The insulin resistance syndrome (IRS) is a constellation of risk factors, including abdominal obesity, dyslipidemia, hypertension, glucose intolerance, and overt diabetes, each a risk factor for cardiovascular disease, the final pathological expression of insulin resistance. Syndrome X, a precursor concept of the IRS, has been defined by Reaven as a cluster of dyslipidemia and hypertension. Syndrome X is present when patients with typical type 2 diabetes and normal glucose tolerance have an accelerated rate of coronary atherosclerosis. The full expression readers may recall glucose intolerance, dyslipidemia, and hypertension embedded in a portion of 15% to 20% of the GASBY trial where patients developed both myocardial infarctions per year. Overt diabetes is present when at least 3 factors exist: they have reduced levels of this point, active ischemia, and myocardial accumulation of nonesterified fatty acids. Subsequent studies identified hyperinsulinemic as the observed abnormality among these patients. Subsequent studies identified IGT, hyperinsulinemia, abdominal adiposity, and hypertension. Family studies have supported aggregation as a syndrome. The importance of understanding the IRS is clear. Based on studies of the pathogenesis of insulin resistance, it is increasingly understood that hyperinsulinemia within the normal glucose tolerance range is far more common in defined population-based samples than are most other common diseases.
Nonetheless, IRS is repeatedly related to data delivered by a number of tests, such as directed and over-provoked blood glucose values, glycosylated hemoglobins, high-density lipoprotein cholesterol, serum triglycerides, abdominal obesity, overall hypertension, and often sub-clinical procoagulatory and proinflammatory actions [1]. Excessive morbidity and mortality of many common disorders are related to their interaction with insulin resistance syndrome (IRS) [2]. Knowledge about its nature and potential prevention and treatment of the whole-cluster of multiple high-risk abnormalities is critical. In fact, while all authorities recognize the fact that the IRS is a cluster of risk factors, there is still much controversy about the value of a single common and dominant factor for operational and action-oriented purposes [4]. Excessive mortality and morbidity of many disorders are related to their association with insulin resistance syndrome (IRS). As IRS may be reduced by effective prevention and treatments, knowledge about its nature and management is critical. In this article, the complex and multi-faced IRS aspect is appraised [2].
Insulin resistance is now appreciated as a very common and major contributor to the glucose dysregulation, a metabolic disease that plays a central role in the manifestations of hypertension, a symptom of the broader insulin resistance syndrome, which encompasses not only glucose dysregulation syndrome but also a "constellation" of hemodynamic disturbances, ranging from reduced endothelium-forming nitric oxide and increased sympathetic nervous system activity to hypertrophy, hyperplasia, and augmented migration of vascular smooth muscle cells [4]. These disorders promote both peripheral and central blood volume expansion and impair both sodium homeostasis and natriuresis. Notably, these disturbances are important determinants of the increased risk of stroke, congestive heart failure, and chronic kidney disease that is known to be associated with the insulin resistance syndrome. To further understand the complexities of this condition, different fruits or vegetables have been used to prevent or delay insulin resistance, improve the risk factors for the development of metabolic syndrome, or inhibit atherosclerosis with various underlying mechanisms [5]. Patients with insulin resistance require increasing concentrations of insulin to maintain metabolic homeostasis. Insulin resistance may result from impairments in a large number of insulin-mediated signaling pathways and can affect multiple sites of glucose metabolism including insulin receptor activity, intracellular glucose transport, or glucose transport through the lipid bilayer, and multiple intracellular signaling targets. Although little is known about insulin itself being an antioxidant, studies have shown that AIIRAs do retain some of their beneficial effects [6]. The up-regulation of renal glucose uptake via the glycogen synthase kinase-3β (GSK-3β) dependent pathway in renal medullary cells of C57 mice is a link to the underlying mechanisms. Interestingly, nonpeptide glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been shown to improve insulin sensitivity in metabolic syndrome ZDF rats [7].
