Carbohydrate Metabolism in Growth Hormone Therapy for Children

Abstract

Growth hormone deficiency is one of the most common causes of short stature in response to growth hormone therapy, and deficiency occurs as a result of either a decrease in the pituitary hormones themselves, which is called hypopituitarism, or a deficiency of hypothalamus. Stunting is a condition that worries many parents because if the body’s growth hormone deficiency is not diagnosed and the appropriate treatment is not taken early, which leads to a high body mass index, that is, weight gain after puberty, high fat and future risks. For type 2 diabetes, diabetes, insulin-dependent heart disease, atherosclerosis and other diseases, the incidence of this deficiency in European societies is about 4000/1 births which is comparable with the proportion in Iraq but increasing the incidence. This study was conducted to investigate the effect of growth hormone therapy on carbohydrate metabolism where growth hormone affects the shape and function of the developing body and apart from these functions such as stimulating growth, it has distinctive effects on the metabolism and energy, and plays a role in regulating blood sugar levels.

1. Introduction

Growth hormone (GH) has effect in carbohydrate metabolism including the stimulation of glucose production from the liver, in particular when it is abundant. The hormone also increases the extent to which beta cells in the Langerhans pancreatic cells can secrete insulin in response to glucose alert [1]. It was found that the daily injection of dogs with this hormone leads to diabetes with total atrophy in the islands of Langerhans as a result of the demoralization of the continued alertness of the islands of Langerhans, which leads to exhaustion due to excessive secretion of the hormone insulin caused by injection pituitary extracts [2]. Because the growth of growth hormone in dogs and cats accompanies the incidence of diabetes, it is not surprising to note the emergence of diabetes in all patients with Acromegaly. In general [3], insulin and growth hormone can be considered as complementary agents, each regulating the supply of energy to the tissues of the body where Insulin becomes active immediately after eating (a time when glucose as the most important source of energy in the body is forming) while growth hormone becomes active in hunger or fasting [4]. Insulin and Insulin-like growth factor-I (IGF-I) are the two hormones that control glucose metabolism; hence, IGF-I is the second factor after insulin that has an antihypertensive effect [5]. The growth element IGF-I, a polypeptide hormone with 70 amino acids and a molecular weight of 7649 Da, is a member of a big family that is highly similar to one another and is very close to the proportion of insulin [6]. It indirectly affects the growth of many cells and tissues in the body. IGF-amino I’s acid sequence was discovered to be 48% similar to that of human proinsulin hormone, often known as “insulin-like,” which is mostly released from the liver, according to Humble and Rinderknecht’s research from 1978. Laron [7], where the body’s nutritional situation is the main secretion. Additional hormones include the most potent one, growth hormone (GH), as well as insulin, thyroxin, and anabolic steroids [8]. Growth hormone is secreted under joint and coordinated control of three hypothalamus hormones: growth hormone-releasing hormone (GHRH). Somatostatin and Ghrelin (GHRH), GHRH and gerlin are positive regulators that stimulate growth hormone release [9]. Somatostatin (SST) is a negative regulator that inhibits the secretion of the hormone. Another factor is insulin-like growth factor (IGF-I), which affects the thalamus and pituitary, reducing growth hormone secretion [10]. Hypoglycemia is a potent stimulant for GH secretion. At the same time, hyperglycemia prevents the secretion of hormone in most cases [11]. Some report that a hypoglycemia level of 50% of normal level promotes hormone secretion. In secretion [12]. Causing Fasting for a long time increase the secretion of the hormone and after eating begins three stages of secretion of the hormone as the secretion of the hormone insulin is predominantly in the first stage while in the second phase less secretion of insulin and increases the secretion of growth hormone and in the third stage is the secretion of growth hormone is predominantly, also Physical exertion causes increased secretion of the hormone and there is a direct relationship between the effort exerted and the amount of the hormone secreted [13]. Some neurotransmitters such as fear, anxiety and noise may activate hormone secretion. It is also observed that hormonal factors influence GH secretion Thyroxin extracted from the thyroid gland, increases the amount of growth hormone releasing factor (GHRF) extracted from the hypothalamus, which increases the secretion of GH from the anterior lobe of the pituitary anterior pituitary gland [14]. The incidence of growth hormone deficiency in European societies is about 1/4000 births, which is similar to the rate in Iraq [15]. However, the increase in diabetes and other endocrine diseases in the context of wars and economic siege, and the increase in children with growth hormone deficiency of the reviewers of the unit of hormone The growth in the women’s and children’s education hospital in Ramadi as a result of war, displacement, lack of health care, interruption of treatment and diagnosis exacerbated this problem. Due to the lack of studies at the level of Al-Anbar province on the condition of lack of growth hormone in children with short stature therefore, this study was conducted in order to investigate the effect of therapeutic hormone growth hormone on the metabolism of carbohydrates, fats and bones in a group of children with hormone deficiency hormone (growth hormone deficiency only) and for 6 months of treatment, where growth hormone affects the form and function of the developing body and regardless of These functions as a stimulus to growth have specific effects on metabolism and energy, affect the fat cells to reduce the amount of stored fat, promote protein synthesis in cells and play a role in regulating blood sugar levels [16]. GH is necessary for natural growth and cell proliferation and regeneration in humans and some other organisms. Apart from these functions as growth stimuli, it has distinct effects on metabolism and energy affects fat cells to reduce the amount of stored fat, promotes protein synthesis in cells and plays a role in regulating Blood sugar levels [17]. The insufficient secretion of growth hormone in the early periods of the life of the individual causes the weakness of the skeleton and the incidence of dwarfism, while excessive secretion of GH before the completion of growth or before the closure of rectangular bones causes the increase of the growth of these bones to a large extent, which is expressed by the disease Gigantism [18]. If the excessive increase in excretion happens in adulthood, the so- called Acromegaly will develop, which is characterized by the swelling of the bones of the head and jaw, hands and feet [3]. In fact, the increase in the secretion of GH after the epiphyseal cartilage is locked (calcified) causes the previous condition, which also the continued growth of bones without Epiphyses (under the influence of the increase in the hormone) contributes to, making the body organs ultimately inconsistent. In general, there are several centers for the formation of the human and animal skeleton, including the aforementioned Epiphyseal cartilage centers. These centers become active under the influence of GH where their cells divide and increase in fish while some of these cells are constantly transformed into bones [19].

