Possible Therapeutic Effects of Growth Hormone on Wound Healing in the Diabetic Patient

Abstract

Growth factors are increasingly investigated for their role in wound healing. The authors present evidence from human and animal studies suggesting that growth hormone induces a positive nitrogen balance, enhances connective-tissue synthesis, and increases lean body mass. The physiology of diabetes and wound healing is reviewed in the context of how growth hormone therapy could benefit this patient population.

Diabetes mellitus, a condition affecting millions of Americans, has profound effects on metabolic pathways throughout the body. Lack of insulin and a relative increase in glucagon are characteristics of the diabetic state. Diabetes also has substantial catabolic effects on skeletal muscle, thereby impairing wound healing. The altered metabolism and protein dynamics are of great importance in the treatment of diabetic patients after surgery. Growth hormone, which creates a positive nitrogen balance, has been shown to have anabolic effects on skeletal muscle and increases connective-tissue synthesis. The authors suggest that administration of growth hormone to these compromised patients will enhance muscle healing and shorten the postoperative recovery period. Primary research is needed to enhance the current understanding of the complex metabolic processes involved in this patient population.

Insulin and Diabetes

Carbohydrate Metabolism

In diabetes, there is significant overlap and interplay of numerous metabolic and physiologic pathways. Insulin plays a critical role in the mobilization and utilization of nutrients in many tissues. Insulin release is mediated through a variety of mechanisms: circulating nutrients, D-glucose, adrenergic agents, cholinergic agents, somatostatin, amino acids, pregnancy, starvation, obesity, and others. Glucose levels are primarily regulated by insulin and glucagon secretion, while epinephrine, growth hormone, cortisol, and other hormones also exert some effect. Maintenance of this steady-state glucose level is determined by the sensitivity of the liver and peripheral tissues to insulin and the sensitivity of the islet cells to glucose.[1] Insulin exerts its diverse cellular actions by binding to high-affinity cell-surface glycoprotein receptors.[2,3] These receptors are not restricted to liver, muscle, and adipose tissue: They are found in virtually all mammalian tissues, with the only variation being the concentration of receptors.[4,5] The insulin receptors are dynamic and in a constant state of turnover. The process involves biosynthesis, degradation, and recycling, as the receptor shuttles from the cell surface to an intracellular membrane pool and back to the plasma membrane.[6,7] In certain physiologic states, such as obesity, elevated insulin levels lead to the downregulation of the cell-surface insulin receptor.[8] Some agents, such as growth hormone,[9] β-adrenergic agents,[10] and glucocorticoids,[1,8] induce insulin resistance. Therefore, the secretion and effects of insulin can be visualized as a series of feedback loops. When a defect occurs within the system and insulin secretion is altered, the effects on metabolism may become extreme and widespread.

Normally, insulin increases the entry of glucose into most mammalian cells, such as muscle and adipose tissue, which is mediated by transport proteins through a facilitated diffusion mechanism. In addition, glycogen synthase activity is increased through a dephosphorylation mechanism.[11,12] In the liver, glycogen breakdown and gluconeogenesis are decreased. Therefore, without insulin, the result would be extreme increases in plasma glucose levels.

Fat Metabolism

The effect of insulin on lipid metabolism is similar to its effect on carbohydrate metabolism. Insulin causes a decrease in circulating levels of fatty acids by increasing fatty acid, cholesterol, and triacylglycerol synthesis, while decreasing fatty acid, cholesterol, and triacylglycerol degradation. When there is an absence of insulin, as in insulin-dependent diabetes mellitus, plasma triglyceride, cholesterol, and verylow-density lipoprotein concentrations are increased. However, low-density lipoprotein and high-density lipoprotein levels can vary.[13,14,15]