Obesity may lead to several consequences included in IRS, such as insulin resistance, diabetes, and hypertension. Diabetes is another problematic issue, especially in developing countries, where the burden of IRS is increasing, and an estimated 368 million people are at increased risk of disease-related complications. Furthermore, diabetes mortality is expected to double between 2005 and 2030 in developed countries, rising from 1.1 million to 2.5 million [8]. It is estimated that the prevalence of diabetes will increase most in the developing world due to the spread of Western lifestyles. As a result, there will be a large number of undiagnosed or untreated diabetes in developing countries. There is also a high prevalence rate of hyperglycemia among the so-called "prediabetics' ', the majority of whom are overweight or have obesity, which constitutes a precursor condition for diabetes and is characterized by impaired glucose tolerance [9]. Furthermore, IRS prevalence increases with progressive aging in all racial and ethnic groups or categories. These demographic changes, coupled with the complications of the disease, point towards the likelihood of an increasing burden and cost of the management and treatment of IRS complications for individuals, public health systems, and private payers [10]. The ongoing epidemiological transition in developing countries has drastically changed the scope of health-related problems. The burden of insulin resistance syndrome (IRS)-related diseases, including diabetes, obesity, hypertension, and cardiovascular disease, has risen dramatically in the last two decades. Physical inactivity and a high dietary caloric intake are the major risk factors for the development of these obesity-related diseases. Obesity values vary among different regions, but during the last 15 years, there has been a consistent increase in the global prevalence of obesity. The condition is particularly alarming in North America, where 50% of the population has a body mass index (BMI) greater than 25 kg/m2. Results from the National Health and Nutrition Examination Survey (NHANES) III showed that 53.9% of women older than 60 years were overweight and 31.1% were obese [11]. Furthermore, the prevalence of diabetes and impaired glucose tolerance in Caucasian men and women aged 60–64 was 13.5% and 30.5%, respectively. These statistics are even worse for some other ethnic groups [12].
Many human and animal studies have suggested that elevated plasma free fatty acid (FFA) levels reduce insulin mediators in the insulin signaling pathway, decrease insulin sensitivity, and increase abnormal gluconeogenesis and lipogenesis [13]. As a result of the insulin signaling abnormality in various tissues, many metabolic-related diseases will have the chance to develop, including glucose intolerance, hypertension, and dyslipidemia. Several syndromes associated with the IRS that share multifaceted actions of hyperinsulinemia have also been introduced, including polycystic ovary syndrome (PCOS), dyslipidemia without weight gain-like type B syndrome, and hypertension associated with a proliferation of smooth muscle cells. Each of these diseases is characterized with an increased risk for developing atherosclerosis in epidemiological investigations (Petersen & Shulman, 2018). Therefore, the unifying criterion of insulin resistance should incorporate other diverse damaging effects mediated by hyperinsulinemia. The purpose of this review is to offer a comprehensive description of the contributing and unifying factors of insulin resistance pathogenesis and their causative relationship to the multiple damaging effects in IRS closely [4]. The insulin resistance syndrome (IRS) is diagnosed with a constellation of clinical, biochemical, and metabolic findings. The condition is most often related to visceral obesity and is associated with an increased risk to develop cardiovascular diseases (CVD). The major components of IRS, such as hypertension, dyslipidemia, and hyperglycemia, have all been shown to be cardiovascular risk factors. Additionally, other cardiovascular risk factors show a robust association with IRS, including sleep apnea, fibrinogen, and plasminogen activator inhibitor (PAI). It is noteworthy that insulin resistance is undeniably the main pathophysiological factor for the IRS [14]. As a significant cellular signaling molecule, insulin performs its action mainly by binding to the insulin receptors situated on the cellular membrane. However, the insulin resistance condition is characterized by a poor response to its major physiological actions and a higher insulin secretion to compensate [4].
