INFLAMMATION, OBESITY, AND INSULIN RESISTANCE: UNDERSTANDING THE CONNECTION AND EVALUATING TREATMENT APPROACHES AND  DIETARY EFFECTS 

IYRC DOI: http://doi.org/10.34614/2023IYRC_F52 

INFLAMMATION, OBESITY, AND INSULIN RESISTANCE: UNDERSTANDING  THE CONNECTION AND EVALUATING TREATMENT APPROACHES AND  DIETARY EFFECTS 


ABSTRACT: Insulin resistance is a widespread disorder that attenuates insulin signalling causing cells to not  respond to insulin properly, thus increasing the amount of glucose in the bloodstream. It is responsible for one of  the most fatal human diseases: Type 2 Diabetes Mellitus. Insulin resistance effects can be traced down to  inflammatory responses, inflammatory pathways, and inflammatory mediators. Obesity was determined to be one  of the most common causes of insulin resistance due to its connection with inflammation which occurs due to  adipose tissue hypoxia. Several treatments are used nowadays to treat insulin resistance such as concentrated  insulin does and metformin. They show great results, especially when used together. Anti-inflammatory drugs are  currently being subjected to testing. They are expected to inhibit the inflammatory response which promotes  insulin resistance. Such drugs include etanercept and anakinra. Both show positive results in inhibiting  inflammation; however, they aren’t ready for mass production. Diet composition and lifestyle greatly influence  insulin resistance as it was proven that acute caffeine intake decreases insulin sensitivity. More plant-based objects  and less animal-based objects in a diet play a role in lowering insulin resistance. Finally, sugar intake plays a huge  role in insulin resistance, and it was proven that added sugars have more severe effects on insulin resistance than  natural sugars. 

1. INTRODUCTION 
The human body has various ways of establishing homeostasis. To establish homeostasis in blood glucose levels,  the pancreas secretes two hormones: glucagon and insulin. Insulin is a peptide hormone secreted by the beta cells  of the pancreas. It is responsible for reducing blood glucose levels by facilitating cellular glucose uptake. Insulin  receptors mediate insulin’s effect via enzymatic activity [1]. However, sometimes cells don’t respond properly to  insulin, and the biological response is attenuated, a phenomenon known as insulin resistance. Insulin resistance is  a severe disorder that shouldn’t be taken lightly as it is responsible for Type 2 Diabetes Mellitus. Patients are  characterized by high levels of glucose in the blood and urine due to the ineffectiveness of the insulin hormone.  Around 462 million individuals suffer from Type 2 diabetes [2]. The number is expected to rise to 552 million by  2030[3]. Type 2 diabetes was also responsible for more than 1 million deaths in 2017 making it the ninth leading  cause of mortality [2]. Obesity is one of the main risk factors for insulin resistance [4]. An obese individual is an  individual who has a body mass index (BMI) greater than 35 (BMI > 35 kg/m^2) [5]. Obesity is characterized by  the accumulation of excess body fat that causes health risks (according to the WHO). It is estimated that a third of  the world’s population suffers from obesity [6]. The accumulation of lipids and fats in adipose tissue causes a  condition called adipose tissue hypoxia causing the tissue to expand and inflame, thus producing an inflammatory  response that promotes insulin resistance [7] Other factors such as mitochondrial dysfunction and genetics  contribute to insulin resistance [4]. Many treatments are currently being used to treat insulin resistance, most  notably U-500 and metformin. Anti-inflammatory drugs are currently being tested as well. They aim to inhibit the  inflammatory response that triggers insulin resistance. Most of them have shown great results in inhibiting  inflammation. However, they aren’t ready for use by the public as they are still under development. Dietary composition plays a major role in insulin resistance. For example, hypercaloric diets cause obesity which causes  insulin resistance. Plant based diets are proven to lower insulin resistance. Excessive sugar intake was also proven  to trigger and improve insulin resistivity especially added sugars that are found in beverages.
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2. INFLAMMATION: DEFINITION AND MECHANISMS 
Inflammation is a fundamental biological response that the body activates in reaction to tissue damage, infection,  or harmful stimuli. This intricate process serves to protect the body from further harm and promote the healing of  affected tissues. Understanding the mechanisms underlying inflammation is crucial for comprehending its role in  various physiological processes and its connection to insulin resistance and other metabolic disorders. [8]  Inflammation is an ancient and evolutionarily conserved defence mechanism that aims to restore tissue  homeostasis following damage or infection. It is characterized by a series of physiological changes that occur at  the site of injury, including redness, swelling, heat, and pain. These visible and perceptible manifestations are  indicative of the body's attempts to counteract harmful stimuli and initiate the repair process.[9] The inflammatory  process involves a complex interplay between various cell types, signalling molecules, and biochemical pathways.  At the cellular level, resident immune cells such as macrophages, neutrophils, and mast cells are activated upon  detection of damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs)  [10]. This activation triggers the release of pro- inflammatory cytokines, which act as alarm signals, alerting the  immune system to the presence of potential threats [9]. Immune cells play a pivotal role in orchestrating the  inflammatory response [9]. Macrophages, for instance, phagocytize cellular debris and pathogens as demonstrated  in Figure 1, while neutrophils are rapidly recruited to the site of injury to counter microbial invasion. Mast cells,  residing in tissues, release histamines and other mediators that promote vasodilation and increase blood flow to  the affected area. Pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukins, are  secreted by immune cells and amplify the immune response. They induce inflammation by activating various  signalling pathways that contribute to the recruitment of more immune cells and the enhancement of tissue repair  processes. 

