Does Body Composition Influence Insulin Sensitivity?
Info: 4591 words (18 pages) Nursing Essay
Published: 26th Oct 2021
Body composition can be used to describe the amount of fat, bone, water and muscle within a human body (10). The varying amounts of fat and muscle tissue present within the body can help determine how sensitive an individual may be to the hormone insulin (11). Insulin sensitivity can be described as how sensitive the body is to the effect of the hormone insulin (11).
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Insulin is the hormone which helps to control the blood sugar levels within an individual by stimulating uptake by cells (12). When there is insulin resistance the body's cells do not respond normally to the hormone meaning that the glucose cannot enter the cells as easily so it causes an accumulation of glucose within the blood. If the insulin resistance is not addressed it can eventually result in the pancreatic beta cells being destroyed (11). This is due to the body trying to compensate for the high glucose levels by secreting more insulin (11). This results in stress within the pancreas and immune cells within the pancreas become activated to the stress response and produce inflammatory signalling molecules which destroy the beta cells (11). Ultimately this results in type 2 diabetes (11). However, during the insulin resistance there are no known symptoms therefore it can be difficult to determine if one may have this resistance (11).
It has been presented from recent studies that those with a higher fat percentage or are categorised as being obese can cause endoplasmic reticulum stress (1). This stress caused in the endoplasm can result in insulin resistance due to the emergence of inflammatory responses (1). Furthermore, it has been identified that obesity presents a cell signalling protein involved in systemic inflammation known as tumour necrosis factor alpha (TNF-alpha) (4).
This is also a type of cytokine and is shown to be overexpressed in obese individuals and is closely linked with circulating insulin levels which can serve as an index for insulin resistance (4). Additionally to this it has been identified previously that obesity can cause insulin receptor substrate (IRS) modifying enzymes to activate c-Jun N-terminal kinases (JNK), inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-ß) and conventional protein kinase C (PKC) (6). This pathway is central to mediating insulin resistance and if activation of these kinases occurs then it can result in insulin resistance (6).
Additionally, studies have also presented the effects of another kinase known as I-kappa-B kinase epsilon (IKK epsilon) (8). This kinase can have increased activity and levels within those who are considered obese (8). IKK epsilon also contribute towards insulin resistance by increasing IRS -1 serine phosphorylation which can weaken insulin signalling transduction (8,9). It is important to consider that those who are obese can have increased activity of this kinase which can result or increase the risk of developing insulin resistance (8).
Overall if an unhealthy body composition consisting of a high fat percentage within the body is not addressed then insulin resistance can result in type 2 diabetes causing serious harm to an individual.
Whilst being obese provides many conditions which could lead to endoplasmic reticulum (ER) stress. Obesity is known as an abnormal or excessive fat accumulation in adipose tissues (1). Alteration in the endoplasmic reticulum leads to an accumulation of unfolded proteins which results in ER stress (1). If there is an excessive amount of ER stress this can lead to apoptic cell death (1).
In a study that observed mice for a period of 16 weeks that were fed on a high fat diet, it indicated that body weight of mice significantly increased on the high fat diet compared to the control subjects who were fed a normal diet(1). It showed that ER stress markers increased along with chronic inflammation for the mice who became obese (1). Overall this study highlighted that ER stressed is initiated by free fatty acid – mediated reactive oxygen species generation along with the upregulation of gene expression of inflammatory cytokines in certain adipocytes (3T3-L1) (1). Furthermore, it is important to consider that the persistence of obesity can initiate ER stress and can be followed by the activation of the unfolded protein response (1).
This study supports the idea that an accumulation of an excessive amount of fat within the body can lead to ER stress. However, it is important to consider how ER stress can lead to insulin resistance. Previous findings suggest that the transcription factor nuclear factor xB (NF-xB) has a central role in the regulation of beta-cell inflammatory responses including the synthesis of several chemokines and cytokines (2).
A study evaluating the pancreatic beta-cells response to low doses of pro-inflammatory cytokines highlights that obesity can induce chronic ER stress in pancreatic beta cells (2). This study showed that pre-existant ER stress even in low amounts can sensitize the beta-cells to low concentrations of interleukin 1 beta (IL-1ß), which is normally released by macrophages due to viral infection or other factors such as obesity (2). Overall this can cause a more intense production of chemokines and other inflammatory mediators via the transcription factor NF-xB (2). Ultimately, this study highlighted that between the unfolded protein response and NF-xB pathways which play a relevant role in the inflammation of the islets of Langerhans which further aggravates and prolongs the inflammation in obese and insulin resistant people which can then result in the development of diabetes (which is caused by the onset of insulin resistance) (2).
There is also a study that was aiming to determine whether fatty acids regulate insulin resistance through an endogenous inhibitor of insulin signalling known as tribbles homologue 3 (TRIB3 is a protein kinase) (3). This study tested whether regulation of TRIB3 occurred though ER stress and whether modulating TRIB3 and ER stress marker genes was necessary for regulation of insulin signalling. The diet fed mice an obesogenic diet and assessed the physiological variables of diabetes, ER stress markers and TRIB3 expression within the liver (3).This study found that hepatic ER stress can be mediated by the composition of dietary fat rather than the total amount (3). The saturated fatty acids reduced the insulin sensitivity and hence the unsaturated fatty acids prevented the insulin resistance (3). Overall this study found that mice fed on an obesogenic diet resulted in a reduced insulin sensitivity (3).