Both guidelines agree on the need to perform OGTT for diagnosis of IR syndrome as people can display different patterns of IR, but ultimately all guidelines reflect the growing consensus that IR and hyperinsulinemia play a fundamental role in the pathophysiology of the metabolic condition currently known as IR syndrome [15]. However, it is also important to note that the classical primer through which IR is calculated, the Hyperinsulinemic euglycemic clamp technique, is not readily available for use in a research study, let alone the medical clinic. Other techniques are often employed in these alternative settings to assess insulin sensitivity such as the X-T Trial, Quantitative Insulin Sensitivity Check Index (QUICKI), HOMA-IR, HOMA-2R, OGIS, and even simpler metrics like BG: INS. Nonetheless, it is important to agree on the general consensus that the Hyperinsulinemic euglycemic clamp remains the gold standard for measurement of insulin sensitivity [16]. Several clinical criteria are used for diagnosis of the IR syndrome. The most common is the World Health Organization (WHO) criteria that define obesity as BMI >30 kg/m2, IGT as plasma glucose at 2 hours after 75 gm glucose ingestion as 140-199 mg/dl, diabetes mellitus as fasting plasma glucose >126 mg/dl, or 2-hour post-75 gm glucose load at >200 mg/dl [17]. ATP I and II criteria notably used fasting plasma glucose of >110 mg/dl as a component adding impaired fasting glycemia as part of its diagnostic criteria. The European Group for the Study of Insulin Resistance (EGIR) uses much stricter diagnostic criteria defining especially more obese subjects with NCEP-ATP III classification of obesity. They also define insulin resistance for individuals who have a first and second tertile for a plasma insulin response to an OGTT requiring the placement of the top 30% of the studied population into the IR group [18].
The intervention in these disorder states becomes essential to avoid the risk factors associated with it. The basic mechanism involved in insulin resistance is still not clear, but recent work on the insulin signaling cascade by GSK-3 has emphasized its role. GSK-3 was originally identified as an essential protein kinase in the cells; its activity is crucial for insulin control of metabolism and cardiological response to stress [19]. Insulin resistance is the process of reduced effectiveness of the glucose utilization of the target cells. Hence, to maintain euglycemia, insulin production increases. There is growing evidence that the pathophysiology of insulin resistance is multifactorial, depending on the genetic, environmental, nutritional, physiological and lifestyle-related factors [4]. Obesity and insulin resistance are strongly associated. Insulin resistance is a typical metabolic abnormality associated with type 2 diabetes, obesity and also occurs in patients with lipid disorders, hypertension, ischemic heart disease, polycystic ovary disorder [20]. The pathophysiology of insulin resistance is highly complex, with a plethora of hormonal regulators like growth hormone, catecholamines, and glucocorticoids, as well as cytokines such as tumor necrosis factor-alpha, interleukin-6, and resistant protein [21]. Recent work points to the role of free fatty acids in the induction of insulin resistance. Insulin stimulates the Na+-K+ pump in skeletal muscle; hence, in states of resistance, intracellular ions get hypertrophied. Recent studies have shown the effect of sugar-induced chronic insulin resistance via persistent downregulation of Akt and activation of nuclear factor-κβ, which finally suppresses myogenic activities and regulates protein turnover via degradation of muscle-specific proteins via calpain. Insulin resistance results in both inflammatory and noninflammatory skin disorders, secondary to the altered dermal remodeling and wound healing [22].
Type 2 diabetes is a common age-related disease and is characterized by both insulin resistance and impaired insulin secretion. The common soil of type 2 diabetes is multifunctional insulin resistance. Unlike monofunctional insulin resistance, which commonly results from a single gene defect, multifunctional insulin resistance results from a complex interplay of genetic and environmental factors that influence both insulin action and insulin secretion. Insulin regulates a variety of cellular processes, such as glucose and lipid homeostasis, cell growth and survival, and gene expression, by activating a host of intracellular signaling intermediates [23]. The insulin signaling pathway consists of insulin protein and insulin receptor, substrates on which the insulin receptor phosphorylates, and molecules that interact with such substrates and participate in a variety of processes [24]. An attractive system, however, is far too complex to be fully understood. Insulin resistance has been shown to be the result of defects in multiple components of the insulin signaling pathway rather than the result of a single gene defect or abnormality at only one part of the pathway. Many other genes which are related with insulin action have been studied, but the molecular mechanism underlying some clinical phenotypes has not been clarified [4]. New molecules have also been discovered to play crucial roles in the regulation of insulin signaling. We therefore also review the molecular actions of these molecules, such as AS160, PIKfyve, and TRB3, whose defects lead to insulin resistance.