3. INSULIN RESISTANCE: DEFINITION AND SIGNIFICANCE 

Figure 1 shows a diagrammatic representation of  
phagocytosis.
Insulin resistance stands as a pivotal concept in the realm of metabolic health, representing a diminished sensitivity  of cells to the actions of insulin, a crucial hormone that regulates glucose homeostasis. The understanding of insulin  resistance is imperative for comprehending the intricate interplay between metabolism, cell function, and the  development of various chronic diseases. Insulin resistance is characterized by a diminished ability of target  cells—predominantly muscle, liver, and adipose tissue—to respond effectively to the actions of insulin. This  diminished sensitivity leads to an impaired capacity of cells to uptake glucose from the bloodstream, resulting in  elevated blood glucose levels. Over time, the pancreas compensates for this resistance by secreting higher levels  of insulin to maintain glucose control. Insulin resistance serves as a critical precursor to the development of type  2 diabetes, a widespread metabolic disorder characterized by chronically elevated blood glucose levels. The  reduced ability of cells to take up glucose, combined with the inability of pancreatic beta cells to secrete sufficient  insulin, culminates in uncontrolled hyperglycaemia. Over time, prolonged exposure to high glucose levels can lead  to a cascade of complications, including cardiovascular disease, neuropathy, and nephropathy [9]. Beyond its role  in diabetes, insulin resistance is intricately linked to the development of various metabolic disorders. It contributes  to the development of obesity by disrupting the balance between energy intake and expenditure. Additionally,  insulin resistance plays a role in dyslipidaemia, the abnormal levels of lipids in the bloodstream, which further  heightens the risk of cardiovascular diseases [11]. The implications of insulin resistance extend beyond metabolic  disorders and encompass a wide range of health conditions. Inflammation, a hallmark feature of insulin resistance,  
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contributes to the progression of atherosclerosis and cardiovascular diseases. Furthermore, insulin resistance has  been linked to non- alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and even certain  types of cancers [12] 