From all of these mechanisms discussed from the previous findings it is indicated that obesity can produced many events causing endoplasmic reticulum stress that leads to insulin resistance from the emergence of inflammatory responses.
It is also observed in previous studies that a cell signalling protein involved in system inflammation known as tumour necrosis factor alpha (TNF-a) can impair insulin action. TNFa is a proinflammatory and immunoregulatory cytokine with diverse actions throughout the body (4). It has been shown that TNF-a production levels are higher in adipose tissue and is associated with obesity (4).
A study observing seventeen obese patients with type two diabetes and thirty three non-obese diabetic controls underwent twelve weeks of a thirty percent energy restriction (4). Throughout every four weeks, weight and blood pressure were measured and fasting venous blood was analysed for lipid, glucose and insulin concentrations (4). At the beginning and end of the energy restriction intervention the TNFa levels were also measured (4). This study's results concluded that maximal production of TNF-a from mononuclear cells decreases with energy restriction and weight loss (4). This study also highlighted that healthy control subjects had a reduction in TNF-a production whilst the subjects with type 2 diabetes had a borderline significant reduction (4). Overall this study highlights that TNF-production is higher in obese subjects which can contribute to insulin resistance (4). The study also suggests that those with an insulin resistance present higher levels of TNF-a from the results given by diabetic subjects (4). However, it is important to consider how TNF-a can actually cause insulin resistance and the mechanisms behind it in order to gain a better understanding.
Regulation of insulin sensitive glucose transporters (GLUT4) and insulin receptors can contribute to insulin resistance (5). It is found that insulin resistance will be multifactorial where multiple mechanisms can contribute to the final phenotype (5). TNF-a clearly has an effect on the catalytic activity of the insulin receptor (5). In many cells types including the adipocytes, fibroblasts, hepatoma cells and myeloid 32D cells TNF-a treatment can lead to a reduction of insulin stimulated insulin receptor autophosphorylation and subsequent inhibition of IRS-1 phosphorylation without affect the number of receptors or the insulin binding capacity (5).
Similarly, a study noted that TNF-a mediated inhibition of insulin induced tyrosine phosphorylation was observed in the muscle of fat tissues of the obese and insulin resistant rats (5). This found that the insulin receptor itself is modified or that TNF-a promotes the production of an inhibitor of the receptor that is associated with the preparations (5). TNF-a can also induce the serine phosphorylation of insulin receptor substrate 1 (IRS-1) in some of the cultured adipocytes and hepatoma cells which modified the IRS-1 and resulting in an inhibition of the signalling mechanism of the insulin receptor (5). However, there were some myeloid cells which lacked the endogenous IRS-1 and were resistant to the effect of TNF-a on the insulin receptor tyrosine phosphorylation (5). When the IRS-1 was present the insulin receptor became very sensitive to the TNF-a meaning that IRS-1 is necessary for the inhibition of the insulin receptor signalling by TNF-a (5). These results provide the knowledge required to present the fact that TNF-a can induce insulin resistance.
Obesity can cause insulin receptor substrate modifying enzymes to activate Jun N terminal kinase (JNK), inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-ß) and protein kinase C which are central to mediating insulin resistance. It has be thought that JNK is essential to the pathogenesis of insulin resistance and type 2 diabetes (6).
Some recent studies have indicated the JNK-1 deficiency results in protection from genetic and dietinduced obesity and insulin resistance (6). The critical role of liver JNK activity was also demonstrated by linking liver-restricted activation or suppression of JNK-1 to strong systemic metabolic regulation indicating this is the role of JNK in insulin resistance (6).
One study shows that JNK-1 activity can be increase when subjects were placed on a high fat diet (6). The results revealed JNK-deficiency had a modest reduction in adiposity for those on a high fat diet (6). Furthermore, this study highlights that JNK1 plays an important role in terms of the regulation of cytokine expression in adipose tissue and the development of insulin resistance in type 2 diabetes (6). It was also seen that the inflammatory kinase IKK-ß where its liver-restricted activation or suppression was sufficient to alter insulin action (6). If there was interference with the regulators of the inflammatory pathways of IKK-ß it has also been demonstrated to give partial protection from insulin resistance (6). Activation of IKK-ß can initiate inhibitory IRS-1 serine phosphorylation which can lead to insulin resistance (8). If inhibition of the IKKß activity occurred in the hypothalamus than insulin sensitivity could be improved (8). Overall this indicates that activation of these kinases shown in those with a higher fat percentage may contribute towards insulin resistance.