The development and progression of obesity involve complex processes that include increased adipocyte mass through cellular hypertrophy and hyperplasia, changes in adipokine secretion, differentiation, inflammation, and matrix remodeling [25]. When obesity becomes excessive and persistent, changes in adipocyte differentiation impairment can result in the generation of small adipocytes, which are less efficient at storing lipids and more prone to undergo apoptosis, leading to adipocyte hypertrophy. Retained lipids stimulate the production and secretion of various inflammatory factors and contribute to the influx, activity, and proliferation of immune cells in adipose tissue (macrophages, neutrophils, lymphocytes, and natural killer cells), leading to both increased synthesis and secretion of proinflammatory mediators and a decrease in the production or release of adipokines, as well as cellular and mitochondrial stress and alterations in energy intake and expenditure [26]. These changes lead to alterations in circulating and locally produced adipokine levels, ultimately contributing to both adipocytokine resistance as well as systemic insulin resistance [27]. Adipose tissue is an essential endocrine and metabolic organ that plays a crucial role in the regulation of systemic insulin sensitivity and many other metabolic pathways [25]. It releases a variety of proteins known as adipokines that affect glucose and lipid metabolism, as well as carbohydrate and fat oxidation, which combined, influence insulin sensitivity. Conversely, in insulin resistance states that accompany obesity and metabolic syndrome, the increased release of alterations in circulating levels of adiponectin, leptin, resistin, visfatin, and other adipokines are thought to be a predominant contributors to decreased insulin action and metabolic disorders oftentimes leading to overt type 2 diabetes and cardiovascular diseases. Notably, some adipokines have lean and fat cell-specific actions and directly link adipose insulin resistance with systemic insulin resistance [27].
Furthermore, increased levels of insulin have been associated with left ventricular hypertrophy, which is an independent risk predictor for CVD. In a meta-analysis by Sesti, the definition for MetSyn was found only in model 2: newly defined MetSyn, which included IR as a determinant, could predict CVD (but not model 1). Animal studies highlight the importance of insulin in vascular damage [2]. The aortic wall becomes thicker in animal models of IR as well as in obesity. However, the effects of insulin elevation in lean animals are mediated by an increase in low-density lipoprotein (LDL) cholesterol levels, as insulin has been shown to increase hepatic synthesis of apo B [28]. The metabolic pathway of IR has long been associated with increased free fatty acids, and some promising preliminary data has identified that IR increases the risk of CVD and CAD as well. Studies have shown that hyperinsulinemia (a precursor to hyperglycaemia) leads to reduced nitric oxide synthesis and secretion, an effect that is subsequently reversed by decreasing plasma insulin levels. Furthermore, hyperinsulinemia may lead to increased synthesis and secretion of endothelial cell-derived vasoactive agents such as endothelin-1. These associations do normalize when adjusted for increased BMI levels [29].
Muscle, liver, and adipose tissue are extremely sensitive to insulin, and it is widely held in the metabolism field that these key metabolic tissues are spoken to by insulin in parallel. Insulin-stimulated glucose uptake by skeletal muscle is excessively dependent upon both insulin-stimulated translocation of glucose transporters (GLUT4) to the plasma membrane and the activation of non-oxidative pathways that are less estimable for glucose. In the postprandial state, about 25% of insulin-stimulated glucose is normally used by muscle, while at rest muscle accounts for around 80% of insulin-stimulated glucose disposal. Recent studies have implicated dysfunctional IRS-1 in the pathogenesis of insulin resistance and type-2 diabetes, underscoring the necessity for scrutinizing regulation of IRS-1 activity at the molecular level. Furthermore, insulin resistance is a key issue in Metabolic Syndrome X, a significant risk factor for the development of coronary cardiovascular disease, and is a feature of many common human disorders such as noninsulin-dependent diabetes and obesity [4]. Metabolic syndrome is a major public health problem. Many groups have added to its description to bring out additional aspects or because debate over it necessitated a variety of new couplings. Many groups have added glucose tolerance or type-2 diabetes as the additional aspect that sparked it, but some enfolded it into their description only as the nature of the debate forced them. Central obesity is a dominant component, but this could also be said for much of its symptoms. The five leading components with different groups, with certain obvious variations, are
Central Obesity
Elevated Triglycerides
Reduced HDL-Cholesterol
Hypertension
Insulin Resistance
A number of additional minor components have been proposed as filling out a description or as being additional markers of the presence of, or being positive feedback loops of the components. Insulin resistance is once again supplementary because although its presence has been strongly linked to all aspects of the metabolic syndrome and is a delicate component of some definitions, it is absent in some definitions of the syndrome [5].