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4. INFLAMMATORY PATHWAYS AND INSULIN SENSITIVITY

Inflammation, once recognized solely as a response to infection or injury, has emerged as a key player in the  complex web of metabolic regulation. The interplay between inflammation and insulin sensitivity is critical to our  understanding of the development and progression of insulin resistance, offering insights into the molecular  mechanisms that link chronic inflammation to disrupted glucose homeostasis [13]. Inflammation has the potential  to disrupt the complicated balance of insulin signalling pathways, leading to diminished insulin sensitivity in target  tissues. This phenomenon, referred to as "inflammatory insulin resistance," involves the dysregulation of  intracellular signalling cascades that underlie glucose uptake, storage, and metabolism [11]. Pro-inflammatory  cytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), are central players in the  crosstalk between inflammation and insulin signalling. These cytokines are secreted by immune cells in response  to various stimuli, including chronic low-grade inflammation associated with obesity. Once released, pro inflammatory cytokines disrupt insulin signalling pathways by phosphorylating insulin receptor substrate-1 (IRS 1) at specific serine residues. This phosphorylation event interferes with the transduction of insulin’s signal  downstream, reducing the ability of cells to efficiently respond to insulin’s glucose-lowering effects.[14].  Intracellular mechanisms that link inflammation to insulin resistance encompass a network of enzymes known as  kinases and transcription factors. The serine/threonine kinases, such as IKB kinase (IKK) and c-Jun N-terminal  kinase (JNK), play pivotal roles in phosphorylating IRS-1 and activating nuclear factor kappa B (NF-B), a  transcription factor that orchestrates inflammatory responses. Activation of NF-B leads to the transcription of pro inflammatory genes, creating a positive feedback loop that amplifies inflammation and exacerbates insulin  resistance. Additionally, inflammatory pathways can cross-communicate with those involved in lipid metabolism,  further complicating the intricacies of insulin signalling [12]. 

5. OBESITY AND INFLAMMATION 
Adipose tissue blood flow rate and muscle blood flow rate are approximately 30 -40% lower in obese individuals  than in healthy individuals [15]. It appears that oxygen delivery to adipose tissue is impaired in obese individuals  [16,15]. It was thought that this happens due to the increase in adipocyte diameter. Excess lipids that are stored in  the adipocytes cause them to expand above the normal diffusion distance of oxygen across tissues (100–200 μm).  Therefore, large adipocytes form a barrier that blocks oxygen diffusion [15]. However, studies have shown that  adipocyte diameter rarely exceeds 100 μm in obese individuals thus debunking the theory [17.15]. This suggests  that reduced blood flow due to obesity causes ATH. When body fat content exceeds more than 20% of body  weight, adipose tissue hypoxia may develop [18,15]. While oxygen tension in adipose tissue decreases by 75%  with obesity, adipose tissue blood flow is still reduced by 40%. In obese adipose tissue, the variations in blood  flow and oxygen tension are not proportionate. However, the difference between the two values may be influenced  by the barrier effect of big adipocytes. ATH is considered the underlying cause of inflammation. It is the cause of  necrosis and macrophage infiltration in adipose tissue, promoting inflammation. By stimulating the gene  expression in adipocytes and macrophages, hypoxia can cause inflammation in adipose tissue. Using primary cells  and cell lines, this possibility was illustrated. TNF-, IL-1, IL-6, MCP-1 (monocyte chemoattractant protein-1),  PAI-1 (plasminogen activator inhibitor-1), MIF (macrophage migration inhibition factor), iNOS (inducible nitric  oxide synthase), MMP9 (matrix metalloproteinases 9), and MMP2 are among the genes that are stimulated. Even  though the adipose tissue is highly vascularized, the over-expansion of existing fat cells can create hypoxia, which  activates the HIF-1 gene [15]. In a recent study, hypoxia was proven to induce insulin resistance in mice [19]. 