Growth hormone is not directly affected by the insulin-like growth factor or somatomedin, as the growth hormone stimulates its secretion in peripheral tissues, especially the liver [2]. GH is believed to perform its functions on the cartilage (multiplying cartilage cells) indirectly by regulating the level of Somatomedins in blood plasma, some of which are known as insulin- like growth factors. These somatomedins therefore have anabolic effects in the cartilage in terms of activating the transfer of amino acids and stimulating the process of protein synthesis, DNA and RNA and increasing absorption of sulfate [7].

2. Growth hormone

Growth hormone (GH), also known as somatotropin, is a hormone that regulates healthy body development and growth. This process is made possible by accelerating the creation of protein in muscle cells and the release of energy from the breakdown of fat. A number of hormones are crucial to human development (GH), also known as somatotropin [20]. It is a 191 amino acid protein that the anterior pituitary gland secretes to regulate healthy growth and development, as depicted in the Figure 1. Human growth is divided into two phases. One at conception, the other at puberty. GH is important in these two stages [22]. Every day of a normal person’s life, amounts of GH are detectable. Nevertheless, because eating and activity have an impact on GH levels, they change throughout the day. There are GH-responsive receptors on the cells and tissues of the body [13]. The metabolic effects of GH are in muscle, liver, and fat cells, which are crucial to their function, but the visible effect of GH is on linear skeletal development [23]. There are two types of GH in humans. It’s unclear how the two vary functionally, though. Although they are both products of the same gene, one of them lacks the amino acids between positions 32 to 46 [24] in Thongh.

Figure 1.

Growth hormone [21].

