Exploring the Function of Inflammatory Routes in Insulin Resistance: Interpreting the Inflammatory Veil of Medusa

Abstract

A common component of metabolic diseases including metabolic syndrome and type 2 diabetes, insulin resistance is now known to be closely linked to persistent low-grade inflammation. This chapter explores the intricate connection between insulin resistance and inflammatory pathways, clarifying the molecular processes that underlie inflammation-induced insulin resistance. We examine the part that important inflammatory mediators play in upsetting insulin signalling pathways and encouraging insulin resistance, including cytokines, chemokines, and adipokines. We also go over how inflammatory signalling cascades, like the JNK and NF-κB pathways, affect insulin sensitivity and cellular metabolism. Understanding the interaction between insulin resistance and inflammation can help to better understand the pathogenesis of metabolic diseases and identify possible treatment targets. In people who are at risk of developing issues associated with insulin resistance, strategies targeted at reducing inflammatory responses may be able to reduce insulin resistance and enhance metabolic health.

1. Introduction

Insulin resistance (IR) is a major contributor to the pathophysiology of metabolic diseases, such as metabolic syndrome and type 2 diabetes mellitus (T2DM), and it has a substantial impact on global health. According to newly available data, insulin resistance develops and progresses as a result of a complex interplay between inflammatory and metabolic pathways and persistent low-grade inflammation. Insulin resistance has many facets, and the idea that it is the “Medusa of the 21st Century” effectively conveys this. One of its veils is inflammation, which obscures its underlying mechanisms.

Several studies have demonstrated the connection between inflammation and insulin resistance, linking inflammatory mediators to insulin signalling pathway disruption and glucose homeostasis impairment [1, 2]. These mediators include cytokines, chemokines, and adipokines. Among them, interleukin-6 (IL-6), adiponectin, and tumour necrosis factor-alpha (TNF-α) have become important participants in the inflammatory cascade, influencing insulin sensitivity both locally and systemically [3, 4].

Furthermore, complex signalling pathways, such as c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-κB), facilitate the interaction between insulin resistance and inflammation, causing metabolic processes to become dysregulated and accelerating the development of metabolic diseases [5, 6]. Insulin receptor substrate (IRS) proteins get phosphorylated when these pro-inflammatory pathways are activated, upsetting insulin signalling cascades and ultimately resulting in insulin resistance [7].

To reduce inflammation and restore metabolic balance, specific therapeutic approaches that comprehend the molecular pathways behind inflammation-induced insulin resistance are necessary. We can create individualised strategies for treating insulin resistance and its related problems by dissecting the intricacies of this complicated interaction.

We explore the role of inflammatory pathways in insulin resistance in this chapter, looking at the molecular mechanisms through which inflammation fuels insulin resistance and the consequences for metabolic health. We seek to clarify the inflammatory veil that covers Medusa and provide insight into prospective targets and tactics for treating insulin resistance-related illnesses by conducting a thorough analysis of recent literature and emerging research discoveries.

2. Literature review

The pathophysiology of insulin resistance and related metabolic problems is largely dependent on persistent low-grade inflammation, as demonstrated by a large number of studies. Clarifying the processes behind inflammation-induced insulin resistance and discovering possible treatment targets require an understanding of the complex interactions between inflammatory mediators and signalling pathways.

TNF-α has been identified as a crucial mediator between inflammation and insulin resistance. Through the activation of serine kinases including c-Jun N-terminal kinase (JNK) and IκB kinase (IKK), which phosphorylate insulin receptor substrate (IRS) proteins and interfere with downstream insulin signalling, TNF-α has been shown in experimental experiments to block insulin signalling pathways [1, 2]. Clinical research has demonstrated increased TNF-α levels in patients with type 2 diabetes mellitus (T2DM) and obesity, further linking TNF-α to the aetiology of insulin resistance [2, 8].

Another pro-inflammatory cytokine linked to the emergence of insulin resistance is interleukin-6 (IL-6). Research has indicated that persistent increase in IL-6 levels impedes insulin signalling and glucose absorption in skeletal muscle, which in turn leads to insulin resistance [9, 10]. Acute-phase proteins like C-reactive protein (CRP), which worsen insulin resistance and prolong the inflammatory response, are also secreted in greater amounts when IL-6 is present [11].