Protein Metabolism

As for protein metabolism, investigators have shown that insulin has a stimulatory effect on both transcription and translation activity of ribosomes.[16,17,18] In some tissues, insulin augments protein synthesis by increasing the efficiency and/or the capacity of the steps involved in translation. In other tissues, insulin acts directly on the genes to stimulate or inhibit their rates of transcription.[17,19,20] Insulin can exert its anabolic effect on protein by suppressing the rate of protein degradation, without altering the rate of protein synthesis.[21] When diabetes is induced experimentally, a marked acceleration of proteolysis occurs.[17,21,22] Although insulin deficiency has been directly linked to proteolysis, there are also indirect effects. Protein degradation is associated with a relative increase in glucagon and low levels of circulating insulin-like growth factor I (IGF-I). Studies have shown that glucagon has catabolic effects on protein metabolism in humans[23] and that IGF-I (somatomedin C) promotes protein anabolism.[23,24]

Muscle

Muscles in diabetics exhibit increased rates of proteolysis and a shift in their oxidative capacities.[25] In addition to causing changes in protein metabolism, diabetes has a pathologic effect on the peripheral nervous system. Because muscle and nerve are dependent on each other for normal growth and development, an alteration in one will result in pronounced changes in the other.[25] It is thought that diabetic neuropathy causes morphological changes in myofibers as a result of innervation changes.[25] Thus the change in myofibers (primarily through a decrease in size) may partially explain the muscle weakness commonly associated with diabetes.[25] In mixed fast-twitch skeletal muscle (eg, extensor digitorum longus), the impaired rate of protein synthesis results from a loss of RNA and the development of a block in peptidechain initiation.[26] A study by Paulus and Grossie[27] revealed that slow-twitch red muscles (eg, soleus) exhibited little impairment of peptide-chain initiation. The soleus muscle maintained its normal isometric and resting potential despite severe diabetic conditions, unlike the extensor digitorum longus.[27] In diabetes, muscle mass is significantly reduced, with fast-twitch muscles being the most affected.[26,27]

Growth Hormone

Muscle

Growth hormone has diverse effects on carbohydrate, lipid, and protein metabolism.[28,29] Of particular importance is its anabolic effect on protein metabolism. Growth hormone therapy has been shown to suppress the loss of nitrogen under catabolic conditions.[30,31] Currently, growth hormone preparation (somatotropin) is used to treat children who have experienced chronically low levels of growth hormone and resultant retardation of skeletal and muscle growth secondary to renal disease, but many other biologic effects are observed as well.[32,33,34] Somatotropin is available as a purified peptide of recombinant DNA origin. This form has exhibited less immunogenic character than the methionyl somatotropin. Growth hormone has effects on cell and skeletal development as well as on organ and muscle growth. Additionally, growth hormone exerts its metabolic action on carbohydrate, lipid, mineral, and connective-tissue metabolism.[35,36,37,38,39]

Regulation and Release

As with some other hormones of the endocrine system, growth hormone is released in a pulsatile manner from the anterior pituitary.[29,40,41] Regulation is achieved via neural, metabolic, and hormonal feedback mechanisms. In addition, circulating metabolites have regulatory actions on growth hormone. Factors increasing growth hormone secretion are hypoglycemia, sleep, stress (physical), various amino acids, and α-adrenergic stimuli.[42] Suppression of growth hormone results from plasma IGF-I, hyperglycemia, and stimulation of β-adrenergic receptors.[42]

Carrier Protein

Growth hormone has a membrane carrier protein and a plasma carrier protein. The carrier protein may compete with the membrane-bound protein.[33,43] This mechanism may have a regulatory function whereby growth hormone activity is altered by interaction with its carrier protein. IGF-I, the mediator of many growth hormone effects, also has a carrier protein.[44,45] Some studies have suggested that growth hormone has a direct effect on muscle protein synthesis and that IGF-I may play a paracrine role (ie, binding to receptors of nearby cells and altering metabolism), but is not directly responsible for mediating the actions of growth hormone.[44] The literature, however, presents no clear thesis regarding this. The IGF-I membrane-bound protein, of which six have been characterized,[45] may enhance or prevent the classic effects of growth hormone.[46,47] The IGF-I receptor has been found in rat heart, muscle, kidney, bone, ovary, cartilage, and uterus, which suggests a paracrine action by locally produced IGF-I.[48,49]

