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Molecular and metabolic mechanisms of cardiac dysfunction in diabetes. Life Sci. Download references. VO, SN, OE, CA and FZ conducted a review of the literature and contributed to conception and design and wrote the first draft the review; CS contributed to conception and design of the article and critically reviewed the drafts of the manuscript.

All authors read and approved the final manuscript. This study was supported by Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT , Lions Medical Research Foundation Australia , and Diabetes Australia.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Faculty of Biological Sciences, Pharmacology Department, University of Concepcion, Concepción, Chile.

Faculty of Pharmacy, Department of Clinical Biochemistry and Immunology, University of Concepcion, Concepción, Chile. Department of Obstetrics and Gynecology, Ochsner Baptist Hospital, New Orleans, Louisiana, USA. You can also search for this author in PubMed Google Scholar. Correspondence to Carlos Salomon.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Ormazabal, V. et al. Association between insulin resistance and the development of cardiovascular disease.

Cardiovasc Diabetol 17 , Download citation. Received : 22 May Accepted : 20 August Published : 31 August Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Review Open access Published: 31 August Association between insulin resistance and the development of cardiovascular disease Valeska Ormazabal 1 , Soumyalekshmi Nair 2 , Omar Elfeky 2 , Claudio Aguayo 3 , Carlos Salomon ORCID: orcid.

Zuñiga 3 Show authors Cardiovascular Diabetology volume 17 , Article number: Cite this article k Accesses Citations Altmetric Metrics details. Abstract For many years, cardiovascular disease CVD has been the leading cause of death around the world. Background The pathological processes and risk factors associated with CVD begin as early as during childhood [ 1 ].

Insulin signaling Insulin is a potent anabolic hormone that exerts a variety of effects on many types of cells. Full size image.

Insulin resistance Insulin resistance is defined as an experimental or clinical condition in which insulin exerts a biological effect lower than expected. Cellular mechanisms of insulin resistance Insulin works on multiple processes, essentially providing an integrated set of signals that allows the correct balance between nutrient supply and demand [ 33 ].

Insulin resistance and cardiovascular disease Elevated levels of LDL, smoking, elevated blood pressure and type 1 and type 2 diabetes, are well known risk factors for CVD, however, insulin resistance, hyperglycaemia and inflammation can also lead to and predict adverse cardiovascular events.

Insulin resistance and dyslipidemia The dyslipidemia induced by insulin resistance and type 2 diabetes diabetic dyslipidemia [ 82 ] is characterized by the lipid triad: 1 high levels of plasma triglycerides, 2 low levels of HDL, and 3 the appearance of small dense low-density lipoproteins sdLDL , as well as an excessive postprandial lipemia [ 35 , 82 , 83 , 84 ].

Insulin resistance and lipoproteins profile alterations VLDL, very low-density lipoprotein, is assembled and produced in the liver, which depends on the availability of substrates and is tightly regulated by insulin [ 91 ]. Insulin resistance and endothelial dysfunction The integrity of the functional endothelium is a fundamental vascular health element.

Chronic hyperglycemia in cardiovascular disease The increased CVD risk in patients with type 2 diabetes has been known for many years [ ]. Insulin resistance and changes in the cardiac metabolism The thickest layer of the heart wall is the myocardium, composed of cardiac muscle cells, thus, the knowledge provided by skeletal muscle cell physiology helps explain the cardiac metabolic function [ ].

Instead, energy is stored in cardiac muscle cells in three forms: 1. Conclusions Insulin essentially provides an integrated set of signals allowing the balance between nutrient demand and availability. References Steinberger J, Daniels SR, American Heart Association Atherosclerosis H, Obesity in the Young C, American Heart Association Diabetes C.

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Article CAS Google Scholar Kim JA, Montagnani M, Koh KK, Quon MJ. This entails filling half your plate with nonstarchy vegetables, one-quarter with lean proteins, and one-quarter with carbohydrates such as whole grains, beans and legumes, fruits and dried fruit, and dairy products like milk and yogurt Get adequate sleep Quit smoking Manage sleep apnea.

If you suspect you have sleep apnea, get evaluated by your doctor and get treated "Most people will see improvements within a few months if they stay committed to adopting healthier habits," Dr. You should see your doctor right away if you have these symptoms: Excessive thirst Excessive urination Excessive hunger Fatigue Blurring vision Numbness in the feet Complications of diabetes Uncontrolled diabetes can lead to a host of other disorders.