Adiponectin is a hormone generated from adipocytes that has anti-inflammatory characteristics. It is essential for regulating insulin sensitivity. Adiponectin levels and insulin resistance are inversely correlated, according to clinical research, with patients with metabolic diseases and obese people having lower adiponectin levels [4, 12]. Mechanistic investigations have demonstrated that adiponectin improves insulin sensitivity by triggering fatty acid oxidation and activating AMP-activated protein kinase (AMPK), which counteracts the inflammatory effects of IL-6 and TNF-α [4, 13].

Adipokines including resistin and leptin, in addition to cytokines, have been linked to the pathophysiology of insulin resistance. The hormone leptin, which is mostly released by adipocytes, controls hunger and energy balance. By influencing hypothalamic signalling pathways, it can also affect insulin sensitivity [14, 15]. Another adipokine called resistin has been demonstrated to increase insulin resistance in skeletal muscle and adipose tissue by obstructing insulin signalling and glucose uptake [16, 17].

One key mechanism connecting inflammation and insulin resistance is the activation of inflammatory signalling pathways, such as c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-κB). Experiments have shown that activation of NF-κB causes the expression of chemokines and pro-inflammatory cytokines, which exacerbates insulin resistance and accelerates the development of metabolic diseases [1, 2]. Similarly, by phosphorylating IRS proteins and upsetting insulin signalling pathways, JNK activation leads to insulin resistance [6, 7].

Overall, the review of the literature emphasises how important it is to target inflammatory pathways to prevent and treat metabolic illnesses, as well as how important inflammation is in the pathophysiology of insulin resistance.

3. Mechanisms of insulin resistance caused by inflammation

Insulin resistance is defined by a reduced ability of target tissues, including adipose, liver, and skeletal muscle, to respond to the effects of insulin. This leads to a decrease in the absorption and metabolism of glucose. As insulin resistance develops and progresses, chronic low-grade inflammation has been shown to play a significant role. Inflammatory mediators interfere with insulin signalling pathways on several levels [1, 2].

3.1 Insulin signalling pathway dysregulation

3.1.1 IRS protein serine phosphorylation

Serine kinases, such as IκB kinase (IKK) and c-Jun N-terminal kinase (JNK), are activated by inflammatory cytokines like TNF-α and IL-6. These kinases phosphorylate insulin receptor substrate (IRS) proteins on serine residues [2, 8]. By preventing the tyrosine phosphorylation of IRS proteins, this serine phosphorylation reduces insulin sensitivity and messes with downstream insulin signalling cascades [9, 10].

3.1.2 Blocking the PI3K/Akt pathway

By phosphorylating Akt (protein kinase B), phosphatidylinositol 3-kinase (PI3K) is essential for modulating the metabolic effects of insulin. Impaired glucose uptake and glycogen production can result from direct or indirect suppression of PI3K/Akt signalling by inflammatory signalling pathways such as NF-κB and JNK [18, 19].

3.1.3 Protein kinase C (PKC) isoform activation

PKC isoforms are activated by elevated amounts of the lipid second messenger diacylglycerol (DAG), which phosphorylates insulin receptor substrate-1 (IRS-1) and inhibits insulin-stimulated glucose uptake. These actions disrupt insulin signalling [20, 21].

3.2 Mitochondrial dysfunction and oxidative stress

3.2.1 Impairment in oxidative metabolism

Prolonged inflammation can cause disturbances in the synthesis and operation of mitochondria, resulting in impaired oxidative metabolism and mitochondrial dysfunction [22]. Insulin resistance is a result of decreased mitochondrial ATP synthesis and elevated reactive oxygen species (ROS) production, which impede insulin signalling and trigger cellular stress responses [23].

3.2.2 ROS-generated inflammatory pathways

Inflammatory signalling pathways, including NF-κB and JNK, are activated by ROS produced during mitochondrial failure, aggravating inflammation and insulin resistance [24].

3.3 Lipid accretion and lipotoxicity

3.3.1 Improved lipolysis and release of free fatty acids (FFA)

TNF-α and IL-6 are examples of inflammatory cytokines that promote lipolysis in adipose tissue, which increases the amount of free fatty acids released into the bloodstream [25]. Increased circulating FFA levels encourage the buildup of lipids in non-adipose tissues such as the liver and skeletal muscle, which exacerbates insulin resistance [26].

