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Currently, according to the pathogenesis of juvenile diabetes and its complications, the most important issue is insulin resistance, which is frequently accompanied by obesity. It is also one of the leading factors in the development of age-associated diseases and accelerated aging of the organism. The term ‘insulin resistance’ should not be identified with ‘insulin resistance syndrome’ or ‘metabolic syndrome’, including the violation of glucose tolerance, or juvenile diabetes mellitus type 2 and some other systemic disorders. In general, insulin resistance is a fairly broad concept that determines the reduction of the biological response to one or several effects of insulin action and may result in obesity. More often, however, insulin resistance is defined as a condition that is accompanied with the reduced glucose uptake by the body tissues under the influence of insulin (Adabimohazab et al., 2016). It results in the resistance of cells and tissues to the sugar insensitive action of insulin or an inadequate biological response of cells to the action of insulin despite its sufficient concentration in the blood. Therefore, obesity is one of the outcomes of the insulin resistance in the juvenile population with diabetes as both obesity and insulin resistance are connected with the level of glucose and how it is affected by insulin.
The Essence of Obesity and Insulin Resistance among Juvenile Diabetes
Insulin is generally known and referred to as a hormone secreted by the pancreas. The foremost, but not the only effect of insulin is the diminution in the concentration of glucose in the blood plasma. Under the action of insulin, glucose from the blood plasma penetrates the cell, wherein it is utilized for the formation of energy. Hence, obesity in the juvenile period of human life takes place due to the lack of physical activity (Adabimohazab et al., 2016). The points of insulin application represent specific receptors on the surface of cell membranes (Adabimohazab et al., 2016). The interaction of insulin with these receptors activates a specific protein carrier, which, when combined with glucose, penetrates the cell.
The term ‘insulin resistance’ is often associated with the concept of ‘insulin resistance syndrome’. It is a combination of clinical and laboratory manifestations. They include a violation of carbohydrate metabolism: an impaired glucose fasting, a violation of glucose tolerance or diabetes, dyslipidemia, central obesity, arterial hypertension, thrombotic factors and, ultimately, high predisposition to the development of atherosclerosis and cardiovascular diseases (Adabimohazab et al., 2016). These diseases frequently occur as a result of obesity among the juvenile population.
The insulin resistance is the central mechanism in the development of diabetes mellitus and the generalized insulin resistance syndrome in general. It is closely associated with cardiovascular risk factors in juvenile population that significantly contribute to the development of coronary heart disease and obesity (Adabimohazab et al., 2016). Therefore, to reduce the risk of complications, it is necessary not only to ensure compensation of carbohydrate metabolism, but also carry out complex correction of other metabolic disorders (Adabimohazab et al., 2016). As a result, the insulin resistance will be lower, while the obesity level will be decreased.
Influence on sensitivity to insulin and genetic features are significant. Thus, relatives of the first degree of kinship with impaired and even normal glucose tolerance have a pronounced insulin resistance compared with those included in the control group (Adabimohazab et al., 2016). Irrespective of the existence of numerous studies indicating the genetic predisposition to insulin resistance and diabetes mellitus, the nature of these genetic factors remains largely unclear (Adabimohazab et al., 2016). This may be due to the fact that the development of the disease in different people depends on a combination of different genes, each of which in itself has an insignificant effect, which makes it difficult to identify these options.
Mechanisms of Obesity and Insulin Resistance Development among Juvenile Diabetes
The mechanisms underlying the insulin resistance have not been fully established. Under the normal conditions, insulin regulates the following processes, connecting with its receptor on the surface of muscle, fat or liver tissue cells. There are three groups of mechanisms responsible for the development of insulin resistance: a (pre-)receptor, a receptor, and a post receptor (Kirwan et al., 2016). Resistance to insulin on the pre-receptor level causes pathological changes in the hormone, along with the interaction of insulin as a carrier of autoantigens with autoantibodies, the release of pancreatic cells into the blood of proinsulin instead of insulin, and blocking the normal interaction of hormone with its receptor on the cell surface among juvenile diabetes (Kirwan et al., 2016). The receptor level is caused by a decrease in the number of receptors on the cell surface and /or a decrease in their affinity for insulin, which can be either genetically predetermined or a manifestation of the influence of external factors on juvenile diabetes (Adabimohazab et al., 2016). A high level of insulin and a decrease in its binding by receptors are caused by obesity, a high-carbohydrate diet and chronic hyperinsulinemia among juvenile diabetes. The decrease in the number of insulin receptors at a chronically elevated level of insulin, which might be due to the acceleration of their intracellular decay, is called ‘decreasing regulation’ (Adabimohazab et al., 2016). It is probably the receptor level of obesity and insulin resistance that cause changes in the cellular mechanisms of the body aging, such as telomere length and telomerase activity within the framework of the juvenile diabetes (Wu et al., 2016). A congenital insulin receptor defect can be a result of the change in the sequence of nucleotide pairs of deoxyribonucleic acid, leading to the loss of the tyrosine kinase domain receptor, which is a point mutation causing the absence of the adenosine triphosphate binding locus in the receptor, etc. (Kirwan et al., 2016). Insulin receptor mutations in various tissues are rarely noted in diabetes patients, and the main factors including obesity and resistance to insulin have post-receptor defects in the transmission of the insulin signal, which are due to structural and functional impairments on the part of the protein participating in signaling processes (Kirwan et al., 2016). As a result of the increase in resistance to insulin, the sensitivity of tissues to insulin is reduced (Kirwan et al., 2016). However, the affinity of receptors for insulin and the sensitivity of cells to it do not always change unidirectionally (Adabimohazab et al., 2016). Thus, when fasting, the affinity of receptors increases, whereas the sensitivity to the hormone (due to post-receptor changes) decreases.
