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Patient Demographics and Injury Severity Score*
Patient Demographics and Injury Severity Score*
1.
Garlick  PJFern  MPreedy  VR The effect of insulin infusion and food intake on muscle protein synthesis in postabsorptive rats. Biochem J. 1983;210669- 676
2.
Fulks  RMGoldberg  AL Effects on insulin, glucose, and amino acids on protein turnover in rat diaphragm. J Biol Chem. 1975;250290- 298
3.
Jefferson  LSLi  JBRannels  SR Regulation by insulin of amino acid release and protein turnover in the perfused rat hemicorpus. J Biol Chem. 1977;2521476- 1483
4.
Lundholm  KSchers  T Determination in vitro of the rate of protein synthesis and degradation in human-skeletal-muscle tissue. Eur J Biochem. 1975;601- 6Article
5.
Louard  RJFryburg  DAGelfand  RABarrett  EJ Insulin sensitivity of protein and glucose metabolism in human forearm skeletal muscle. J Clin Invest. 1992;902348- 2354Article
6.
Gelfand  RABarrett  EJ Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest. 1987;801- 6Article
7.
Biolo  GFleming  RYDWolfe  RR Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest. 1995;95811- 819Article
8.
Newman  EHeslin  MJWolf  RFPisters  PWTBrennan  MF The effect of systemic hyperinsulinemia with concomitant amino acid infusion on skeletal muscle protein turnover in the human forearm. Metabolism. 1994;4370- 78Article
9.
Fukagawa  NKMinaker  KLRowe  JW  et al.  Insulin-mediated reduction of whole body protein breakdown. J Clin Invest. 1985;762306- 2311Article
10.
Clements  RPinson  TBorghesi  LLaws  HLong  C Nitrogen balance is achieved and myofibrillar protein catabolism is inhibited by insulin and total parenteral nutrition in trauma patients. Surg Forum. 1996;47147- 148
11.
Long  CLSchaffel  NGeiger  JWSchiller  WRBlakemore  WS Metabolic response to injury and illness: estimation of energy and protein needs for indirect calorimetry and nitrogen balance. JPEN J Parenter Enteral Nutr. 1979;3452- 456Article
12.
Abumrad  NNJefferson  LSRannels  SRWilliams  PECherrington  ADLacy  WW Role of insulin in the regulation of leucine kinetics in the conscious dog. J Clin Invest. 1982;701031- 1041Article
13.
Jefferson  LS Role of insulin in the regulation of protein synthesis. Diabetes. 1980;29487- 495Article
14.
Flakoll  PJKulayalt  MFrexes-Steed  M  et al.  Amino acids augment insulin's suppression of whole body proteolysis. Am J Physiol. 1989;257E839- E847
15.
Valarini  RSousa  MFKalil  RAbumrad  NNRiella  MC Anabolic effects of insulin and amino acids in promoting nitrogen accretion in postoperative patients. JPEN J Parenter Enteral Nutr. 1994;18214- 218Article
16.
Inculet  RIFinley  RJDuff  JH  et al.  Insulin decreases muscle protein loss after operative trauma in man. Surgery. 1986;99752- 758
17.
McMenamy  RHShoemaker  WCRichmond  JEElwyn  D Uptake and metabolism of amino acids by the dog liver perfused in situ. Am J Physiol. 1962;202407- 414
18.
Rose  WC The amino acid requirements of adult men. Nutr Abstr Rev. 1957;27631
19.
Cerra  FBShronts  EPKonstantinides  NN  et al.  Enteral feeding in sepsi: a prospective, randomized, double-blind trial. Surgery. 1985;98632- 638
20.
Shronts  EPKonstantinides  NNTeasley  KMLysne  JKonstantinides  FNCerra  FB Modified amino acid support in metabolic stree: enteral vs parenteral. Nutr Suppl Serv. 1987;712- 17
21.
Watters  JMKirkpatrick  SMNorris  SBShamji  FMWells  GA Immediate postoperative enteral feeding results in impaired respiratory mechanics and decreased mobility. Ann Surg. 1997;226369- 380Article
Original Article
March 1999

Insulin's Anabolic Effect Is Influenced by Route of Administration of Nutrients

Author Affiliations

From the Departments of Surgery, Carraway Methodist Medical Center and the Norwood Clinic Inc, Birmingham, Ala.