3.3.2 Lipid intermediate formation

Overindulgence in free fatty acids (FFAs) leads to the metabolism of lipid intermediates, including DAG and ceramides, which impede insulin signalling and enhance cellular stress responses [27]. For example, ceramides activate protein phosphatase 2A (PP2A), which inhibits insulin signalling and dephosphorylates Akt [28].

3.4 Dysregulation of adipokines and inflammation of adipose tissue

3.4.1 Macrophages in adipose tissue infiltration

Adipose tissue experiences dynamic remodelling in obesity and insulin resistance, which is typified by an increase in the infiltration of immune cells and pro-inflammatory macrophages [29]. TNF-α and IL-6 are among the inflammatory cytokines secreted by these activated immune cells, which lead to both local inflammation and systemic inflammation [30].

3.4.2 Dysregulated adipokine secretion

Insulin sensitivity and energy balance are regulated by adipokines, which are secreted by adipose tissue and include adiponectin, leptin, and resistin [31]. Dysregulated insulin signalling and metabolic dysfunction might result from adipocyte malfunction and inflammatory cytokines upsetting the balance of adipokine production [32].

Comprehending the complex processes via which inflammation leads to insulin resistance offers valuable perspectives on possible treatment targets and intervention tactics.

4. Clinical implications and associations

The development and progression of several metabolic disorders, such as type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and non-alcoholic fatty liver disease (NAFLD), are closely linked to insulin resistance, which is characterised by impaired target tissue responsiveness to insulin action. Insulin resistance has significant clinical implications. The pathophysiology of insulin resistance is largely influenced by chronic low-grade inflammation, which also contributes to the clinical symptoms and related consequences of the condition.

4.1 Correlation to T2DM (type 2 diabetes mellitus)

One of the main characteristics of type 2 diabetes is insulin resistance, which is characterised by peripheral organs such as the liver, adipose tissue, and skeletal muscle having decreased sensitivity to insulin action [1, 2].

Pro-inflammatory cytokines including TNF-α and IL-6, which are high in chronic inflammation, lead to insulin resistance and β-cell dysfunction, which in turn accelerates the development and progression of type 2 diabetes [2, 8].

High-sensitivity C-reactive protein (hs-CRP) and the risk of acquiring type 2 diabetes (T2DM) have been linked to inflammation through epidemiological research, indicating the clinical importance of inflammation-induced insulin resistance in the pathophysiology of diabetes [9, 10].

4.2 Correlation with cardiovascular disease (CVD)

Atherosclerosis, hypertension, and coronary artery disease are all made more likely in people who are insulin-resistant [33]. Insulin resistance is a major factor in determining cardiovascular risk.

By encouraging endothelial dysfunction, oxidative stress, and vascular inflammation, chronic inflammation adds to the pathophysiology of CVD by hastening the development of atherosclerosis and raising the risk of cardiovascular events [34].

The clinical relevance of inflammation-induced insulin resistance in cardiovascular health is highlighted by the greatly increased risk of cardiovascular disease (CVD) in patients with metabolic syndrome and insulin resistance [35].

4.3 Correlation with non-alcoholic fatty liver disease (NAFLD)

The emergence of NAFLD, a group of liver diseases that includes cirrhosis, non-alcoholic steatohepatitis (NASH), and simple steatosis, is directly linked to insulin resistance [36].

The aetiology of non-alcoholic fatty liver disease (NAFLD) is aided by hepatic insulin resistance, which raises hepatic glucose synthesis, de novo lipogenesis, and triglyceride accumulation [37].

Pro-inflammatory cytokines stimulate hepatic inflammation, fibrosis, and hepatocyte death, all of which are important factors in the development of non-alcoholic fatty liver disease (NAFLD) [38].

4.4 Clinical relevance for risk evaluation and control

Evaluation of inflammatory markers, including hs-CRP, interleukins, and adipokines, might give important information on the underlying inflammatory state and cardiovascular risk profile of insulin-resistant people [39].

It has been demonstrated that dietary changes, physical activity, and weight loss are among the lifestyle therapies that target inflammation and can enhance insulin sensitivity and lower cardiovascular risk in people with metabolic disorders [40].