These include: Heart disease Stroke Eye problems Kidney disease Nerve problems Amputations "Remember, prediabetes and Type 2 diabetes are preventable," says Dr.

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Subscribe to Advancing Health Link activates modal. Insulin is a key player in developing type 2 diabetes. Here are the high points:. But this finely tuned system can quickly get out of whack, as follows:.

Lots of blood sugar in the bloodstream is very damaging to the body and needs to be moved into cells as soon as possible. Yep, weight gain. You do not have to be overweight to have insulin resistance.

If you have insulin resistance, you want to become the opposite—more insulin sensitive cells are more effective at absorbing blood sugar so less insulin is needed.

These lifestyle changes really work. Talk with your health care provider about how to get started. Skip directly to site content Skip directly to search. Español Other Languages. Insulin Resistance and Diabetes.

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The IRS-activated PI3K in turn affects several downstream signaling pathways through the generation of a lipid second messenger, phosphatidyl-inositol-3, 4, 5-triphosphosphate. It also drives cell growth and cell survival via pathways both dependent and independent of activation of the rapamycin-sensitive kinase known as mammalian target of rapamycin, with the downstream targets p70 S6 kinase and 4E-BP1.

GSK-3β phosphorylates IRS-1 at serine , which in turn attenuates the insulin response by inhibiting IR-mediated tyrosine phosphorylation of IRS Despite several years of intense investigation, the pathogenesis of obesity-induced insulin resistance has not been fully elucidated.

Recently, however, some of the derangements in insulin signaling have been clarified, along with the etiologic factors that lead to obesity-associated hyperglycemia. Adipocytes decrease glucose uptake in peripheral tissues by the release of free fatty acids.

These cytokines have been implicated in the pathogenesis of insulin resistance. Obesity-associated adipocyte apoptosis cell death appears to be the primary event underlying insulin insensitivity. The subsequent cell death-associated infiltration of macrophages appears to explain the presence of chronic inflammation.

These adipogenic cytokines appear to function in a paracrine fashion, because circulating cytokines are not consistently elevated. The concomitant release of reactive oxygen species exaggerate or play a causal role in cytokine-related insulin resistance.

Obesity leads to an inflammatory response in the liver and in adipose tissues. Obesity-induced inflammation results in infiltration of macrophages and release of cytokines, tumor necrosis factor-α TNF-α , interleukin-6 IL-6 , and interleukin-1β IL-1β.

The downstream effector of cytokine-induced inflammation is induction of inducible nitric oxide synthase iNOS. The extremely high levels of nitric oxide that are released, together with reactive oxygen species, generate reactive nitrogen species including peroxynitrite, which leads to S-nitrosylation and tyrosine nitration posttranslational modifications of proteins.

This calcium-independent process alters the function of many proteins, including those involved in insulin signaling. Gene manipulation of iNOS or treatment with iNOS inhibitors ameliorates the deranged insulin signaling as shown in figure 3.

Magnification: × Nuclei are stained with diamidinophenylindole. Adapted from Fujimoto et al. Other etiologic factors have been proposed in the pathogenesis of obesity-induced insulin resistance. These factors include oxidative stress, mitochondrial dysfunction, intracellular lipid accumulation in skeletal muscle and liver, and decreased β-oxidation.

Recent studies have begun to answer some of these questions, by elucidating that these pathologic and etiologic factors converge to activate inflammatory or stress signaling pathways. Skeletal muscle is the major site of glucose disposition in the body.

The glucose that is transported into muscle is used or stored as glycogen. In skeletal muscle, lipid accumulation has been implicated in the induction of obesity-related insulin resistance. In humans, intramyocellular lipid content correlates quite well with insulin resistance.

However, the molecular bases that would explain these differences in obesity-induced insulin resistance in skeletal muscle versus the liver remain largely unknown. Circulating glucose levels reflect a balance between glucose production by the liver and glucose uptake by the muscle.

This effect is enhanced and coordinated through multiple genes that control glycolysis, fatty acid synthesis, gluconeogenesis synthesis of glucose from proteins , and glycogenolysis breakdown of glycogen.

