoadrenal response to surgery.14 In addition, increased insulin plasma concentrations have been found to promote the formation of small hormone– antibody complexes that easily disintegrate and serve as insulin depots with the risk of late, uncontrolled hypoglycemia. Hypophosphatemia causing a shift in the oxygen dissociation curve, a decrease in the red-cell ATP content, and even hemolysis is another adverse effect of high-dose GIK treatment.15 Although there is convincing evidence that patients with myocardial infarction can benefit from GIK therapy, the role of GIK infusions in the treatment of inflammatory disease needs to be better defined. Mere correlations between the magnitude of insulin resistance or plasma substrate concentrations and indices of severity of illness should be interpreted carefully. At present, they certainly do not justify the hypothesis that GIK treatment by increasing insulin sensitivity improves the survival of septic patients, which, despite numerous efforts, have remained unchanged during the past 20 y. As long as the practical issues of GIK therapy in surgical and critically ill patients, including dose, duration, and target insulin plasma concentration, are not resolved, it might be worthwhile to explore alternative approaches to ameliorate the body’s sensitivity to endogenous insulin such as avoidance of long preoperative fasting periods,16 early postoperative mobilization,17 and optimal pain control.18
Thomas Schricker, MD, PhD Ralph Lattermann, MD Department of Anesthesia McGill University Montreal, Quebec, Canada
REFERENCES 1. Alberti KGMM, Thomas DJB. The management of diabetes during surgery. Br J Anaesth 1979;51:693 2. Das UN. Is insulin an antiinflammatory molecule? Nutrition 2001;17:385 3. Rassias AJ, Marrin CAS, Arruda J, et al. Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Anesth Analg 1999;88:1011 4. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999;67:352 5. Pomposelli JJ, Flores EA, Bistrian BR. Role of biochemical mediators in clinical nutrition and surgical metabolism. J Parent Enteral Nutr 1988;12:212 6. Black PR, Brooks DC, Bessey PQ, Wolfe RR, Wilmore DW. Mechanisms of insulin resistance following injury. Ann Surg 1982;196:420 7. Brandi LS, Frediani M, Oleggini M, et. al. Insulin resistance after surgery: normalization by insulin treatment. Clin Sci 1990;79:443 8. Shangraw RE, Jahoor F, Mioyoshi H, et. al. Differentiation between septic and postburn insulin resistance. Metab Clin Exp 1989;38:983 9. Sonksen P, Sonksen J. Insulin: understanding its action in health and disease. Br J Anaesth 2000;85:69 10. Dahn MS, Lange P, Mitchell RA, Lobdell K, Wilson R. Insulin production following injury and sepsis. J Trauma 1987;27:1031 11. Pierre EJ, Barrow RE, Hawkins HK. Effects of insulin on wound healing. J Trauma 1998;44:342 12. Sakurai M, Aarsland A, Herndon DN, et al. Stimulation of muscle protein synthesis by long-term insulin infusion in severely burned patients. Ann Surg 1995;222:283 13. Woolfson AMJ, Heatley RV, Allison SP. Insulin to inhibit protein catabolism after surgery. N Engl J Med 1979;300:14 14. Boldt J, Knothe C, Zickmann B, et al. Influence of different glucose–insulin– potassium regimes on glucose homeostasis and hormonal response in cardiac surgery patients. Anesth Analg 1993;76:233 15. Swaminathan R, Morgan DB, Ionescu M, Hill GL. Hypophosphatemia and its consequences in patients following open heart surgery. Anaesthesia 1978;33:601 16. Nygren J, Thorell A, Soop M. Perioperative insulin and glucose infusion maintains normal insulin sensitivity after surgery. Am J Physiol 1998;275:E140 17. Galassetti P, Coker RH, Lacy DB, Cherrington AD, Wasserman DH. Prior exercise increase hepatic glucose uptake during a glucose load. Am J Physiol 1999;276:E1022 18. Schricker T, Wykes L, Carli F. Epidural blockade improves substrate utilization after surgery. Am J Physiol 2000;279:E646
PII S0899-9007(01)00511-1
On the Delayed Effects of Exercise on Leptin: More Questions Than Answers Over the past two decades, the U.S. population has been experiencing an increase in the incidence of obesity and a decrease in daily physical activity. A concern to many in the health care field has been the accumulating evidence that lower levels of physical activity and physical fitness have been associated with increased risk of certain chronic diseases and premature death.1 A group of experts brought together by the Centers for Disease Control and Prevention formulated specific exercise recommendations for North Americans: “Every U.S. adult should accumulate 30 min or more of moderate intensity physical activity on most, preferably all, days of the week.”2 A year before, the ob gene product leptin was discovered,3 and several reports since have demonstrated a positive relationship between leptin and adipose-tissue mass.4 Little is known about the interactions of exercise and leptin, with almost no data available on the exercise effects on leptin in obesity and diabetes. Thus, future information obtained from exercise
Correspondence to: Marc C. Torjman, PhD, Department of Anesthesiology, Jefferson Medical College, Thomas Jefferson University, 111 S. 11th Street, Suite G-8490, Philadelphia, PA 19107, USA. E-mail: marc. [email protected]