Furthermore a study looking at another kind of enzyme IKK epsilon and it effects on mice fed a high fat diet aimed to determine the role it has in insulin resistance (8). IKK epsilon is expressed in neurons and upregulated in the hypothalamus of obese mice which can contribute to insulin sensitivity (8). The results from this study highlighted that by blocking IKK epsilon in the hypothalamus it reduces IRS -1 serine phosphorylation and decreases the risk of developing insulin resistance (8). This particular study emphasized that IKK epsilon levels have been shown that have higher levels in the liver and adipose tissues of animals fed a high-fat diet (8). Furthermore, the results showed that IKK epsilon expression and activity was increased in obese mice (8). The obese mice had increased protein levels of IKK epsilon compared to the control mice (8). It was also shown that activity of IKK epsilon was also increased in the hypothalamus of the mice who were fed a high fat diet compared to the mice on a regular control diet (8). This study highlights that by following a diet high in fat which can lead towards obesity or becoming overweight can increase the activity and effect of the kinase IKK epsilon (8). This study showed that increased activity of IKK epsilon can contribute to insulin resistance as its hypothalamic inhibition can improve insulin action towards energy and glucose metabolism (8).
Overall it is found from this supporting evidence that body composition can influence insulin sensitivity. Studies have supported that obesity can cause endoplasmic reticulum stress which results in an accumulation of unfolded proteins (1). Due to this response the supporting evidence found that there was a decrease in insulin sensitivity (1). Furthermore, there were also many studies which found those who obtained a higher fat percentage within their body composition also expressed higher levels of tumour necrosis factor alpha which is a proinflammatory cytokine which can impair insulin action (4).
Obesity can also have the effect of activating certain kinases known as JNK and IKK-ß (6). These kinases have a role in insulin resistance by initiating inhibitory IRS-1 serine phosphorylation which can lead to insulin resistance (6). JNK1 plays an important role in terms of the regulation of cytokine expression in adipose tissue and the development of insulin resistance in type 2 diabetes (6). However, it has been identified in previous studies if IKK-ß inflammatory pathway was interfered with then insulin sensitivity would be improved (6).
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Another study looked at the kinase IKK epsilon and was shown to have increased levels in obese mice (8). IKK epsilon can contribute towards insulin resistance by also contributing to IRS1-serine phosphorylation and decreasing the effects of insulin and its sensitivity (8). Ultimately this evidence found from the previous studies identify that body composition can contribute towards insulin sensitivity and furthermore indicate that obesity can lead towards insulin resistance.
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Reference 3: The significance of this paper was that it researched how saturated fatty acids causes insulin resistance (3). A reason why this paper was chosen was because it is known that saturated fatty acids are linked to increasing the risk of obesity within individuals and it identified how this can effect insulin sensitivity (3). I aimed one of my arguments towards looking at endoplasmic reticulum stress and how it can induce insulin resistance (3). This paper was helpful in clarifying how a diet influencing body composition can initiate endoplasmic reticulum stress leading to a decrease in insulin sensitivity (3).
Reference 4: This paper was used throughout my argument as it assessed Tumour Necrosis Factor-alpha production in adipose tissue (4). This study was relevant to the critical essay as it has been identified that production of Tumour necrosis factor-alpha is a proinflammatory cytokine that is associated with insulin resistance (4). This study helped to develop my argument that body composition can cause insulin resistance as the results indicated that weight loss causes a decrease in Tumour-Necrosis Factor-Alpha (4). This means that those with a lower body fat percentage would produce lower amounts of this cytokine which will decrease the risk of developing insulin resistance (4).
Reference 8: This research was used throughout the essay as it identified how IKK Epsilon can contribute towards insulin resistance (8). It also looked at the activity levels of the enzyme between obese and non-obese mice (8). The results supported my arguments that body composition can contribute to insulin resistance as the expression and activity of the enzyme in the hypothalamus were increased in obese mice (8). It is identified throughout the study that IKK epsilon can contribute towards insulin resistance as it is a key inflammatory mediator in the hypothalamus (8). Overall these results supported the argument that due to increased activity and expression of IKK epsilon in obese mice this identifies that obesity can contribute towards insulin sensitivity (8).
Reference 6: This paper was used as evidence throughout the critical essay as c-Jun Nterminal kinase 1 is identified as being essential to the pathogenesis if insulin resistance (6). The results from this study identified that JNK-1 deficiency in the bone marrow was sufficient to improve insulin sensitivity (6). It also highlighted that JNK-1 deficiency was less likely to occur in those who followed a high fat diet (6). A diet higher in fat is linked to increasing body fat percentage concluding that body composition can influence insulin sensitivity (6).
Reference 9: The reason for using this paper was it allowed for a better understanding of how insulin resistance can occur and the mechanisms behind it (9). In particular this paper looks at the serine phosphorylation of insulin receptor substrate 1 (signalling adaptor protein) (9). It highlights that insulin resistance can be induced by the serine phosphorylation of insulin receptor 1 and suggests that under conditions of nutrient saturation it can negatively regulate insulin signalling and sensitivity (9). This nutrient saturation can lead towards individuals becoming overweight or obese underlining the fact that again body composition is a contributing factor of insulin sensitivity (9).
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