These effects may be mediated by a host of transcription factors and cofactors including forkhead and peroxisome proliferators that activate receptors α and γ and their coactivators. Increase in sterol regulatory element-binding protein expression can increase expression of gluconeogenic and lipogenic genes and vice versa.

Our recent studies in rodents indicate that inducible nitric oxide synthase iNOS is a pivotal downstream effector of insulin resistance in many pathologic states, including obesity. Three isoforms of nitric oxide synthase are expressed in mammalian tissues.

Endothelial and neuronal nitric oxide are constitutively expressed and generate small amounts of nitric oxide, which produces physiologic action by elevating cyclic guanosine monophosphate in a calcium-dependent manner. Initially, we tested the beneficial effects of iNOS inhibition on inflammation and hyperglycemia induced by lipopolysaccharide.

S-nitrosylation of tyrosine residues leads to decreased signaling via these proteins. In the liver, obese leptin-deficient mice have a 2. The immunoreactivity for nitrotyrosine, a marker for nitrosative stress, is elevated in the liver of these obese mice.

Treatment with the iNOS inhibitor L-N6- 1-Iminoethyl lysine, better known as L-NIL, reverses elevated nitrotyrosine immunoreactivity in the liver fig. In hepatic insulin resistance, there is decreased expression of IRS proteins. The improved insulin sensitivity was evidenced as lower fasting insulin and glucose levels in L-NIL-treated animals fig.

It is also interesting to note that the expression of sterol regulatory element-binding protein, which is usually increased in hepatic insulin resistance, also was reduced after treatment with L-NIL. From an evolutionary standpoint, the ER stress response is a cellular mechanism that evolved in eukaryotes as a coping mechanism for glucose or nutrition deprivation.

The ER stress response in mammals was first characterized as the transcriptional activation of glucose-regulated proteins e. A critical role for ER stress in obesity-induced hepatic insulin resistance has been demonstrated by the following observations: 28,47,71 Expression of glucose-regulated protein 78 and RNA-dependent protein kinase-like endoplasmic reticulum kinase PERK , both indicators of ER stress response, was increased in the liver of leptin-deficient mice and in mice fed a high-fat diet.

The clinical significance of ER stress in obesity, steatosis, and insulin resistance in humans is unclear, but pharmacologic agents are being developed to counteract these effects and have proved successful in rodents. Recently, inflammatory or stress signaling pathways have been highlighted as a major culprit in obesity-induced insulin resistance, 28 and iNOS has been proposed as an important component of feed-forward mechanisms that lead to insulin resistance, in which it functions as both a downstream effector and an upstream enhancer of inflammation.

Contrary to findings in liver, however, published studies do not find increased ER stress in skeletal muscle of obese, diabetic mice, 71,75 and although it is conceivable that ER stress may contribute to apoptosis in adipocytes, this has not been investigated. A close connection between output from the central nervous system CNS and glucose homeostasis is now well established.

In addition to exerting insulin-enhancing effects in peripheral tissues, leptin also affects the CNS by controlling food intake through its actions on the mediobasal hypothalamic area arcuate nucleus , which contains high concentrations of leptin receptor fig.

Thus, the actions of leptin on energy and food intake are independent of its peripheral endocrine effects, in which, among other physiologic functions, it also enhances insulin sensitivity and bone density. Central nervous system control of glucose homeostasis.

Leptin and long-chain fatty acids released from adipocytes influence food intake via the hypothalamus depicted in blue. Ghrelin and other hormones from the gut also influence food intake and satiety blue.

Afferent and efferent autonomic signals from and to the fat pad, via the sympathetic and parasympathetic nerves to and from the hypothalamus, influence fat synthesis and breakdown of fat depicted in red. In obesity, the ability to sense these afferent inputs to the hypothalamus is impaired, resulting in increased or orexigenic signals decreased satiety and increased nerve-mediated glucose output by the liver.

Afferent nerve fibers from fat modulate sensitivity of the CNS to leptin and this effect can be abrogated by denervation. Several other gut hormones also control food intake, and these humoral circuits from fat and gut are dysfunctional in obesity.