Additional advantages in lowering cardiovascular risk and enhancing clinical outcomes for people with insulin resistance may come from pharmacological therapies like anti-inflammatory drugs and statins [41].

In order to reduce the burden of metabolic disorders and cardiovascular consequences, it is imperative to understand the clinical implications and connections of inflammation-induced insulin resistance. This will help with risk assessment, early detection, and focused intervention options.

5. Diagnostic tools and biomarkers

Determining the risk of the disease, directing therapeutic approaches, and gauging the effectiveness of treatment all depend on the accurate diagnosis and monitoring of inflammation-induced insulin resistance. In clinical practice and research settings, a variety of diagnostic instruments and biomarkers have been developed to measure insulin sensitivity and identify inflammation.

5.1 Inflammatory markers

5.1.1 High-sensitivity C-reactive protein (hs-CRP)

hs-CRP is a commonly used biomarker of cardiovascular risk and systemic inflammation. Insulin resistance, metabolic syndrome, and an increased risk of cardiovascular events are all linked to elevated levels of hs-CRP [42, 43].

5.1.2 Interleukins (ILs)

The pro-inflammatory cytokines IL-6, IL-1β, and IL-18 are linked to the aetiology of metabolic diseases and insulin resistance. When circulating IL levels are measured in insulin-resistant individuals, it offers valuable information about their level of inflammation and the severity of their condition [9, 10].

5.1.3 Tumour necrosis factor-alpha (TNF-α)

TNF-α is an important modulator of insulin resistance brought on by inflammation, causing IRS protein serine phosphorylation and disrupting insulin signalling. Obesity, type 2 diabetes, and other metabolic diseases are associated with elevated levels of TNF-α [3, 8].

5.2 Adipokines

5.2.1 Adiponectin

This hormone, which is produced from adipocytes, has anti-inflammatory and insulin-sensitising characteristics. Obesity, insulin resistance, and cardiovascular risk are linked to decreased adiponectin levels [4, 12].

5.2.2 Leptin

Adipocytes secrete the hormone leptin, which controls hunger and energy balance. Obesity and insulin resistance are associated with elevated leptin levels, which are indicative of leptin resistance and dysfunctional adipose tissue [14, 15].

5.3 Lipid biomarkers

5.3.1 Free fatty acids (FFAs)

By encouraging fat accumulation in non-adipose tissues and disrupting insulin signalling, elevated circulating FFAs contribute to insulin resistance. In those with metabolic diseases, measuring FFAs offers information on insulin sensitivity and lipid metabolism [26].

5.3.2 Lipid intermediates

Insulin resistance and metabolic dysfunction have been linked to ceramides, diacylglycerols (DAGs), and other lipid intermediates. Type 2 diabetes, NAFLD, and obesity are all associated with elevated levels of lipid intermediates [44].

5.4 Imaging techniques

5.4.1 Magnetic resonance imaging (MRI) and positron emission tomography (PET)

These methods provide non-invasive evaluation of metabolic activity, insulin sensitivity, and tissue-specific glucose uptake. The pathogenesis of insulin resistance and metabolic diseases can be better understood by using these imaging modalities [45].

5.4.2 Dual-energy X-ray absorptiometry (DEXA) and computed tomography (CT)

These scans are used to measure visceral adiposity and ectopic fat deposition. Insulin resistance and an elevated risk of cardiovascular disease are linked to ectopic fat deposition and abdominal obesity [46].

5.5 Functional tests

5.5.1 Hyperinsulinemic euglycemic clamp and oral glucose tolerance test (OGTT)

Both are the gold standard tests for determining insulin sensitivity and glucose tolerance, respectively. In those with insulin resistance, these functional tests offer quantitative assessments of insulin action and metabolic function [47].

5.6 Molecular and genetic biomarkers

5.6.1 Single-nucleotide polymorphisms (SNPs)

The pathophysiology of insulin resistance and metabolic diseases has been linked to genetic variants linked to genes related to inflammation, such as TNF-α and IL-6. People who are more likely to develop insulin resistance due to inflammation may benefit from genetic testing [48].

5.6.2 Gene expression profiling

This technique enables a thorough examination of the gene expression patterns linked to insulin resistance and inflammation. The development of tailored therapeutics may be aided by molecular profiling approaches, which offer insights into the molecular pathways underlying disease pathogenesis [49].