6. MOLECULAR CROSSTALK BETWEEN IMMUNE SYSTEM 
and Insulin Signalling intricate interplay between the immune system and insulin signalling pathways highlights  the dynamic nature of metabolic regulation [14]. Molecular crosstalk between immune cells and insulin-sensitive  tissues serves as a critical nexus where inflammation and metabolic responses converge, unveiling a complex array  of interactions that impact insulin sensitivity and resistance. The dialogue between immune cells and insulin  sensitive tissues is a multifaceted process that influences metabolic outcomes. Adipose tissue, for instance, houses  both immune cells and adipocytes. Macrophages infiltrate adipose tissue during obesity, fostering an inflammatory  microenvironment. This altered milieu compromises insulin signalling in adipocytes, reducing their ability to  uptake glucose and promote lipid storage [10]. Beyond adipose tissue, immune cells such as macrophages infiltrate  the liver, contributing to hepatic inflammation and impairing insulin’s ability to suppress gluconeogenesis. This  interaction ultimately promotes hyperglycaemia, a hallmark of insulin resistance [13]. Inflammatory mediators,  such as free fatty acids and cytokines, further exacerbate insulin resistance by interfering with insulin action at 
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multiple levels. Free fatty acids, released during lipolysis in adipose tissue, accumulate in no adipose tissues such  as muscle and liver. They disrupt insulin signalling pathways by activating kinases that phosphorylate IRS-1 and  hinder its function. Also, cytokines like TNF-α and IL-6 activate signalling pathways that converge with insulin  signalling, promoting inflammation and insulin resistance. These cytokines can disrupt insulin receptor function,  impair insulin receptor substrate phosphorylation, and hinder the translocation of glucose transporters to the cell  membrane [14].

 
VII. INFLAMMATION IN SPECIFIC METABOLIC DISORDERS

The intertwining of inflammation and metabolic disorders underscores the far-reaching implications of chronic  immune activation in the context of insulin resistance. Examining specific metabolic disorders unveils the intricate  mechanisms through which inflammation contributes to the pathogenesis and progression of these conditions [12].  Type 2 diabetes, characterized by hyperglycaemia resulting from impaired insulin sensitivity and secretion,  presents a clear link between inflammation and metabolic dysfunction. Chronic low-grade inflammation is a  hallmark of type 2 diabetes, fuelled by adipose tissue dysfunction and infiltrating immune cells. Elevated levels of  proinflammatory cytokines contribute to insulin resistance by disrupting insulin signalling pathways, ultimately  exacerbating hyperglycaemia. The activation of inflammatory pathways, such as those mediated by NF-B and  JNK, compromises pancreatic beta-cell function and insulin secretion. This dual impact of inflammation on insulin  sensitivity and secretion creates a vicious cycle that contributes to the progression of type 2 diabetes [11].  Cardiovascular diseases, intimately connected to insulin resistance and metabolic disorders, are also profoundly  influenced by inflammation. Atherosclerosis, atherosclerotic plaque formation, and subsequent cardiovascular  events share a strong association with inflammation. Inflammation within the vascular endothelium initiates the  recruitment of immune cells, promoting the development of fatty streaks and atherosclerotic lesions. In individuals  with insulin resistance, the inflammatory milieu further enhances the risk of cardiovascular diseases. Pro inflammatory cytokines contribute to endothelial dysfunction, impairing nitric oxide production and promoting  vasoconstriction. Moreover, inflammation disrupts lipid metabolism, fostering a state of dyslipidaemia that  exacerbates atherosclerotic processes [20]. Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic  fat accumulation in the absence of significant alcohol consumption, is intrinsically linked to insulin resistance and  inflammation. The activation of inflammatory pathways within the liver contributes to the progression from simple  steatosis (fatty liver) to non-alcoholic steatohepatitis (NASH), which involves inflammation and liver cell injury  [20]. 

Figure 2 shows general guidelines for U-500 doses for patients  
transitioning from U-100
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8. PHARMACOLOGICAL TREATMENTS TO INSULIN RESISTANCE