These sensors then may use this input to regulate efferent pathways responsible for fuel intake and utilization. Centrally mediated neural autonomic sympathetic and parasympathetic actions can modulate adipocyte functions. It is well known that fat pads are well innervated by the sympathetic nervous system, and sympathetic nerve-mediated lipolysis via the adrenoceptor can lead to alterations in lipolysis.

They also substantiated preexisting evidence that the brain controls fat growth by a selective group of neurons. These investigators, in fact, hypothesize that obesity and metabolic syndrome are diseases more of the brain than of any other organ or system.

Insulin and blood glucose levels, known to target liver glucose output via glycogenolysis and gluconeogenesis, have now been shown to act on the CNS to control glucose output by the liver.

The studies of Pocai et al. By opening and closing these potassium adenosine triphosphate channels, the hypothalamus controls output to the liver via the vagus, because isolating the hepatic branches of the vagus obviates this response.

The physiologic significance of this finding is that increases in insulin concentration in response to feeding in turn decrease the hepatic glucose output.

It is also noteworthy that the ability to sense increased concentrations of glucose or insulin e. Sulfonylureas acting on the potassium adenosine triphosphate channels in the hypothalamus decrease neural signal output from the hypothalamus and decrease hepatic glucose output.

It is now clear that aggressive control of hyperglycemia in patients with diabetes can attenuate the long-term cardiovascular and renal complications of this disease. Metformin is a biguanide.

It has a well established, beneficial effect on peripheral tissues and mitochondrial function, in which it enhances the oxidation of fat and glucose presumably by activating adenosine monophosphate kinase. In severe obesity, the adipose tissue macrophage is switched from its alternative activated form to its proinflammatory form.

Thiazolidinediones, however, are associated with a high incidence of adverse cardiovascular events, including congestive heart failure and myocardial infarction, and therefore caution should be exercised when using these drugs.

There are several reports of success with such approaches. GSK-3β inhibitors, which have multipronged effects on insulin signaling and inflammation as well as glycogen synthesis, could also prove beneficial. Experimental evidence on GSK-3β inhibitors exists, 26,27 but clinical studies in obesity are lacking.

Although salicylates have proved useful, 41 the use of these derivatives in surgical patients needs careful evaluation. Complications associated with salicylates, particularly in the high doses recommended for treatment of diabetes, include gastric ulceration, increased bleeding, and renal dysfunction.

Future therapeutic regimens probably will include the use of iNOS inhibitors, which are currently in development for human use.

The rationale for this line of treatment already has been discussed. Obesity is associated with worse prognosis in patients with trauma, although conflicting results also have been reported.

The deleterious impact of obesity has been postulated to be attributable, at least in part, to derangements in metabolic function.

Insulin resistance is a major denominator and a central player of obesity-related metabolic derangements. Attenuated actions of insulin result in hyperglycemia, decreased protein synthesis, increased protein degradation, increased susceptibility to infection, and reduced antiapoptotic prosurvival and antiinflammatory actions of insulin, 10—14 all of which contribute to exacerbation of critical illness.

For critically ill patients with hyperglycemia, therefore, intensive insulin therapy has been employed in intensive care units to achieve tight glycemic control. Hyperinsulinemia is an independent risk factor for the development of atherosclerosis, a major complication in type 2 diabetes.

It is conceivable, therefore, that even if tight glycemic control without hypoglycemia is achieved by insulin therapy, the combination of hyperinsulinemia and insulin resistance may elicit some deleterious outcomes in critically ill patients.

Hyperglycemia is usually a good indicator of insulin insufficiency. However, there are some exceptions in the intensive care unit.

Rarely, some patients may exhibit euglycemia or even hypoglycemia despite serious insulin resistance with normal or decreased plasma insulin concentration. Critical illness, such as sepsis and trauma, induces impaired hepatic glucose production independent of insulin action, leading to hypoglycemia, , despite the coexisting attenuation of insulin action caused by insulin resistance.

In these cases, although hyperglycemia is not observed, other beneficial actions of insulin—including anabolic, antiinflammatory, and antiapoptotic functions—are impaired owing to insulin resistance. Improvement in insulin sensitivity is accompanied by decreased inflammation and vice versa.

This suggests that insulin-sensitizing drugs may be candidates for reducing the mortality of critically ill patients by their ability to improve insulin sensitivity and reverse excessive inflammation.