6. Therapeutic strategies

Targeting both inflammatory pathways and metabolic dysfunction is necessary for the effective therapy of inflammation-induced insulin resistance. Numerous medication and lifestyle strategies have been created to enhance insulin sensitivity, lower inflammation, and lessen the chance of related metabolic problems.

6.1 Pharmacological interventions

6.1.1 Anti-inflammatory agents

The potential of nonsteroidal anti-inflammatory medicines (NSAIDs) like aspirin and ibuprofen, as well as selective inhibitors of inflammatory pathways like TNF-α antagonists and IL-1β blockers, to reduce systemic inflammation and improve insulin sensitivity has been studied [50, 51].

6.1.2 PPAR-γ agonists

The nuclear receptor known as peroxisome proliferator-activated receptor gamma (PPAR-γ), which is involved in the control of adipogenesis and insulin sensitivity, is agonistic to thiazolidinediones (TZDs), which include pioglitazone and rosiglitazone. By regulating adipokine production and reducing the expression of inflammatory genes, TZDs enhance insulin sensitivity and decrease inflammation [52, 53].

6.1.3 AMPK activators

A major modulator of insulin sensitivity and cellular energy metabolism is AMP-activated protein kinase (AMPK). Metformin and thiazolidinediones are examples of AMPK activators that improve insulin signalling and glucose absorption in target tissues by blocking mTOR signalling and activating AMPK [54, 55].

6.1.4 SGLT2 inhibitors

In people with type 2 diabetes mellitus, sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as dapagliflozin and empagliflozin, decrease renal glucose reabsorption and increase urine glucose excretion, improving glycemic control and insulin sensitivity [56, 57].

6.1.5 GLP-1 receptor agonists

GLP-1 receptor agonists (GLP-1RAs) have surfaced as promising therapeutic options, boasting potent anti-inflammatory characteristics and a wide range of clinical applications [58].

6.2 Combination therapies

6.2.1 Dual PPAR-α/γ agonists

Preclinical and clinical investigations have demonstrated the potential of combination treatments that target various metabolic pathways to improve insulin sensitivity and reduce inflammation [59, 60].

6.2.2 Multimodal interventions

Behavioural counselling, exercise, and diet combined with pharmaceutical medications may provide synergistic effects in the management of metabolic diseases and inflammation-induced insulin resistance [61, 62].

6.3 Emerging therapeutic targets

6.3.1 Microbiome modulation

There may be a connection between insulin resistance, inflammation, and the gut microbiota composition, as per emerging research. Probiotics, prebiotics, and faecal microbiota transplantation are examples of strategies that target the gut microbiome and show promise as innovative therapeutic approaches for enhancing metabolic health [63, 64].

6.3.2 Epigenetic modification

Patterns of gene expression linked to inflammation and insulin resistance are regulated by epigenetic changes, including DNA methylation and histone acetylation. Histone deacetylase inhibitors and DNA methyltransferase inhibitors are examples of epigenetic modulators that may be used as therapeutic targets [65, 66].

7. Lifestyle interventions

7.1 Dietary changes

Embracing a nutritious diet high in fruits, vegetables, whole grains, and lean meats can help lower inflammation and enhance insulin sensitivity. Low-glycemic index and Mediterranean-style diets have been linked to better metabolic health and decreased systemic inflammation [67, 68].

7.2 Frequent exercise

Exercise is essential for lowering inflammation, encouraging weight loss, and enhancing insulin sensitivity. In those with insulin resistance, aerobic exercise and resistance training have both been demonstrated to improve glucose uptake, insulin action, and metabolic function [69, 70].

7.3 Handling weight

Insulin resistance and systemic inflammation are closely linked to obesity. Insulin sensitivity and metabolic parameters can be significantly improved by weight loss attained through calorie restriction, behavioural therapies, and bariatric surgery [71, 72].

8. Prospects for future research and directions

Progress in comprehending the intricate relationship among inflammation, insulin resistance, and metabolic dysfunction has created opportunities for novel approaches to treatment and investigation. It is highly promising that future research will clarify the molecular processes of inflammation-induced insulin resistance and find new targets for treatment, as these efforts will help to improve metabolic health and lessen the burden of related disorders.