Arch Surg. 1999;134(3):274-277. doi:10.1001/archsurg.134.3.274
Abstract

Objective  To determine if the anabolic effects of intravenous insulin on protein kinetics could be exploited in the enterally fed trauma victim.

Design  Randomized, crossover control protocol.

Setting  Level I trauma center.

Patients  Ten trauma patients with an Injury Severity Score higher than 20. Exclusion criteria included diabetes mellitus, pregnancy, steroid use, and aged younger than 18 years or older than 65 years.

Interventions  Within the first 24 hours of admission to the intensive care unit, each patient had a transpyloric feeding tube inserted radiographically. Enteral nutrition was provided with a protein supplement (Ensure, Ross Laboratories, Columbus, Ohio) and Promod, supplemented with protein powder to supply 1.5 g/kg per day of protein and 156.9 kJ/kg per day. Intravenous insulin was provided at 0.043 U/kg per hour beginning on the second or fourth day.

Main Outcome Measures  Urinary nitrogen balance and 3-methylhistidine excretion rates were measured at the end of the third and fifth days. Plasma glucose, insulin, and C-peptide levels were obtained at these same times.

Results  Urinary nitrogen balance was not significantly different with or without the administration of insulin (−4.58±50.1 mg/kg per day vs −9.38±50.9 mg/kg per day, respectively). 3-Methylhistidine excretion rates did not change significantly with or without the administration of insulin (5.77±0.67 µmol/kg per day vs 6.15±0.43 µmol/kg per day, respectively). Serum insulin levels did not differ significantly when exogenous infusions were added (57.8±17.9 µU/mL vs 82.1±44.9 µU/mL), but serum C-peptide levels did decrease significantly when exogenous insulin was added (5.11±3.2 µU/mL vs 10.28±3.5 µU/mL; P=.04). Serum glucose levels decreased significantly when insulin was administered (5.8 ± 0.4 mmol/L [104.6±7.2 mg/dL] vs 7.7 ± 0.4 mmol/L [138.1±7.4 mg/dL]; P=.004).

Conclusion  The anabolic effect of intravenous insulin on protein kinetics is not evident when nutrition is provided enterally in the trauma victim.

EARLY NUTRITIONAL support is an integral part of the care of the acutely injured patient. Enteral feeding is the preferred method of providing nutrition to the victims of major trauma because it maintains the integrity of the gut mucosal barrier by directly providing the enterocyte with necessary nutrients. Equally important, early nutritional support provides the necessary components for wound healing and for ameliorating muscle wasting during convalescence. Providing more protein to the catabolic patient to attain a more favorable nitrogen balance has its advantages. However, there should be concern as to the effect of high protein intake on renal function. Therefore, until the body becomes more efficient in the retention of protein during the convalescent period, the use of anabolic hormones should be contemplated to stimulate nitrogen assimilation.

Insulin has been shown to increase skeletal muscle protein synthesis and to decrease it degradation in numerous in vitro and in vivo studies when amino acids are provided intravenously,13 but to our knowledge, no studies have been published regarding its effect when nutrition is provided enterally. Using human skeletal muscle in vitro, Lundholm and Schers4 demonstrated a decrease in protein degradation and an increase in protein synthesis. Human in vivo studies across a muscle bed have produced conflicting results58 Fukagawa et al9 showed a reduction in proteolysis when studying insulin's effect on whole-body protein kinetics. We have previously demonstrated a reduction in myofibrillar protein breakdown and an increase in protein synthesis leading to positive nitrogen balance as a result of infusing insulin and total parenteral nutrition (TPN) in the trauma victim.10 To date we are not aware of any reported studies of the effect of insulin on protein synthesis and breakdown from nutrients provided by the preferred enteral route in the trauma victim. Knowing insulin's anabolic effect, and to determine if the benefit of enteral nutrition and hormonal manipulation with insulin could be combined, we investigated the effect of intravenous insulin on nitrogen balance and muscle protein breakdown in the enterally fed trauma victim.