Somatotrophs in the anterior pituitary gland create growth hormone (GH) under the guidance of hormonal signals in the hypothalamus [25]. GH is regulated by two hypothalamic hormones. GHRH (growth hormone-releasing hormone) and GHIH (growth hormone-inhibiting hormone) are the two (GHIH). This procedure’ mechanism may be fully explained. As a result, when blood glucose levels decrease. The secretion of reserve GH is induced by GHRH. GHRH release is inhibited as blood glucose levels rise [26]. The effect is comparable when blood protein levels rise. This hypothalamic feedback loop causes GH levels to change during the course of the day. 1 to 3 ng/ML of normal plasma GH levels. The hormones insulin, glucagon, and adrenaline also control the availability of plasma glucose and amino acids for growth [27]. GH is primarily released during night. At 10 o’clock, midnight, and 2 a.m., GH release peaks. The rationale behind this time of day is that other hormones, such as the somatomedins, IGH-1 and IGH-2, mediate the majority of GH effects. As a result, GH’s effects are more uniformly distributed throughout the day [25]. Due to their vital involvement in the production of GH and other hormones, a number of hormonal disorders can result in excessive or reduced development. However, a pituitary tumor frequently results in abnormal growth. Underproduction of GH, a deficiency in IGH-1, or a problem with the target tissue’s reaction to either of these growth hormones can all contribute to dwarfism (extremely short stature). Gigantism and acromegaly, both of which are characterized by a very enormous stature, can result from an excessive production of GH or IGH-1, or from an exaggerated response to these hormones [28]. Early childhood overproduction of GH, which can result in gigantism, can generate skeletal heights of up to 8 feet (2.5 meters) or more [3]. When GH is overproduced after the onset of puberty, acromegaly develops. The body’s long bone’s epiphyseal plates are unable to close in this situation. In addition, they continue to respond to GH-stimulated further growth. An enlarged nose, throat, tongue, hands, feet, and cranium are features of this condition [28].

2.1 Growth hormone chemistry

A single chain polypeptide hormone of 191 amino acids and a molecular weight of 22,000 Daltons, human growth hormone is depicted in Figure 2. Four helices in the structure are required for a proper interaction with the GH receptor [31]. Growth hormone, chorionic somatomammotropin (placental lactogen), and prolactin have similar sequences.

Figure 2.

Structure of growth hormone [29]. Pituitary GH is also found in deaminated and N-acetylated forms, as well as different GH oligomers [30].

Only the placenta secretes the 22-KD GH variant (hGH-V), which differs from pituitary GH by 13 amino acids [32]. Approximately 75% of the pituitary’s typical GH secretion is in the mature 22-KD form. The loss of amino acids 32 to 46 caused by the second codon’s alternative splicing produces in a 20 KD variant, which normally makes up 5 to 10% of pituitary GH.

2.2 Secretion of GH

Growth hormone (GH) is secreted into the blood by the somatotrope cells in the anterior pituitary gland as shown in the Table 1, more than any other pituitary hormone in significant quantities. These cells’ growth and GH synthesis are both accelerated by the transcription factor PIT-1. GH shortage is the result of the anterior pituitary gland being destroyed and these cells failing to grow [33]. The main regulators of GH secretion by somatotropes are peptides produced by neurosecretory nuclei of the hypothalamus into the portal venous circulation surrounding the pituitary. Arcuate nucleus growth hormone-releasing hormone (GHRH) and Somatostatin from the periventricular nucleus suppresses GH secretion while ghrelin promotes it. Negative feedback from circulating GH and IGF-1 concentrations also affects GH secretion [20]. Even though the ratio of this stimulating to inhibitory peptide regulates GH release, various physiological stimulators and inhibitors of GH secretion can alter this ratio. Among other things, sleep, exercise, hypoglycemia, dietary protein, and estrogen are stimulators of GH secretion. Glucocorticoids and dietary carbohydrates are GH secretion inhibitors [22]. Throughout life, GH secretion follows a different rhythm. Early childhood has the highest basal levels. During the pubertal development spurt, the amplitude and frequency of peaks are at their highest. A healthy youngster or adolescent experiences eight peaks on average every day. Adults typically have five peaks. Throughout adulthood, basal levels, as well as the frequency and amplitude of peaks, decrease [34].

Table 1.

Secretion of growth hormone.