There is no clear solution or treatment for patients with severe insulin resistance. Until recently, insulin was the  only treatment for insulin resistance. However, new pharmacological treatments are emerging to help combat  insulin resistance. Anti-inflammatory drugs were also proposed to improve insulin sensitivity. I. Concentrated  Insulin Doses When a patient requires very high doses of insulin, concentrated insulin solutions can help improve  insulin delivery. U-500 insulin is the primary treatment for most patients with severe insulin resistance [21]. Each  1 ml of U-500 regular insulin (U-500R) contains 500 units of the hormone after being five times concentrated. As  a result, the amount of insulin injected is lowered by 80%, leading to fewer injections, less pain, and possibly  better insulin absorption [22]. When daily insulin doses exceed 200 units/day, delivering the required amount of  U-100 insulin can be challenging. A syringe can only hold a maximum of 100 units of insulin, while an insulin  pen device can hold 60-80 units [21]. Furthermore, administering doses larger than 1 mL in volume can be  uncomfortable for the patient and may affect how well the insulin is absorbed. The onset time of U-500 is quite  like the onset time of U100 which is about 30 to 45 minutes and duration of action (12–14 hours) for U-500 is like NPH insulin. Several studies were conducted on patients with severe insulin resistance who switched from U-100  to U-500. These studies showed a decrease in the mean of A1C by 1.59% (an A1C test measures the amount of  sugar-coated haemoglobin in the blood). The patients also didn’t exhibit signs of severe hypoglycaemia when  converting [21]. Doses should be administered accordingly when transitioning. Figure 2 shows a general guideline  for patients who are transitioning from U-100. 

8.1. Metformin 
The American Diabetes Association recommends metformin as the first pharmacological option for patients with  severe insulin resistance. Metformin is widely prescribed as an insulin-sensitizing agent. It mainly works by  improving the suppression of the production of hepatic glucose caused by insulin and enhancing insulin-triggered  disposal of glucose in peripheral tissues. It is common practice to combine U-500 and metformin. In patients who  don’t exhibit severe insulin resistance metformin reduces the insulin requirements and contributes to glycaemic 
control and weight. Experiments show that combining metformin and insulin therapy provides superior glycaemic control [23]. However, metformin is known to have gastrointestinal side effects which may cause discontinuing  therapy [21]. 

8.2. Anti-inflammatory Drugs 
Since inflammation and inflammatory mediators play a major role in promoting insulin resistance, drugs are being  developed to help inhibit the inflammatory response. These drugs are still in testing and not available for  commercial use. One example is etanercepts, a dimeric fusion protein that links the Fc portion of human  Immunoglobin G1 (IgG1) to the extracellular ligand binding domain of the Tumour Necrosis Factor Receptor  (TNFR), effectively blocking the receptor [24]. The peripheral absorption of glucose in response to insulin  significantly increased in obese rats after TNF-alpha was neutralized. These findings suggest a function for TNF 
alpha in obesity, particularly in the diabetes and insulin resistance that frequently accompany fat [25]. 56  individuals with the metabolic syndrome were randomly assigned to receive either etanercept 50 mg  subcutaneously once a week for 4 weeks or an identical placebo. The main outcome was the concentration of C reactive protein, a protein whose concentration increases during inflammation. The results show that the  concentration of CRP decreased more significantly because of etanercept opposed to the placebo (-2.4 +/- 0.4 vs  0.5 +/- 0.7 mg/L) as shown in Figure 3[26]. However, it did not improve insulin sensitivity in those patients. This  might be because the concentration of TNF- inside cells is almost two times higher than it is outside cells, and  because etanercept did not prevent the paracrine actions of intracellular TNF- that cause insulin resistance [24].A  non-glycosylated version of the Human IL-1 Receptor Antagonist (IL-1Ra), Anakinra (153 amino acids, 17.3 kilo  Dalton) varies from IL1Ra only by the inclusion of a single methionine residue at the amino terminus.  Recombinant DNA technology is used in E. coli to create it. Inhibited insulin production, reduced cell proliferation,  and pancreatic cell death are all caused by IL-1. Patients with T2DM have lower quantities of IL-1Ra, which is  produced endogenously, in their pancreatic islets. When used to treat T2DM, anakinra showed promise in boosting  beta cell secretory function, lowering blood sugar levels, and reducing signs of systemic inflammation. Other drugs  such as Vitamin D, Salsates, and more were tested for the same purpose. However, they are still in testing and  aren’t ready for mass production [24]. 