Insulin resistance in type 2 diabetes also includes specific defects in liver metabolism after ingestion of mixed meals. This is reflected in increased, prolonged, and/or exaggerated postprandial glucose absorption, increased lipogenic response to nutrient ingestion and incomplete switch from glucose output to hepatic glucose uptake; thereby resulting in chronic overproduction of glucose which impedes glycemic control. Besides alterations in the time course of insulin secretion and action, exaggerated glucagon secretion appears to play a role in defective suppression of endogenous glucose production after nutrient ingestion by insulin in insulin-resistant individuals. Increased glucagon effect on glucose metabolism is evident in fasting and postprandial states and it is associated with hyperglucagonemia. Insulin resistance in type 2 diabetes also extends to excess absorption of fatty acids from adipose tissue. Profile of glucose regulation and post-absorptive glucose metabolism and lipolysis under low-dose portal insulin infusion, starting at the arrival of the ingested glucose into the splanchnic circulation, provides insight into the mechanisms of hepatic insulin resistance in type 2 diabetes [15]. In a classic series of studies carried out by Defronzo and colleagues, hepatic insulin resistance, as reflected in the liver, is evinced by (partial) inhibition of hepatic glucose production by glucose and insulin. Insensitivity of the liver to the inhibitory action of insulin is a consistent marker of hepatic insulin resistance and is a robust predictor of type 2 diabetes [24]. Insulin sensitivity in this group reflects a decreased ability of the target tissues to respond to the inhibitory action of the hormone. The presence of hepatic insulin resistance is a consistent characteristic of type 2 diabetes and is present in normoglycemic obese and nonobese insulin-resistant individuals regardless of degree of glucose tolerance. In order to achieve and sustain normoglycemia, the hormone insulin maintains glucose homeostasis through inhibition of hepatic glucose production and regulation of glucose use by skeletal muscle and adipose tissue. In healthy humans, insulin acts as a potent inhibitor of hepatic glucose production [11].
Optimal control of adipose tissue and hepatic lipid metabolism to minimize toxic FFA accumulation, hepatic, pancreas, and muscle lipidosis, and subsequent lipotoxicity and the negative effects on glucose homeostasis is severely compromised by insulin resistance [30]. Insulin must also maintain this balance amidst acute lipid entry into hepatocytes and times of relative inactivity or nutritional deficit. However, hepatic triglyceride export as both very-low-density lipoprotein (VLDL) and very high-density lipoprotein (VHDL) is stimulated by insulin, in contrast to the suppression of adipocyte lipolysis. Deficient insulin action during the postprandial state leads to impaired net hepatic fabrication and sequestration of lipid, physiological tasks that contribute to defective clearance and disposal of dietary sources of fat, fatty acids, and atherogenic lipoproteins from the circulation [31]. Insulin action is pervasive in postprandial glucose-lipid homeostasis, a function of nutrition that is performed largely by the liver. With normal hepatic metabolic function, insulin action and signaling suppress adipocyte lipolysis, increase adipocyte lipoprotein lipase (LPL) activity, promote de novo lipogenesis, and inhibit hepatic glucose production to keep postprandial serum lipid and nonesterified fatty acid concentrations low, increase adiposity, and return serum glucose concentrations to the fasting state [28]. There is a close relationship between insulin resistance and NAFLD, whether it is related to obesity or other etiological factors for fatty liver disease. Hepatic steatosis is extremely prevalent in cohorts with obesity and adipocyte hypertrophy that are characterized by insulin resistance and substantially increased risk for type 2 diabetes, other components of the metabolic syndrome, and cardiovascular disease [32].
We also suspect the possibility of subtle errors of insulin action unlikely to be unmasked unless rigorous genetic studies are performed. Obese women with PCOS manifest more severe insulin resistance. The consequent hyperinsulinemia potentiates hyperandrogenism by direct as well as indirect mechanisms. The major difficulty encountered with the obese PCOS patient does not result from their environment but from an unknown number of genetically predisposed defects in insulin action. These patients have several physiological diseases that have common as well as distinct symptoms. However, the presence of PCOS does predispose patients to PCOS-specific conditions, which helps to focus attention on subtle clues to the diagnosis of PCOS [13]. The presence of insulin resistance in PCOS is well recognized, and subjects with PCOS have an increased risk of developing impaired glucose tolerance, type 2 diabetes, and gestational diabetes. It is unclear, however, if the risk is intrinsic to the biological entity of PCOS or if the presence of insulin resistance in these patients represents a random event. The essential features of PCOS are hyperandrogenism and anovulation. Many women with PCOS are also obese and have peripheral insulin resistance. Several contributing factors are thought to be responsible for insulin resistance in PCOS, including obesity (more specifically body fat distribution), severity of the hyperandrogenism, generalized and localized cortisol metabolism, the presence of low circulating levels of steroid hormone-binding globulin, lipid levels, and specific inherited genetic predispositions. In conclusion, physicians should consider whether PCOS is caused by pathological changes in insulin, insulin receptors, or post-receptors, which may make everyday practice not feasible [24].