2.3 Function of GH

The actions of growth hormone on the body’s tissues are referred to as anabolic effects (building up). GH, like the majority of other protein hormones, works by binding to a specific receptor on the surface of cells. The most well-known effect of GH activity is childhood height growth. There are at least two processes that seem to promote it [20]. Direct stimulation from GH causes cartilage chondrocytes to divide and multiply. These are the main cells of children’s growing long bones (arms, legs, and digits), known as epiphyses [22]. In addition, GH promotes the synthesis of the proinsulin-like hormone insulin-like growth factor 1 (IGF 1, originally known as somatomedin C). The liver, which is the main location of IGF-1 synthesis, is a significant target organ of GH in this process. According to the table, IGF-1 exerts growth-stimulating effects on a range of tissues as shown in the Table 2. Target tissues produce more IGF-1, demonstrating that it is both an endocrine and an autocrine/paracrine hormone [22]. Although height growth is the most well-known consequence of GH, it also performs a variety of other metabolic tasks. GH improves bone mineralization, bone strength, and calcium absorption. Additionally, it builds muscle. Additionally, it stimulates the body’s many organ systems to expand and produce more protein, creating a “positive nitrogen balance”. GH boosts immunological function [20]. GH’s part in maintaining fuel homeostasis. A counterproductive impact of GH was a reduction in the liver’s absorption of glucose. It also helps keep pancreatic islets healthy and functioning. GH tends to encourage lipolysis, which causes a small decrease in adipose tissue (body fat) and an increase in the blood’s levels of free fatty acids and glycerol [33].

Growth hormone effects
Epiphysis (chondrocyte): Linear growth before puberty. Increase bone density and mineralization.	Liver: Secretion of IGF-1 (somatomedicine-c) Autocrine-paracrine hormone.	Target tissues: Increase muscle mass. Positive nitrogen balance. Stimulate immune system. Decrease hepatic glucose uptake. lipolysis: Increase fatty acid in blood.; Increase glycerol in blood.

Table 2.

Effect of growth hormone.

2.4 Genetic factors

2.4.1 Factors controlling growth

The aspects of growth are influenced by genetic mechanism, which is polygenic in nature. The first mechanism is the regulation of the rate cellular multiplication, affecting the overall size. The second is the control of the pace of maturation [35]. Both x and y chromosomes contain growth regulating genes. The special influence of X-chromosome is referred to in growth studies in females, asaril, girls develop 2 years earlier than boys [36]. Genetic factors such as body size are also known to be influenced by race. Black children stature and pace of osseous maturation during the childhood years.

2.4.2 Tissue-specific factors

The mechanism, by which control cellular multiplication, differentiation, and organ development during embryonic period of fetal life, remain a mystery. The concept that classic hormones directly regulate growth and maturation has been replaced by the hypothesis, that growth is controlled by variety of growth factors. Those factors production is stimulated by the classic hormones, these considered as mediator hormones because they mediate some of the biological actions of classic hormone [37].

2.4.3 Nutrition

Retardation of growth occurs, if malnutrition is severe, and in such cases there is always the additional possibility of chronic diseases such as anemia, congenital heart diseases etc. Improved nutrition and freedom from chronic disease are factors which have contributed to taller stature and earlier puberty of European and American prevalent, while poor linear growth, and delay adolescence are common among the children in the countries where malnutrition is prevalent. Chronic malnutrition through the childhood and early adult years, of prospective mothers, places their infants in jeopardy physically and intellectually [35].

2.5 Hormone AL regulation

In healthy children, statured growth is controlled by the action of circulating hormones. On skeletal system, GH and thyroid hormone (T4) are the major determinants of growth rate during the childhood [38]. They are working synergistically. T4 is predominantly required for skeletal maturation and GH for linear growth. While growth sprout and skeletal maturation of adolescent are primarily depending on gonad steroid in conjunction with GH and T4. Insulin and glucocorticiods influence carbohydrate, fat and protein metabolism, which provides sources of energy needed for growth and exerts a permissive influence on anabolic action of GH [39].

2.6 Growth hormone actions

Growth hormone (GH) has a wide range of biological effects, many of which are carried out directly by the GH-R and indirectly by IGF-1. The majority, if not all, tissues are affected by GH/IGF-1, which has no specific organ as a target as shown in the Figure 3 [40].

Figure 3.

The GH/IGF-1 axis and its effects on bone, muscle, and body metabolism. +, stimulation: −, inhibition: GHRH, Growth hormone-releasing hormone: cardiovascular system; VO2 Max: maximum oxygen consumption; CVS: cardiovascular system.