PATIENTS, MATERIALS, AND METHODS

After obtaining informed consent, 10 victims of blunt trauma were enrolled in this randomized, crossover controlled protocol that had been approved by our institutional review board. Patients aged 18 to 65 years were eligible, and diabetes mellitus, pregnancy, steroid administration, or an Injury Severity Score (ISS) of less than 20 were exclusion criteria. Each patient underwent standard evaluation and treatment at our level I trauma center and was admitted to the intensive care unit (ICU). Within 24 hours of admission to the ICU, each patient was administered enteral nutrition through a radiographically placed transpyloric feeding tube. Nutrition consisted of Ensure (Ross Laboratories, Columbus, Ohio) supplemented with Promod protein powder (Ross Labortories) to provide 1.5 g/kg per day of protein and 156.9 kJ/kg per day. After 1 day of incrementally increasing the rate to the desired level, each patient was maintained at this rate for 4 additional days. Beginning on either the second or fourth day of the protocol, each patient was given intravenous regular insulin at 0.043 U/kg per hour. After 48 hours of insulin infusion, the patient was crossed over into the other limb of the protocol, either to receive insulin or to discontinue its use.

Twenty-four–hour urine collections from the third and fifth days of the protocol were analyzed for total urinary nitrogen levels using a nitrogen analyzer (Antek Nitrogen Analyzer; Antek, Houston, Tex) and for 3-methylhistidine (3-MH) excretion using an amino acid analyzer (Beckman Automatic Amino Acid Analyzer; Beckman Instruments, Palo Alto, Calif). Serum samples were analyzed for glucose using the glucose oxidase method, and serum insulin and C-peptide levels were determined by Labcorp (Birmingham, Ala) after each 48-hour study period. Results were analyzed using the paired Student t test and are expressed as mean±SEM. Significance was determined at P=.05.

RESULTS

The demographics and injuries of the 10 patients in this study are given in Table 1. There were 6 male and 4 female patients, with an average age of 31.4 years (age range, 21-64 years). The mean ISS was 33.3 (range, 27-50). The mean weight of this group was 73.0 kg (range, 61-103 kg), and height averaged 176 cm (range, 160-185 cm). There was no mortality during the study period and no morbidity (diarrhea or hypoglycemia) related to the protocol.

Urinary nitrogen balance was not significantly different whether or not insulin was administered (−4.58±50.1 mg/kg per day vs −9.38±50.9 mg/kg per day, respectively). Similarly, urinary 3-MH excretion was not significantly different with or without insulin infusion (5.77±0.67 µmol/kg per day vs 6.15±0.43 µmol/kg per day, respectively). Serum glucose was significantly lower when insulin was administered (5.8±0.4 mmol/L [104.6±7.2 mg/dL] vs 7.7±0.4 mmol/L [138.1±7.4 mg/dL]; P=.004). Serum insulin levels did not differ significantly when exogenous infusions were added (415±128 pmol/L vs 589±322 pmol/L), but serum C-peptide levels did decrease significantly when exogenous insulin was added (5.11±3.2 µU/mL vs 10.28±3.5 µU/mL; P=.04). Serum glucose values decreased significantly when insulin was administered (5.8±0.4 mmol/L [104.6±7.2 mg/dL] vs 7.7±0.4 mmol/L [138.1±7.4 mg/dL]; P=.004).

COMMENT

Following injury, there are hypercatabolic and hypermetabolic responses that may last for days depending on the severity of the traumatic episode.11 The negative nitrogen balance due to protein catabolism seen in patients who have suffered severe trauma is detrimental in several ways, including longer recovery time, increased morbidity and mortality, decreased wound healing, and inhibition of the immune response. Nutritional intervention during convalescence has proved beneficial in decreasing muscle wasting. Although the provision of energy intake and nitrogen does have an impact on improving nitrogen balance, a positive nitrogen balance is difficult, if not impossible, to attain at the peak of the catabolic response. The catabolic response to injury is thought to be mediated by the increase in catacholamines, cortisol, and glucagon values and by the increased resistance to insulin.