9. IMPACT OF DIET COMPOSITION ON INSULIN RESISTANCE

Diet composition and lifestyle greatly influence insulin sensitivity in cells. For example, caffeine was proven to  increase blood pressure and decrease insulin sensitivity in cells [29, 30]. More recently, it was discovered that a  long-term intake of coffee prevents insulin resistance [29], suggesting that acute intake of caffeine and chronic  intake have inverse effects on insulin sensitivity. As a result, in recent decades, physicians have advised 
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hypertensive and diabetic patients to limit their caffeine intake. An increasing fraction of the global population is  adopting a variety of varied food habits. The volumes, proportions, variety, or mix of various foods, beverages,  and nutrients in diets, as well as the regularity with which they are consumed, are referred to as diet patterns. Some  of these diets are known to have adverse effects on health such as hypercaloric diets, however, others are known  to have health benefits. Research conducted by Banaszak et al to investigate the effects of plant-based diets on  insulin resistance, states that vegetarian and vegan populations have better blood parameters, and that more plant 
based foods and fewer animal foods in a diet result in lower insulin resistance and a lower risk of prediabetes and  type 2 diabetes [30]. It can be agreed that increased sugar intake is associated with insulin resistance. Sugar can  be categorized into two types: intrinsic or natural sugars and extrinsic or added sugars. Natural sugars are naturally  present in fruits (as the name suggests). Added sugars include sucrose, fructose, glucose, starch hydrolysates and  other isolated sugar preparations added during food preparation and manufacturing [27]. These medical illnesses  have been shown to be affected differently by both intrinsic and added sugars, with added sugars being strongly  linked to metabolic diseases. But whether the natural sugars found in fruit juices are equally hazardous as those  added to beverages is still up for debate. Research conducted by Monteiro-Alfredo et al aims to answer this  question [31]. The impact of four different fruit juices administered across four weeks with sugary solutions having  a similar sugar profile and concentration on weight, hyperglycaemia, glycation and oxidative stress in control and  diabetic animal models were compared. They showed that added sugars, which have a worse glycaemic profile  and raise levels of glycation and oxidative stress, especially in tissues like the heart and kidney, have a more severe  effect on metabolic control than naturally occurring sugars in fruit juices [31]. 

10. FUTURE DIRECTIONS AND IMPLICATIONS 

Figure 3 shows changes in CRP concentrations when etanercept was  
administered and when a placebo was administered in mg/ml.
The exploration of the intricate relationship between inflammation and insulin resistance not only enhances our  understanding of metabolic health but also points toward promising avenues for future research and therapeutic  interventions. Anticipating the trajectory of this field holds potential for advancing personalized medicine and  improving clinical outcomes. Numerous avenues remain ripe for exploration in the realm of inflammation and  insulin resistance. Unravelling the molecular intricacies of immune-metabolic crosstalk, understanding the role of  gut microbiota in inflammation-induced insulin resistance, and deciphering the dynamics of chronic versus acute  inflammation in metabolic disorders represent areas of ongoing research. Investigations into the influence of  genetic factors on susceptibility to inflammation-related insulin resistance is also gaining prominence, as are  studies elucidating the role of epigenetic modifications in mediating the impact of environmental factors on  metabolic outcomes. The era of personalized medicine holds immense promise for individuals at risk of or already  grappling with insulin resistance and related metabolic disorders. The individualized assessment of inflammatory  markers, genetic predispositions, and metabolic profiles can guide tailored interventions aimed at mitigating  inflammation and enhancing insulin sensitivity. By identifying subgroups of individuals who may respond more  favourably to specific anti-inflammatory interventions, personalized approaches hold the potential to optimize  therapeutic outcomes and reduce the burden of metabolic diseases. Precision targeting of inflammation-related  pathways could revolutionize the management of insulin resistance and its associated health complications.  Translating research findings into clinical practice represents a pivotal step in the journey toward improving  metabolic health. As our understanding of the interplay between inflammation and insulin resistance deepens, the  
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development of evidence-based guidelines for clinicians becomes paramount. Clinical interventions that integrate  anti-inflammatory strategies, such as lifestyle modifications, pharmacological agents, or even targeted dietary  interventions, have the potential to mitigate insulin resistance and its downstream consequences. The collaboration  between researchers, clinicians, and policymakers ensures that advancements in understanding inflammation’s  role in insulin resistance led to meaningful improvements in patient care and public health. 

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