2.6.1 Muscles growth and metabolism

By increasing protein synthesis and, presumably, limiting protein breakdown by up-regulating the production of Lipoprotein Lipase (LPL), both GH and IGF-1 regulate how quickly muscles break down protein [41, 42]. IGF-1 appears to control the size of human myotubes by promoting protein synthesis, preventing protein breakdown, and causing the reserve cells needed for maximum growth to fuse. Additionally, it has been found that GH causes muscular growth, which is most likely mediated by naturally occurring IGF-1’s autocrine and paracrine effects [34]. Additionally, GH has been demonstrated to cause lipid buildup in the muscles, which has been well reported in people with excessive GH (acromegaly), causing skeletal muscle to switch from using glucose to lipids as a substrate [43]. Additionally, there is insufficient evidence—mostly from hypothetical animal studies—to support the idea that growth hormone (GH) may influence the composition of skeletal muscle fibers and cause a switch from glycolytic fast-twitch fibers (type II) to oxidative slow-twitch fibers (type I), which may indicate how GH affects muscle power and strength [44].

2.6.2 Protein metabolism

Growth hormone (GH) promotes protein synthesis while suppressing proteolysis either directly or through IGF endocrine and paracrines processes, which has an anabolic influence on protein metabolism [45, 46]. The majority of research point to GH’s modest anabolic effects, which may include boosting body wide protein production while reducing protein breakdown, as well as reducing muscle-specific amino acid oxidation and degradation [1].

2.6.3 Glucose metabolism

Growth hormone (GH) is necessary to maintain the metabolism and homeostasis of glucose. While some of these actions are directly induced by IGF-1, others are mostly mediated through its effects that resemble those of insulin (in contrast to those of GH) [1]. The GH lipolytic impact appears to be the most important component of GH anti-insulin actions, preventing insulin-stimulated glucose absorption through the oxidation of FFA and consequent inhibition of glycolytic enzymes [47] Additionally, due to its lipolytic properties, GH produced anti-insulin effects that improved hepatic and peripheral insulin sensitivity, increased hepatic glucose production, decreased carbohydrate oxidation, and decreased insulin resistance [48]. Additional mechanisms for the metabolic effects of GH through downregulation of insulin signaling have been proposed, including increased expression of the p85 regulatory subunit of PI3K activity in adipose tissue and enhanced suppressors of cytokine signaling (namely SOCS 1 and 3). [49].

Factors which increase GH release.

1. The hypothalamic hormone growth hormone releasing hormone (GHRH) which is necessary for GH synthesis and stimulates GH release [50].

2. A second stimulatory system, parallel to that involving the GHRH receptor is activated that binds the GH secretagogue receptor to induce GHRH and GH [51]. Ghrelin is produced in the arcuate nucleus of the hypothalamus and in much greater quantity by the stomach, but also in the heart, lung and adipose tissue. Fasting increases gastric ghrelin gene expression Administration of ghrelin stimulates food intake and raises plasma GH concentration [52].

3. Sleep: The nighttime is when GH secretion peaks, particularly at the start of the first slow-wave sleep. But is connected to poor GH secretion [53].

4. Exercise: Exercise and physical stress include trauma with hypovolemic shock and sepsis increased GH levels [54].

5. Hypoglycemia: Chronic malnutrition and prolonged fasting increases the number and amplitude of GH secretion and enhanced GHRH release [51].

6. Protein intake: High protein meals and intravenous single amino acid (arginine leucine) stimulate growth hormone secretion [50].

2.7 Factors that inhibit GH release

Somatotropin release-inhibitory factor (SRIF) also known as somatostatin which inhibits.

GH release [37].

2.8 Obesity

Obesity is characterized by significantly increased GH synthesis, as evidenced by a nearly pronounced increase in the frequency of GH secretary bursts and half-life duration [55].

2.9 Growth hormone physiology and regulation

Growth hormone (GH, somatotropin) is secreted by somatotrophs which make up about 50 percent of anterior pituitary cells [56]. During these peaks, the plasma concentration of GH may range from 5 to 35 ng/ml or higher. Peaks may last for five to 30 minutes before resuming baseline levels. A hour or so after the start of sleep, these GH peaks reach their highest and most consistent heights [57]. There are many factors which modulate the production of growth hormone, including stress, nutrition, sleep as stimulator, and free fatty acids which are inhibitor of GH secretion. Several molecular isoforms of GH circulate in the plasma. Much of the growth hormone in the circulation is bound to a protein (growth hormone binding protein GHBP) which is derived from the growth hormone receptors [15]. Peptides released by neurosecretory nuclei of the hypothalamus (Growth hormone releasing hormone and somatostatin) into the portal venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotrophs [31].

