After serious injuries, more than 80% of the human genome is significantly changed. This genomic storm is seen not only in the immune system, but also in basic metabolism causing metabolic rates to double. Most metabolically active organs (liver, cardiac and skeletal muscles, fat) change the molecules that they normally prefer to support these new requirements. The liver makes more glucose for the brain and muscles switch to free fatty acids as their main energy substrate. Also, proteins in skeletal muscle break down releasing amino acids into the bloodstream for the liver to convert to glucose and urea, a waste product. A major feature of these metabolic changes is insulin resistance, which supports unchecked muscle catabolism that is unresponsive to nutritional supplements. When this altered metabolism lasts for weeks or months, morbidity and mortality rates rise. It is critical that we understand what drives this altered metabolism and learn how to control it to reduce morbidity and death rates after serious injury.
Read MoreWhat is injury-related insulin resistance?
Depiction of insulin and leukocytes inside the blood vessel
Injury-related insulin resistance is a form of “stress diabetes” that presents as a relative deficiency in the effectiveness of insulin after serious injury. For critically-injured patients demonstrating persistent injury-related insulin resistance, blood glucose is elevated above normal levels (<100 mg/dl). Patients require treatment for their injury-related insulin resistance when their glucose levels persistently exceed an acceptable level (>150 mg/dl). In these cases more insulin than might be expected is needed to reduce the glucose to acceptable levels (<150 mg/dl).
In those patients in whom insulin administration alone is not effective to bring the glucose levels to acceptable levels, any glucose infusions given to the patient for nutritional support must also be reduced. In patients with clinically significant insulin resistance, the maximum rate of glucose infusion is reduced below 5-7 mg/kg/min, which is nearly half of the normally tolerated rate. If the patient’s caloric intake from glucose must be reduced to these levels, it is more difficult to reach the patient’s daily caloric requirement.
High blood glucose levels (>150 mg/dl) in injured patients should be avoided because they are associated with increased rates of infections and higher morbidity and mortality. Extremely high glucose levels (>500 mg/dl) can lead to diabetic coma, which lowers the patient’s consciousness, life-threatening complications, and even death.
What are the physiological features of insulin resistance?
Insulin works by binding to an insulin receptor that is present on many cells in the body. Insulin can be administered like a drug (exogenous insulin) and it also occurs as a natural hormone that is synthesized and secreted by the pancreas (endogenous insulin). Both endogenous and exogenous insulin interact with receptors that are specific for insulin in the liver, muscle, and fat. Insulin binding to its receptor initiates a second messenger (tyrosine phosphorylation) of insulin receptor substrates (IRS). This second message effect results in insulin-dependent glucose uptake into cells.
Insulin resistance is a condition that reduces insulin-dependent glucose uptake into muscle, fat, other peripheral tissues and results in elevated blood glucose levels known as hyperglycemia. In addition, insulin binding to its receptors in the liver normally suppresses the synthesis and secretion of new glucose into the bloodstream (gluconeogenesis). Insulin resistance enhances gluconeogenesis by the liver further contributing to more significant hyperglycemia. Of these two independent effects, the enhancement of gluconegenesis is likely the most important contributor to the post-injury hyperglycemia because the glucose uptake in peripheral tissues is normal or above normal even in injured patients with insulin resistance.
In addition to the hyperglycemia, even more serious consequences are created. Insulin resistance reduces not only IRS function, but it also reduces protein kinase B (PKB, also known as Akt) function. Downstream consequences of these reductions lead to breakdown of most muscle proteins (muscle catabolism), which release amino acids into the blood. Also, reductions in these functions lead to serious metabolic dysregulation of mitochondrial function disrupting energy balance in muscle and fat. Both muscle catabolism and mitochondrial dysfunction weaken muscles including the diaphragm, which is the principal muscle that enables breathing. These more dire consequences can be lethal to patients who require prolonged mechanical ventilation. We must understand what drives these consequences and learn how to attenuate them to the benefit of our critically-injured patients.
Can insulin resistance be overcome by nutrition alone?
Much of what we know today has resulted from studies that focused on the biochemistry of proteins (particularly enzymes) and small molecules before genomic techniques became available. It was thought that muscle catabolism was preventable by nutritional supplementation with nutrients including carbohydrates (glucose), proteins (AA, amino acids), and triglycerides (FFA, free fatty acids). The theory was that muscle wasting resulted from altered biochemistry and that there were imbalances among these three nutrient groups. Particularly, proteins are composed of amino acids humans can synthesize (non-essential AA) but also amino acids the body could not synthesize (essential AA). However, most proteins require both essential and non-essential AA. It was possible that metabolic abnormalities post-injury were simply the result of inadequate amounts of essential AA (e.g. tyrosine, proline, and arginine) that must be supplied exogenously. After many decades of biochemical studies, nutritional supplementation was shown not to reverse muscle catabolism. The added weight attributed to nutritional therapy was extra- and intracellular water and electrolytes and not retained lean muscle mass. Whatever drives the muscle catabolism had persisted and its effect had not been reduced by nutritional supplementation alone.
Can insulin resistance be treated with hormones and biologicals?