That insulin plays a major role in protein metabolism is well known. Numerous in vitro studies have shown that insulin inhibits protein breakdown and increases protein synthesis.2,12,13 Fukagawa et al9 have demonstrated insulin's ability to decrease protein breakdown in a dose-dependent manner in vivo. The availability of amino acid substrates is also vital for maximization of the anabolic effect of insulin to be maximized.14 In patients who had undergone a major operative procedure, Valarini et al15 showed that insulin further improved the positive nitrogen balance achieved with a TPN solution that contained 0.25 g/kg of nitrogen and an energy-nitrogen ratio of 150:1 but not with 0.5 g/kg of nitrogen and an energy-nitrogen ratio of 75:1, suggesting that the effect of amino acids on the improvement of nitrogen balance is saturable. Inculet et al,16 using an isolated forearm skeletal muscle model, showed a decrease in nitrogen balance and 3-MH excretion in patients who were given insulin and TPN after surgery. We have recently demonstrated that intravenous insulin and TPN produced a positive nitrogen balance, decreased 3-MH excretion, and facilitated whole-body protein synthesis within 5 days of major trauma.10 These findings prompted us to perform the present protocol to determine if the anabolic effect of insulin could be combined with the advantages of enteral nutrition.

In our study, intravenous insulin produced no change in either urinary nitrogen balance or the excretion of 3-MH when given as a supplement to enteral nutrition. A possible explanation for a lack of effect is that the amino acids underwent modification by the liver before reaching the muscles. Some of the amino acids may have been incorporated into acute-phase reactants whose synthesis is increased after trauma. The anabolic effect of insulin has been previously evaluated mainly using an intravenous amino acid infusion model. It may be assumed that the provision of amino acids by either route would be equivalent in terms of protein synthesis. However, amino acids provided by the enteral route are first processed through the liver where it is known that this organ temporarily stores a part of the ingested amino acids as proteins, modifies the amino acid flux to muscle, and deaminates and oxidizes others as shown by McMenamy et al17 with use of a dog model. They showed a wide range in the portion of added amino acids taken up by the liver, from 90% for tryptophan and phenylalanine to approximately 20% for threonine, valine, leucine, and isoleucine. This remodeling of amino acids presented to the muscle might negate the effect of insulin that requires or favors a more appropriate blend of amino acids for protein synthesis as is present in TPN based on requirements as proposed by Rose.18 Increasing the amount of protein administered in the tube feedings to a level that could overcome the hepatic effect would likely produce undesirable side effects such as diarrhea, azotemia, and impaired renal function.

The intent of nitrogen losses should be reflected during the first 2 days of the protocol since the target rate of the enteral infusion was achieved within the first 24 hours. There should be no question that the third and fifth days are comparable to a steady nutritional state. This short equilibration time is supported by Cerra et al19 who showed urinary nitrogen losses on a constant elemental feeding to be 11.4 g of nitrogen on day 1, 12.2 g of nitrogen on day 3, and 10.6 g of nitrogen on day 7. Shronts et al20 showed nitrogen losses on a standard elemental infusion formula to be 16.0 g of nitrogen on day 1 and 18.2 g of nitrogen on day 3. On a modified enteral formula, losses were 15.8 g of nitrogen on day 1 and 18.9 g of nitrogen on day 3. Additionally, Watters et al21 began full-strength feeding via jejunostomy tubes within 6 hours of major operations and increased to the target rate of either 125% of preoperative energy expenditure or 2500 mL/d (whichever was the lesser) on the second postoperative day. Urine losses were 8.5 g of nitrogen on day 1, 8.9 g of nitrogen on day 2, and 9.3 g of nitrogen on day 3. These data also support the fact that a steady state of nitrogen dynamics is attained by day 2 and certainly by day 3 of this randomized, blinded study even when bypassing the small gastric component of digestion.

In conclusion, the route of administration of nutrition does affect insulin's anabolic effect. Although we had previously demonstrated insulin's ability to produce positive nitrogen balance, increase protein synthesis, and decrease protein breakdown using TPN, this effect could not be achieved with enteral feeding. We believe this is owing to the modification and use of amino acid substrates by the liver before they can reach the skeletal muscle tissue.

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Article Information

Presented as a poster at the Southeastern Surgical Congress, Atlanta, Ga, February 4, 1998.