High blood sugar levels, dyslipidemia, high blood pressure, diabetes, gout, fatty liver, and polycystic ovaries in females are usually found among patients with insulin resistance. Recent data, including the association of insulin resistance with inflammation, atherosclerosis, and activation of both the clotting and fibrinolytic systems, prompt the consideration of pancreatic disorder as a syndrome encompassing multiple diseases within the same patient. Pancreatic disorders in some cases are related to obesity, particularly those with central fat distribution, devoid of concomitant insulin resistance. In order to clarify some of these physiological and pathophysiological associations, the present chapter will focus on the properties of insulin in relation to the central nervous system [11]. Insulin is produced in the pancreas and is released in response to meals to regulate the level of glucose in the bloodstream and assist in the storage of excess nutrients. It facilitates the disposal of blood glucose by increasing the rate of uptake of glucose to different tissues. Insulin also inhibits lipolysis. Tissues in insulin target organs have different biological actions. For example, the liver produces new glucose, and insulin directly suppresses its release and stores lipids from fatty acids. Adipose tissues are targeted for inhibition of lipolysis and storage of lipids, skeletal muscle is for disposal of blood glucose and for storage of excess nutrients in the form of muscle glycogen or long-chain triglyceride, whereas the whole brain takes up glucose without the need for insulin. The clinical signs of insulin resistance in patients are based on the severity of insulin resistance and occur regardless of the etiology [18].
Decades of negative conditioning by society have caused overweight people to simply avoid healthcare, to avoid this weight-related criticism. More troublingly, over the past decade or so, paraclinical investigations and even surgical procedures have been denied to overweight people undergoing these conditions. This is a poor state of affairs that healthcare professionals must address to maximize the health of the populations they serve. Alongside effective pharmacological and surgical interventions, long-term benefit will result from support services and long-term follow-up. Obesity, especially with associated metabolic disease, is a chronic condition and one that will benefit from the long-term relationship that exists between clinician and patient [2]. Understanding the various levels of insulin resistance means that both pharmacological and lifestyle interventions can be combined to address these defects, thereby optimizing long-term metabolic health and reducing chronic disease risk. Clearly, prevention is always better than cure; thus, advising on beneficial lifestyle and dietary changes from young adulthood is an important adjunct to diagnosing prediabetes and type 2 diabetes. Appropriate antihyperglycemic therapies, lipid-lowering agents, and anticoagulants should then be used to reduce long-term morbidity and mortality in those affected by metabolic disorders [33].
Insulin resistance is a very large and complex subject, and this review has not been able to do justice to it in the way of studying all aspects of the many potential mediators of insulin resistance, including the secreted messengers, their receptors, and the downstream elements they use. However, with limitations, what has been presented is practically significant and represents a summary of studies. The cause of obesity in western society is complex, and developed societies may have effectively undone the systems of protection developed by our societal ancestors in preparation for famine. Although many potential mediators of insulin resistance may be altered in obesity, only the free fatty acids consistently show increased fluxes. The identification and control of the key mediator of insulin resistance will require further study. The clinical and research demands of modern healthcare systems placed on the practitioners of health are significant. However, lifting our heads up from the minutiae of the everyday clinical practice to catch a glimpse of the bigger picture can be greatly rewarding. With a better understanding of a subject, we treat our patients better [34]. Although much has been learned about the pathogenesis of insulin resistance in the last 70 years, there is still a great deal we do not know. With the increasing prevalence of insulin resistance and its associated illness in many countries, and with healthcare systems worldwide under great stress to find a solution to this problem, it greatly helps us in our awareness if we have some idea of where we might be heading to find new and useful answers. This section will review possible future expected directions for research on the regulation of insulin sensitivity, pointing out major obstacles in current research and four main areas that require future attention on the part of the basic scientist in studies exploring potential mediators of insulin resistance: studies utilizing animal models, microvascular structure and function, genetic factors affecting insulin action, and fatty acid metabolism [35].