3. Insulin like growth factor-1 (IGF-1)

Insulin like growth factor-1 (IGF-1), and do Mains see polypeptide targets hormone for GH. The 70 amino acids IGF-1 protein consists of 4 domain as shown in the Figure 4. IGF-1 mediates most of the growth-promoting actions [59]. It is synthesized in the liver and extra hepatic tissue (principally muscle, bone, and kidney). It is a 7.7 kDa single-chain polypeptide that is also found in the pituitary gland [18, 60]. IGF-1 has an A and B chain that are joined by disulfide bonds, just like insulin does. The 12 amino acids in the C-peptide region. IGF-1’s ability to attach to the insulin receptor (with low affinity) is demonstrated by its comparable structure to insulin [61]. IGF-1 provides negative feedback regulation of GH production and secretion by acting at the endocrine and paracrine level. The liver, high-affinity binding proteins like IGF-binding protein 3 (IGFBP3), and transport are where about 80% of IGF1 is produced. It controls IGF1 cell-surface receptor availability to mediate IGF-1 peptide activity as well [62].

Figure 4.

Structure of IGF-1 [58].

Based on the person’s age, circulating IGF-1 levels change. As a result of the decreased GH levels, there is initially an uptick from birth to puberty, which is then followed by a steady decline with age [63] IGFBP1–6, a group of six IGF-binding proteins, control the bioavailability and half-life of circulating IGF-1. Each IGFBP can bind to IGF-1 with a high degree of affinity, and it is controlled by a number of particular IGFBP proteases [64]. IGF-1 is a potent inhibitor of apoptosis and has a significant impact on cell proliferation and differentiation [65]. The liver is where IGF-1 is primarily produced [66]. Age and nutrition are just two of the variables that affect serum IGF-1 levels. However, GH is the main factor controlling IGF-1 release into the bloodstream and synthesis in the liver [67].

3.1 Insulin-like growth factor-1(IGF-1) production and circulation

Insulin-like growth factor-1 is produced primarily by the liver. Then it is carried in blood bound to a carrier protein, which prolongs its half-life. Its level is therefore more constant than that of growth hormone [68]. Human growth hormone stays in the blood stream only for a short time, (few minutes). Every organ and system of the body is affected by growth hormone, either directly or indirectly, through the mediator IGF-1 [69]. Similar to that, it encourages young children’s bone growth. The majority of organs and tissues experience growth, including the brain, which is also impacted. Most of the advantages and effects of human growth hormone are caused directly by IGF-1. IGF-1 has a ten-fold greater potency than HGH [70]. With a half-life of 21 to 40 hours. In addition, it is tightly bound to its binding protein in plasma. GH stimulates IGF-1 not only secretion but also the production of IGF binding protein [71]. IGF-1 mediates the anabolic growth promoting effects of GH in the muscle [72].

4. Carbohydrate metabolism

4.1 Growth hormone effect and treatment on the metabolism of carbohydrates

Growth hormone (GH) therapy blocks insulin’s effects on peripheral tissues such skeletal muscle, the liver, and adipose tissue, increasing glucose synthesis from these tissues and reducing adipose tissue glucose uptake [73]. Following GH injection, insulin synthesis is enhanced to counteract the elevated blood glucose. Chronic exposure to high FFA may have a direct harmful effect on beta cells due to GH-induced visceral adipose tissue lipolysis and the subsequent increase in circulating FFA [74]. Because IGF-1 mimics insulin in the liver and skeletal muscle, increasing its levels following GH injection may improve insulin resistance and glucose balance [75]. The effects of GH treatment on the glucose metabolism of the pediatric population have only been the subject of a modest number of studies. The majority of these studies have shown that increased insulin resistance, as shown by elevated fasting insulin and homeostasis model assessment of insulin resistance levels, was seen in GH-deficient children and adolescents during GH therapy, but their fasting/postprandial glucose and HbA1c levels remained within in normal range [76].