There have been multiple hormones and biological compounds studied in severely injured patients with the intention to reduce metabolic rates and muscle catabolism. Both anabolic hormones (recombinant human growth hormone (rHGH), insulin, insulin-like growth factor (IGF-1), insulin-like growth factor binding protein (IGFBP-3), oxandrolone, or testosterone) and catecholamine antagonists (propranolol, metoprolol) have been studied.
Studies with the anabolic hormones (rHGH, insulin, IGF-1, and IGFBP-3) have shown multiple beneficial effects when used during the initial hospitalization after injury, but have not shown complete correction of muscle catabolism. There were significant side effects of hyperglycemia with rHGH and severe hypoglycemia and other side effects with insulin and IGF-1 that were improved by adding IGFBP-3. Oxandrolone and testosterone have been shown to be reduce muscle catabolism but both hormones are androgenic steroids that stimulate or control the development and maintenance of male characteristics, which can be particularly problematic when treating pre-puberty males and females of any age.
After serious injuries, the levels of catecholamines rise as much as ten-fold and drive catecholamine effects (e.g. hyperdynamic circulation, elevated metabolic rate, and muscle catabolism). atecholamine antagonists (e.g. propranolol and metoprolol) have been shown to not only produce blockade of the beta adrenergic receptors but also counteract raised catecholamine effects. Ongoing studies in both children and adults, when used post-hospital discharge after burn injury, have shown promising results to reduce catecholamine effects.
Other promising compounds have recently been identified to effectively eliminate elevated metabolic rates and muscle catabolism in animal studies. One of these compounds, Bendavia®, which is in multiple human trials to reduce the effects of ischemia-reperfusion injury, is very promising but has not been studied yet in severely-injured patients.
Do genomics support insulin resistance?
There is encouraging evidence that changes in protein structure and function known from previous biochemical studies may, in part, be driven and supported by genomic changes. These data have arisen from the Glue Grant studies and their analysis is ongoing. What is known is that approximately 10% of the human genome (~ 3,000 genes) is significantly changed at the 1.5 fold level in the peripheral tissues of the skeletal muscle and peripheral fat of patients after serious burn injury. Many of these highly regulated genes are involved in metabolic pathways and offer the possibility that altered metabolism can be attributed to or at least supported by genomic changes. It is possible that future therapies incorporating the genomic information can be directed toward correcting metabolism to a more normal, pre-injury state and thereby correcting glucose uptake, muscle catabolism, and mitochondrial dysfunction that are seen after burn injury.
Relevant publications
Yo K, Yu YM, Zhao G, Bonab AA, Aikawa N, Tompkins RG, et al. Brown adipose tissue and its modulation by a mitochondria-targeted peptide in rat burn injury-induced hypermetabolism. Am J Physiol Endocrinol Metab. 2013 Feb 15;304(4):E331-41. PubMed PMID: 23169784; PubMed Central PMCID: PMC3566510
Carter EA, Bonab AA, Goverman J, Paul K, Yerxa J, Tompkins RG, et al. Evaluation of the antioxidant peptide SS31 for treatment of burn-induced insulin resistance. Int J Mol Med. 2011 Oct;28(4):589-94. PubMed PMID: 21805045; PubMed Central PMCID: PMC4090514
Padfield KE, Astrakas LG, Zhang Q, Gopalan S, Dai G, Mindrinos MN, et al. Burn injury causes mitochondrial dysfunction in skeletal muscle. Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5368-73. PubMed PMID: 15809440; PubMed Central PMCID: PMC556259
Herndon DN, Tompkins RG. Support of the metabolic response to burn injury. Lancet. 2004 Jun 5;363(9424):1895-902. PubMed PMID: 15183630
Chen CL, Fei Z, Carter EA, Lu XM, Hu RH, Young VR, et al. Metabolic fate of extrahepatic arginine in liver after burn injury. Metabolism. 2003 Oct;52(10):1232-9. PubMed PMID: 14564672
Sugita H, Kaneki M, Tokunaga E, Sugita M, Koike C, Yasuhara S, et al. Inducible nitric oxide synthase plays a role in LPS-induced hyperglycemia and insulin resistance. Am J Physiol Endocrinol Metab. 2002 Feb;282(2):E386-94. PubMed PMID: 11788371
Yu YM, Ryan CM, Fei ZW, Lu XM, Castillo L, Schultz JT, et al. Plasma L-5-oxoproline kinetics and whole blood glutathione synthesis rates in severely burned adult humans. Am J Physiol Endocrinol Metab. 2002 Feb;282(2):E247-58. PubMed PMID: 11788355
Yu YM, Ryan CM, Castillo L, Lu XM, Beaumier L, Tompkins RG, et al. Arginine and ornithine kinetics in severely burned patients: increased rate of arginine disposal. Am J Physiol Endocrinol Metab. 2001 Mar;280(3):E509 -17. PubMed PMID: 11171607
Yu YM, Tompkins RG, Ryan CM, Young VR. The metabolic basis of the increase of the increase in energy expenditure in severely burned patients. JPEN J Parenter Enteral Nutr. 1999 May-Jun;23(3):160-8. PubMed PMID:10338224
Contacts
| Ronald Tompkins, M.D., Sc.D. | Wenzhong Xiao, Ph.D. | Morris White, Ph.D. | David Herndon, M.D. |
| 617-726-3447 | 617-724-7261 | 409-770-6733 |
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