We understand that individuals with such defects need to have lifestyle changes and need to follow the treat-to-target principle of the International Diabetes Federation in order to render better glycemic control. In such individuals, we also know that metformin can sensitize the compromised insulin activity. Endorsing "exercise is medicine," it follows that these individuals who benefit from exercise should follow the recommended levels of physical activity to improve the intrinsic function of the skeletal muscle. Accordingly, those insulin-resistant individuals who have prediabetes and type 2 diabetes that has not progressed to severe complications can practice yoga under qualified guidance to improve alpha-blockade and muscle insulin action and decrease alpha-adrenergic tone, which will benefit them in terms of lowering insulin resistance as well as cardio-metabolic risk factors by improving both dependence and insulin resistance.
Houser, K.A. et al. “The Use of Big Data Analytics by the IRS: Efficient Solutions or the End of Privacy as We Know It.” [Journal Name Unknown], 2016, p. 817.
Ormazabal, V. et al. “Association Between Insulin Resistance and the Development of Cardiovascular Disease.” Clinical Diabetes, vol. 17, 2018, pp. 1–14.
Andersson, E. “A Transactional and Action-Oriented Methodological Approach to Young People’s Political Socialisation.” Education, Citizenship and Social Justice, vol. 15, no. 3, 2020, pp. 243–257.
Petersen, M.C. and G.I. Shulman. “Mechanisms of Insulin Action and Insulin Resistance.” Physiological Reviews, 2018.
Mirabelli, M. et al. “Mediterranean Diet Nutrients to Turn the Tide Against Insulin Resistance and Related Diseases.” Nutrients, vol. 12, no. 4, 2020, p. 1066.
Besse-Patin, A. and J.L. Estall. “An Intimate Relationship Between ROS and Insulin Signalling: Implications for Antioxidant Treatment of Fatty Liver Disease.” International Journal of Cell Biology, 2014, article 519153.
Zhao, F. et al. “Structural Insights into Hormone Recognition by the Human Glucose-Dependent Insulinotropic Polypeptide Receptor.” eLife, vol. 10, 2021, e68719.
Lavin, D.P., M.F. White and D.P. Brazil. “IRS Proteins and Diabetic Complications.” Diabetologia, vol. 59, no. 11, 2016, pp. 2280–2291.
Dorcely, B. et al. “Novel Biomarkers for Prediabetes, Diabetes and Associated Complications.” Diabetes Therapy, 2017, pp. 345–361.
Crossley, M.J. “Health and Taxes: Hospitals, Community Health and the IRS.” Journal of Health Politics, Policy and Law, vol. 16, 2016, p. 51.
Salo, P.M. et al. “Allergy-Related Outcomes in Relation to Serum IgE: Results from the National Health and Nutrition Examination Survey 2005–2006.” Journal of Allergy and Clinical Immunology, vol. 127, no. 5, 2011, pp. 1226–1235.
Ntuk, U.E. Exploring Ethnic Variations in Lifestyle and Diabetes: Using Evidence from UK Biobank Data. University of Glasgow, 2024.
Mastrototaro, L. and M. Roden. “Insulin Resistance and Insulin Sensitizing Agents.” Metabolism, vol. 125, 2021, article 154892.
Berlanga-Acosta, J. et al. “Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review.” Frontiers in Endocrinology, vol. 11, 2020, article 560375.
Bello-Chavolla, O.Y. et al. “METS-IR, a Novel Score to Evaluate Insulin Sensitivity, Is Predictive of Visceral Adiposity and Incident Type 2 Diabetes.” European Journal of Endocrinology, vol. 178, no. 5, 2018, pp. 533–544.
Baroni, M.G. et al. “SID/SIE Guidelines on the Treatment of Hyperglycemia in Cushing’s Syndrome and Acromegaly.” Nutrition, Metabolism and Cardiovascular Diseases, vol. 26, no. 2, 2016, pp. 85–102.