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An important component in the development of obesity and insulin resistance and, as a result, in the development of different disorders of carbohydrate metabolism is the influence of age and aging of the organism. It is believed that the level of insulin gradually decreases with age, which is associated with the decrease in its clearance (Kirwan et al., 2016). At the same time, the degree of insulin resistance increases, which is accompanied by a steady increase in the concentration of glucose (an increase of 1% for every decade of life) (Wu et al., 2016). As a person grows up, the increase in the insulin resistance is observed during puberty and during pregnancy (with the degree of insulin resistance increasing in the gestation period) (Wu et al., 2016). Therefore, the prevalence of impaired glucose tolerance increases with age and as a rule, is manifested to the greatest extent in juvenile period (Wu et al., 2016). However, the effects of different age-dependent conditions (such as the decrease of physical activity with age, the change in the nature of nutrition, and the development of abdominal obesity) are not taken into account. The role of drug correction of obesity and insulin resistance in the prevention of aging can be characterized as follows. The regular aerobic exercises provide a synthesis of new mitochondria and, as a result, lead to the prevention of juvenile diabetes type 2 in individuals with obesity and insulin resistance.
Juvenile diabetes mellitus is generally developed in the second decade of life. Traditionally, it is characterized by a heavy course with ketosis and an increase in the content of free fatty acids, which poorly decline despite the introduction of exogenous insulin. The study by Wu et al. (2016) points to the fact that the disease is frequently complicated by the development of cirrhosis and portal hypertension. The cases of development of gigantism and acromegaly in such patients are described. The expressed insulin resistance in this syndrome is associated with various mutations in the insulin receptor gene. Wu et al. (2016) also believe that the presence of defects in the post-receptor mechanism of the action of insulin should be also assumed. The cause of the development of congenital generalized lipostrophy is unknown to this day (Wu et al., 2016). It is assumed by Wu et al. (2016) that the provision of a full picture of the disease requires the interaction of the receptor gene with insulin and other genes that regulate the number of adipocytes. The scholars suggest two hypotheses explaining the elevated level of lipids in the blood (Wu et al., 2016). According to one of them, hyperlipidemia is a result of the increased lipolysis due to the lack of functioning adipocytes (Wu et al., 2016). On the other hand, hyperlipidemia can be a consequence of intravascular hydrolysis of triglycerides (Wu et al., 2016). The authors fairly conclude that in case of monogenic diseases, including genetic syndromes associated with diabetes mellitus in juveniles, the establishment of a single mutant gene or several genes is less difficult than isolating the entire spectrum of genes involved in the development of polygenically inherited diseases (Wu et al., 2016). These include the juvenile diabetes mellitus of the 1st and 2nd types etiopathogenesis (Wu et al., 2016). When studying the genetic syndromes, insulin resistance and obesity in juveniles with diabetes mellitus, it is important to reveal their genetic and pathogenetic nature (Wu et al., 2016). This can help in the understanding of etiopathogenesis of idiopathic juvenile diabetes and its specific complications.
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In accordance with the generally accepted international clinical guidelines for diabetes, a change in lifestyle and metformin is a promising step on the way to recovery. According to the study by Kirwan et al. (2016), the basis of this stage and the subsequent ones includes the modification of the lifestyle, which is not so easy for the patient. However, non-compliance with this condition leads to permanent inadequate treatment of diabetes (Kirwan et al., 2016). The authors provide that when examining a juvenile patient with the juvenile diabetes type 2 and overweight or obesity, it is necessary to identify the type of dietary behavior of the patient (Kirwan et al., 2016). Without taking into account its specificity, it is impossible to construct an adequate therapeutic scheme and to achieve a long-term clinical effect (Kirwan et al., 2016). It is not easy to change one’s lifestyle at the initial stage of juvenile diabetes treatment for many patients, and most patients cannot achieve this throughout the entire course of treatment (Kirwan et al., 2016). Doctors often do not pay attention to this important step, and tend to control only the purpose of metformin. By recommending the patient to change the type of juvenile diabetes, it is necessary to pay attention to the eating disorders of a particular patient. Without taking into account the specifics of the eating behavior of each individual patient, it is impossible to construct an adequate scheme of therapy and to achieve a clinical effect in the treatment of obesity and insulin resistance (Kirwan et al., 2016). There are three types of eating disorders in juveniles, which are connected with the development of obesity and insulin resistance: external, emotional and limited eating behavior (Kirwan et al., 2016). External food behavior is characterized by the juvenile patient’s reaction not to the internal stimuli of food intake (glucose level), but to the external ones (Kirwan et al., 2016). People with external eating behaviors always eat whenever it is possible. The onset of saturation in patients with overweight is delayed being defined as a mechanical overflow of the stomach. Another type of eating disorder that occurs in 60% of people is the emotional one (Kirwan et al., 2016). A hyperphagic reaction to stress and an intake of excessive amounts of food due to certain emotions experienced by the patient is equal to the emotional aspect (Kirwan et al., 2016). The third type is limited eating behavior, which is represented by the so-called superfluous food in self-restraint diets, which the juvenile patients can practice from time to time. By comparing carbohydrate metabolism rates before and after the treatment, Kirwan et al. (2016) conclude that the real difference in blood sugar was on and off after comparing the two groups. In the main group, glycemia has almost reached the desired compensation level and has a positive tendency to decrease by 27% (Kirwan et al., 2016). The results in the control group were less positive (Kirwan et al., 2016). A similar trend was observed in blood glucose level after nutritional loading, which is the result of the correct three-month treatment.