In individuals with GH deficiency, GH injection has been linked to a reduction in visceral adiposity and an improvement in cardio-metabolic dysfunction, according to a number of human investigations. While taking GH, certain studies have raised concerns about increased insulin resistance and impaired fasting glucose, particularly in obese and older patients. Studies on children and teenagers have suggested that GH injection may result in short-term treatment-induced insulin resistance, although its long-term effects have not yet been extensively analyzed [77]. It is advisable to monitor any potential detrimental effects on glucose metabolism both before and after GH delivery because international cohort studies indicate that GH therapy may increase the prevalence of type 2 diabetes mellitus in children and teens with predisposed risk factors. The long-term effects of GH therapy on cardiovascular outcomes in GH-deficient children with or without GH continuing following end of skeletal development require extensive longitudinal cohort studies [78].

5. Glycosylated hemoglobin (HbA1c)

Hemoglobin that has been glycosylated (also known as hemoglobin A1c, or HbA1c) is one type of hemoglobin (Hb) that is primarily evaluated to determine the average blood glucose level over a long period of time. This protein is created by hemoglobin’s regular exposure to plasma glucose in a gradual, nonenzymatic glycation reaction [79]. Hemoglobin that has been irreversibly glycosylated at either or both of the amino-terminal valines (Val) of the beta-polypeptide chains is referred to as glycosylated hemoglobin [80]. The most widely used and widely approved test for assessing the glycemic management of people with diabetes is HbA1c. Red blood cells (RBCs) retain the glycated form of hemoglobin (Hb) for the duration of the RBC’s existence [81]. In clinical settings, HbA1c is employed to precisely reflect glycemic management over the previous (120 days). For individuals without diabetes, the optimal HbA1c test range is often less than 7%; for those with diabetes, the usual range is between 4 and 6%. [82]. The test can be taken at any time of day and requires no special preparation, such as fasting. These characteristics have made it the best test for assessing diabetics’ glycemic control. The American Diabetes Association (ADA) now advises using HbA1c as a diagnostic test for diabetes as there has been much interest in doing so in recent years.

As a method for identifying those with a high risk of getting diabetes [83]. Furthermore, nephropathy and retinopathy in diabetes mellitus have been connected to hemoglobin glycosylation. Since its introduction in clinical settings in the 1980s, HbA1c has been a standard test for determining average plasma glucose over the preceding 8 to 12 weeks.

The relationship between HbA1c percent and plasma glucose levels is well recognized; the higher blood glucose levels, the higher the level of HbA1c percent, which is useful for monitoring and management; also, as HbA1c percent rises, the risk of complications from diabetes tends to rise. HbA1c% is a helpful indicator of how well plasma glucose level has been controlled recently and can be used to track the effects of exercise, diet, and medication therapy on plasma glucose in diabetic patients because HbA1c levels are unaffected by daily variations in plasma glucose levels and instead reflect average glucose levels over the prior 6 to 8 weeks [84]. The best tool available to doctors to assess the overall management of diabetes is HbA1c% as a consequence [85].

5.1 Insulin

A hormone produced in the pancreas is insulin (an organ located behind the stomach). Islets, or cell clusters, are found in the pancreas. Insulin is produced by beta cells within the islets and released into the circulation. In metabolism, insulin is important [86]. It is a key anabolic hormone that is secreted in response to increased amino acid blood and glucose followed by ingestion of a meals. Similar to many hormones, insulin works by attaching to certain receptors on the body’s cells, including those in the fat, muscle, and liver cells [87]. Insulin’s primary function is to promote the absorption of glucose. Figure 5 shows the two polypeptide chains that make up the protein insulin: A (21 amino acid residues) and B (30 amino acid residues). Disulfide bridges connect chains A and B. An intrachain disulfide bridge connecting residues 6 and 11 [89] is also present in the A-chain.

Figure 5.

Insulin structure [88].

5.2 Insulin resistance (IR)

Cells with insulin resistance (IR) do not react to the hormone’s typical effects, which is a physiological condition [90, 91]. High blood sugar results from the body’s cells becoming resistant to the insulin it generates, making them unable to utilize it properly [92]. A subsequent increase in insulin synthesis by beta cells in the pancreas furthers the rise in blood insulin levels [93].