Kêkê, L. et al. “Body Mass Index and Childhood Obesity Classification Systems: A Comparison of the French, International Obesity Task Force (IOTF) and World Health Organization (WHO) References.” Revue d'Épidémiologie et de Santé Publique, vol. 63, no. 3, 2015, pp. 173–182.
Kopprasch, S. et al. “Association Between Systemic Oxidative Stress and Insulin Resistance/Sensitivity Indices: The PREDIAS Study.” Clinical Endocrinology, vol. 84, no. 1, 2016, pp. 48–54.
Hermida, M.A., J.D. Kumar and N.R. Leslie. “GSK3 and Its Interactions with the PI3K/AKT/mTOR Signalling Network.” Advances in Biological Regulation, vol. 65, 2017, pp. 5–15.
Bozkurt, B. et al. “Contributory Risk and Management of Comorbidities in Chronic Heart Failure: A Scientific Statement from the American Heart Association.” Circulation, vol. 134, no. 23, 2016, pp. e535–e578.
Marketon, J.I.W. and R. Glaser. “Stress Hormones and Immune Function.” Cellular Immunology, vol. 252, no. 1–2, 2008, pp. 16–26.
Loreto, J.S. et al. “Human Type 2 Diabetes Mellitus-Associated Transcriptional Disturbances in a High-Sugar Diet Long-Term Exposed Drosophila melanogaster.” Computational Biology and Genomics, vol. 39, 2021, article 100866.
Saltiel, A.R. “Insulin Signaling in Health and Disease.” The Journal of Clinical Investigation, vol. 131, no. 1, 2021.
Boucher, J., A. Kleinridders and C.R. Kahn. “Insulin Receptor Signaling in Normal and Insulin-Resistant States.” Cold Spring Harbor Perspectives in Biology, vol. 6, no. 1, 2014, a009191.
Luo, L. and M. Liu. “Adipose Tissue in Control of Metabolism.” Journal of Endocrinology, vol. 231, no. 3, 2016, pp. R77–R99.
Usman, A. et al. “From Lipid Retention to Immune-Mediated Inflammation and Associated Angiogenesis in the Pathogenesis of Atherosclerosis.” Journal of Atherosclerosis and Thrombosis, vol. 22, no. 8, 2015, pp. 739–749.
Al-Mansoori, L. et al. “Role of Inflammatory Cytokines, Growth Factors and Adipokines in Adipogenesis and Insulin Resistance.” Inflammation, 2022, pp. 1–14.
Haas, M.E., A.D. Attie and S.B. Biddinger. “The Regulation of ApoB Metabolism by Insulin.” Trends in Endocrinology and Metabolism, vol. 24, no. 8, 2013, pp. 391–397.
Gallo, G. and C. Savoia. “New Insights into Endothelial Dysfunction in Cardiometabolic Diseases: Potential Mechanisms and Clinical Implications.” International Journal of Molecular Sciences, vol. 25, no. 5, 2024, p. 2973.
Conway, P.H. et al. “Recurrent Urinary Tract Infections in Children: Risk Factors and Association with Prophylactic Antimicrobials.” JAMA, vol. 298, no. 2, 2007, pp. 179–186.
Chirurgii, R.V. et al. “Multidisciplinary Surgical Approach to Renal Cancer with Vena Cava Invasion and Pulmonary Embolism.” Rozhledy v Chirurgii, vol. 100, no. 2, 2021, pp. 88–93.
Iber, B.T. et al. “A Review of Various Sources of Chitin and Chitosan in Nature.” Journal of Renewable Materials, vol. 10, no. 4, 2022, p. 1097.
Wouters, H.J. et al. “Epidemiology of Thyroid Disorders in the Lifelines Cohort Study.” PLOS ONE, vol. 15, no. 11, 2020, e0242795.
Zheng, Y., S.H. Ley and F.B. Hu. “Global Aetiology and Epidemiology of Type 2 Diabetes Mellitus and Its Complications.” Nature Reviews Endocrinology, vol. 14, no. 2, 2018, pp. 88–98.
Gasco, V. et al. “Traumatic Brain Injury as Frequent Cause of Hypopituitarism and Growth Hormone Deficiency: Epidemiology, Diagnosis and Treatment.” Frontiers in Endocrinology, vol. 12, 2021, article 634415.
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