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After the introduction of glucose into the intestine or parenterally, the balance of glucose production is destroyed by the liver. According to the study by Shomaker et al. (2016), in the state of absolute fasting, most of the glucose is metabolized by insulin-independent tissues: 50% of glucose is absorbed by the brain and 25% is utilized by internal organs. Insulin-dependent tissues, especially muscles, are responsible for the disposal of the remaining 25% of glucose (Shomaker et al., 2016). In this case, the maintenance of normal glucose homeostasis depends on several precisely coordinated processes: secretion of insulin and suppression of glucose production by the liver (Shomaker et al., 2016). The sensitivity of peripheral tissues to insulin is determined by the presence of specific receptors, the function of which is to ensure the stimulating effect of insulin with the participation of glucose transporters (Shomaker et al., 2016). The process of binding insulin to the receptor leads to different cellular responses. The receptor performs three main functions (Shomaker et al., 2016). The first is to recognize the insulin binding sites in the molecule with high specificity and perform complexation with the latter with the help of the α-subunit (Shomaker et al., 2016). The second function implies the transmission of a corresponding signal directed to the activation of intracellular processes by means of conformational changes and activation of the β-subunit tyrosine kinase (Shomaker et al., 2016). The third function is to carry out endocytosis (immersion inside the cell) of the hormone-receptor complex, which leads to lysosomal proteolysis of insulin with simultaneous return of the subunit to the cell membrane (Shomaker et al., 2016). It is known that a violation of the autophosphorylation of the insulin receptor can lead to the cessation of the further cascade of reactions necessary for the action of insulin and the insulin resistance of skeletal muscles (Shomaker et al., 2016). However, the mechanism of decreasing the activity of insulin-receptor tyrosine kinase in juvenile diabetes is not clear (Shomaker et al., 2016). This is largely explained by the secondary metabolic changes rather than the mutation of the insulin receptor gene.
It can be assumed that there is a poorly expressed insulin resistance in juvenile patients with the onset of diabetes, due to the decrease in the number of receptors to insulin. The study by Caprio, Perry, and Kursawe (2017) demonstrates that in patients with high hyperglycemia on an empty stomach and severe insulin resistance, the post-receptor defect is predominant. In addition, Caprio, Perry, and Kursawe (2017) suggest that the relative importance of receptor and postreceptor disorders varies between the two described manifestations of insulin resistance in the juvenile diabetes. Metabolic syndrome is the most frequent manifestation of insulin resistance. However, the concept of the insulin resistance is much broader (Caprio, Perry & Kursawe, 2017). The sensitivity of tissues to insulin is influenced by various factors such as age, gender, overweight and especially the distribution of adipose tissue, blood pressure, ischemic heart disease, along with a number of somatic diseases, a family history of diabetes, quality of nutrition, level of physical activity, and psychoemotional factors (Caprio, Perry & Kursawe, 2017). As the insulin resistance increases, the signs of the post-receptor defect also increase.
Insulin resistance also occurs in patients with other diseases accompanied by metabolic disorders. The findings by Adabimohazab et al. (2016) point out that insulin resistance occurs in more than 25% of practically healthy individuals without obesity, and its degree of expression is comparable with the severity of insulin resistance observed in patients with diabetes. The study also shows that approximately 80-90% of the juvenile patients with diabetes suffer overweight or obesity (Adabimohazab et al., 2016). Hence, with obesity of the 1st degree, the risk of juvenile diabetes increases twofold (Adabimohazab et al., 2016). An exceptional role is played by the delivery of fat in such patients. Abdominal instinctual fat deposition is associated with impaired glucose tolerance and insulin resistance, regardless of the body weight (Adabimohazab et al., 2016). Fatty tissue is currently considered one of the endocrine organs, which are the site of the synthesis of a significant amount of hormones and biologically active peptides, most of which may lead to the increase in insulin resistance.
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