Protein Metabolism

Growth hormone stimulation of protein synthesis and osteogenesis is primarily mediated by IGF-I, although evidence for this may not be complete.[27] One hypothesis, known as the dual effector theory, suggests that growth hormone and IGF-I work together. This theory indicates that growth hormone promotes cell differentiation while IGF-I promotes multiplication and growth.[50] When growth hormone is administered to humans on a daily basis, the plasma IGF-I concentration increases threefold,[51] while the total body protein also increases.[52] However, the rate of proteolysis is unchanged. Other studies in humans have reported either a decrease in proteolysis or no change in whole-body protein breakdown.[53] It is apparent that carrier proteins play a significant role in the regulation of IGF-I.[54]

Yarasheski [29] categorized the direct effects of growth hormone into transient, insulin-like, and diabetogenic. The insulin-like effects of growth hormone are as follows: potentiation of lipolysis in adipocytes, an increase in amino-acid uptake,[36] and an increase in glucose uptake with elevated oxidation of glucose by muscles and adipocytes.[37] Studies on human leg and forearm skeletal muscle showed an increase in protein synthesis with an accompanying decrease in proteolysis. In amino-acid uptake in leg skeletal muscle, heavy-chain messenger RNA was

increased with growth hormone administration.[55] In a similar experiment with forearm skeletal muscles, proteolysis was also decreased while protein synthesis was increased.[56] Interestingly, IGF-I was not elevated. This suggests a direct stimulatory effect of growth hormone on protein synthesis. Growth hormone stimulates an increase in muscle mass, with IGF-I playing a minor role in this process.[57] Growth hormone–deficient adults displayed a diminished body lipid content and an increased protein content after growth hormone therapy.[58]

Possible Adverse Effects

The diabetogenic characteristics of growth hormone are a decrease in peripheral utilization of glucose and subsequent down-regulation of insulin receptors due to chronic elevated plasma glucose.[29,59] Lipolysis is also induced by growth hormone, as mentioned earlier.[29] Undesirable side effects of exogenous growth hormone therapy have been noted.[29,35] Among them are carpal tunnel compression, arthralgia, myalgia, and fluid retention in the extremities. This should be taken into account when considering growth hormone therapy for humans. One other notable feature of growth hormone therapy is the effect of dose frequency and duration on the outcome. Subjects experienced a positive nitrogen balance when growth hormone was administered continuously for up to 1 month.[38] However, when growth hormone therapy was interrupted in these patients for 1 week, the positive nitrogen balance effects of growth hormone were restored upon reinstitution of the growth hormone regimen.

Growth Hormone Therapy

Growth hormone therapy has demonstrated a greater anabolic effect than IGF-I administration alone.[60] However, the simultaneous use of growth hormone and IGF-I was shown to result in greater nitrogen and potassium retention with a diminished initial hypoglycemic response.[61] Binding proteins are thought to play a primary role in regulating the permissive effects of growth hormone and IGF-I.[29]

During growth hormone therapy, the increase in lean body mass does not appear to be due to an increase in synthesis of contractile units (somatic muscle).[62] Evidence suggests that growth of other lean tissues, such as connective tissue, and organ mass account for the increase in lean body mass.[62] Connective-tissue growth would explain the above-mentioned finding of carpal tunnel compression as a side effect of prolonged growth hormone therapy. Experiments with exogenous growth hormone administration have shown an increase in spleen, thymus, and kidney growth in hypophysectomized rats.[39]

Growth hormone has been shown to result in a positive nitrogen balance in muscle and enhance connective-tissue synthesis in wound healing.[28,63,64,65,66] Therefore, it appears that wound healing in diabetic rat skeletal muscle and connective tissue will be enhanced by growth hormone treatment.

Conclusion

The effects of growth hormone on protein synthesis and nitrogen balance may benefit the postoperative diabetic patient, in whom diminished protein synthesis and a negative nitrogen balance are common. Primary research is needed to provide more insight into the diabetogenic effects of growth hormone and how various dosing regimens may alleviate this. Although carbohydrate metabolism is most notably affected in the diabetic, the diminished protein synthesis and lower lean muscle mass are also significant factors affecting wound healing. Growth hormone therapy is an ideal means of promoting protein synthesis and facilitating the wound-healing process in this compromised patient population. With further animal studies, growth hormone may become a beneficial postoperative therapy for diabetics.