Reprints: Ronald H. Clements, MD, Surgical Education, 1600 Carraway Blvd, Birmingham, AL 35234.

References
1.
Garlick  PJFern  MPreedy  VR The effect of insulin infusion and food intake on muscle protein synthesis in postabsorptive rats. Biochem J. 1983;210669- 676
2.
Fulks  RMGoldberg  AL Effects on insulin, glucose, and amino acids on protein turnover in rat diaphragm. J Biol Chem. 1975;250290- 298
3.
Jefferson  LSLi  JBRannels  SR Regulation by insulin of amino acid release and protein turnover in the perfused rat hemicorpus. J Biol Chem. 1977;2521476- 1483
4.
Lundholm  KSchers  T Determination in vitro of the rate of protein synthesis and degradation in human-skeletal-muscle tissue. Eur J Biochem. 1975;601- 6Article
5.
Louard  RJFryburg  DAGelfand  RABarrett  EJ Insulin sensitivity of protein and glucose metabolism in human forearm skeletal muscle. J Clin Invest. 1992;902348- 2354Article
6.
Gelfand  RABarrett  EJ Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest. 1987;801- 6Article
7.
Biolo  GFleming  RYDWolfe  RR Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest. 1995;95811- 819Article
8.
Newman  EHeslin  MJWolf  RFPisters  PWTBrennan  MF The effect of systemic hyperinsulinemia with concomitant amino acid infusion on skeletal muscle protein turnover in the human forearm. Metabolism. 1994;4370- 78Article
9.
Fukagawa  NKMinaker  KLRowe  JW  et al.  Insulin-mediated reduction of whole body protein breakdown. J Clin Invest. 1985;762306- 2311Article
10.
Clements  RPinson  TBorghesi  LLaws  HLong  C Nitrogen balance is achieved and myofibrillar protein catabolism is inhibited by insulin and total parenteral nutrition in trauma patients. Surg Forum. 1996;47147- 148
11.
Long  CLSchaffel  NGeiger  JWSchiller  WRBlakemore  WS Metabolic response to injury and illness: estimation of energy and protein needs for indirect calorimetry and nitrogen balance. JPEN J Parenter Enteral Nutr. 1979;3452- 456Article
12.
Abumrad  NNJefferson  LSRannels  SRWilliams  PECherrington  ADLacy  WW Role of insulin in the regulation of leucine kinetics in the conscious dog. J Clin Invest. 1982;701031- 1041Article
13.
Jefferson  LS Role of insulin in the regulation of protein synthesis. Diabetes. 1980;29487- 495Article
14.
Flakoll  PJKulayalt  MFrexes-Steed  M  et al.  Amino acids augment insulin's suppression of whole body proteolysis. Am J Physiol. 1989;257E839- E847
15.
Valarini  RSousa  MFKalil  RAbumrad  NNRiella  MC Anabolic effects of insulin and amino acids in promoting nitrogen accretion in postoperative patients. JPEN J Parenter Enteral Nutr. 1994;18214- 218Article
16.
Inculet  RIFinley  RJDuff  JH  et al.  Insulin decreases muscle protein loss after operative trauma in man. Surgery. 1986;99752- 758
17.
McMenamy  RHShoemaker  WCRichmond  JEElwyn  D Uptake and metabolism of amino acids by the dog liver perfused in situ. Am J Physiol. 1962;202407- 414
18.
Rose  WC The amino acid requirements of adult men. Nutr Abstr Rev. 1957;27631
19.
Cerra  FBShronts  EPKonstantinides  NN  et al.  Enteral feeding in sepsi: a prospective, randomized, double-blind trial. Surgery. 1985;98632- 638
20.
Shronts  EPKonstantinides  NNTeasley  KMLysne  JKonstantinides  FNCerra  FB Modified amino acid support in metabolic stree: enteral vs parenteral. Nutr Suppl Serv. 1987;712- 17
21.
Watters  JMKirkpatrick  SMNorris  SBShamji  FMWells  GA Immediate postoperative enteral feeding results in impaired respiratory mechanics and decreased mobility. Ann Surg. 1997;226369- 380Article
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