8.1 Targeted therapies

8.1.1 Precision medicine methods

Individualised treatment plans based on genetic predispositions, inflammatory status, and metabolic profiles may enhance therapeutic efficacy and minimise side effects. Targeted therapeutics for inflammation-induced insulin resistance can be developed more easily when genomic, proteomic, and metabolomic data are integrated into clinical practice [73, 74].

8.1.2 Novel drug targets

The discovery and confirmation of new pharmacological targets related to the control of insulin signalling, metabolic homeostasis, and inflammatory pathways present promising prospects for the creation of next-generation treatments. The potential of emerging targets, like cytokine receptors, Toll-like receptors (TLRs), and inflammasomes, to reduce inflammation and enhance insulin sensitivity calls for more research [75, 76].

8.2 Metabolic crosstalk and immunometabolism

8.2.1 Immunometabolic pathways

Immunometabolism, the integration of immunological and metabolic signalling pathways, offers new perspectives on the aetiology of metabolic diseases including insulin resistance. Finding new treatment targets for inflammation-induced insulin resistance may be possible by clarifying the molecular mechanisms underlying immune cell metabolism, cytokine signalling, and metabolic reprogramming [77, 78].

8.2.2 Metabolic crosstalk

The control of systemic inflammation and insulin sensitivity is greatly influenced by communication between several metabolic organs and tissues, including adipose tissue, the liver, muscle, and the gut microbiota. Novel treatments that target metabolic crosstalk and dysregulation may be developed as a result of a better understanding of the reciprocal connections between immune cells and metabolic organs [78, 79].

8.3 Integrated omics methods

8.3.1 Multi-omics profiling

Integrating data from multiple fields, including proteomics, metabolomics, transcriptomics, and genomes, holds potential for a thorough understanding of the molecular mechanisms driving inflammation-induced insulin resistance. Network analysis and pathway modelling are two examples of systems biology techniques that can offer comprehensive insights into the pathophysiology of disease and suggest possible targets for treatment [80, 81].

8.3.2 Artificial intelligence and machine learning

Identification of predictive biomarkers, disease subtypes, and therapeutic response profiles are made possible by the use of artificial intelligence (AI) techniques and machine learning algorithms to large-scale omics datasets. The development of innovative therapeutic approaches and individualised treatment plans for inflammation-induced insulin resistance may proceed more quickly if AI-driven analytics is fully utilised [82, 83].

8.4 Behaviour interventions and lifestyle changes

8.4.1 Digital health technologies

By incorporating wearables, smartphone apps, and remote monitoring platforms with lifestyle treatments and behavioural change programmes, digital health technologies can improve patient outcomes, adherence, and engagement. Digital health platforms that enable social support networks, real-time feedback, and personalised coaching may enhance metabolic results and long-term adherence to healthy behaviours [84, 85].

8.4.2 Behavioural economics

The development of successful interventions targeted at encouraging healthy lifestyle choices and reducing the risk of inflammation-induced insulin resistance can be aided by behavioural economics insights such as choice architecture and nudge theory. Behavioural interventions that apply behavioural economics concepts—like default options, framing effects, and incentive structures—may help modify behaviour in a sustainable way and enhance metabolic health outcomes [86, 87].

9. Conclusion

Insulin resistance brought on by inflammation is a complicated metabolic disease with wide-ranging effects on human health. Despite tremendous advancements in our comprehension of the underlying pathophysiological pathways, effective therapeutic approaches for insulin resistance caused by inflammation are still unattainable.

In order to fully understand the complex interactions between inflammation and insulin signalling pathways, a multidisciplinary approach integrating knowledge from immunology, metabolism, genetics, and systems biology is essential going ahead. Personalised treatment plans, lifestyle changes, and targeted pharmaceutical interventions have the potential to enhance metabolic health and lessen the impact of comorbidities linked to inflammation-induced insulin resistance.

Furthermore, improving our knowledge of inflammation-induced insulin resistance and integrating scientific findings into clinical practice depend on ongoing research efforts focused on identifying novel therapeutic targets, clarifying the molecular mechanisms underlying disease pathogenesis, and creating cutting-edge diagnostic tools and biomarkers.

We can overcome the obstacles presented by inflammation-induced insulin resistance and open the door to the creation of efficient preventive and treatment plans that enhance the lives of those impacted by this common and crippling metabolic illness by adopting a collaborative and interdisciplinary research paradigm.