Unfortunately, thiazolidinediones and metformin, the two clinically approved insulin sensitizers, cannot always be used for critically ill patients because of adverse side effects e.

Therefore, novel types of insulin-sensitizing drugs, which do not elicit such adverse side effects, would need to be developed to help improve the mortality of critically ill patients by reversal of inflammation and insulin resistance. As discussed in this review, obesity-induced insulin resistance is closely linked to the inflammatory response and stress signaling pathways.

The implication of hyperglycemia in critical illness has been an intense area of investigation for a number of years. Of interest, a recent study showed that the severity of insulin resistance is associated with the severity of critical illness and body mass index, although no significant association was found between insulin resistance and basal blood glucose level.

Thus, a potential hyperglycemia-independent impact of insulin resistance on prognosis during and after critical illness is worthy of further investigation. For individuals born in the United States in , the lifetime probability of being diagnosed with obesity and diabetes is substantial.

Interventions to reduce body weight have beneficial effects on decreasing cardiac complications in the perioperative period. Correction of hyperglycemia in critically ill patients decreases intensive care unit stay and improves hospital mortality, an effect particularly evident in surgical patients.

Obesity-induced diabetes is related to decreased insulin-signaling via IR and its downstream proteins. A chronic inflammatory state seems to play a pivotal role in the insulin resistance. Differences do exist in the mechanisms of insulin resistance between liver, muscle, and adipocyte.

The role of the CNS in insulin sensors sensing and glucose homeostasis is now well established. Understanding the impairments of insulin-signaling related to obesity-induced diabetes may lead to better pharmacologic methods, not only to treat but also to prevent obesity and type-2 diabetes.

In this regard, in addition to behavior modifications that modify food calorie intake or alter the composition of foods ingested, development of drugs to decrease appetite and increase metabolism also may prove useful. Recent studies do confirm that multimodal, multifactorial interventions including behavior modifications and surgery have sustained beneficial effects on insulin sensitivity, cardiovascular complications, and mortality.

The authors acknowledge the invaluable assistance of Don Poulsen, Senior Medical Illustrator, Shriners Hospital for Children, Boston, Massachusetts, for the artwork presented in the text. Sign In or Create an Account.

Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Publications Anesthesiology. Advanced Search. Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume , Issue 1. Previous Article Next Article. Physiologic Actions of Insulin and the Insulin-Signaling Network.

Pathogenesis of Insulin Resistance and Hyperglycemia in Obesity. Obesity-induced Insulin Resistance in Skeletal Muscle.

Insulin Resistance and Glucose Homeostasis in the Liver with Obesity. Evidence for the Role of Inducible Nitric Oxide in Obesity-induced Insulin Resistance. Endoplasmic Reticulum Stress, Hyperglycemia, and Insulin Resistance. Central Nervous System Control of Glucose Homeostasis.

Therapeutic Choices for Treatment of Obesity-induced Insulin Resistance. Potential Hyperglycemia-independent Impact of Insulin Resistance in Critical Illness. Article Navigation. Review Article July Obesity-induced Insulin Resistance and Hyperglycemia : Etiologic Factors and Molecular Mechanisms J A.

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Wellen KE, Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest ; —9. Hossain P, Kawar B, El Nahas M: Obesity and diabetes in the developing world—a growing challenge. N Engl J Med ; —5. Wild S, Roglic G, Green A, Sicree R, King H: Global prevalence of diabetes: Estimates for the year and projections for Diabetes Care ; — Rocchini AP: Childhood obesity and a diabetes epidemic.

Kahn SE, Hull RL, Utzschneider KM: Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature ; —6. Bray GA, Bellanger T: Epidemiology, trends, and morbidities of obesity and the metabolic syndrome.

Endocrine ; — Rosen ED, Spiegelman BM: Adipocytes as regulators of energy balance and glucose homeostasis.

Nature ; — Trayhurn P: Endocrine and signalling role of adipose tissue: New perspectives on fat. Acta Physiol Scand ; — Bagry HS, Raghavendran S, Carli F: Metabolic syndrome and insulin resistance.

Anesthesiology ; — Saltiel AR, Kahn CR: Insulin signalling and the regulation of glucose and lipid metabolism. Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den Berghe G: Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels.

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Circ Res ; — White MF: IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab ; E— Taniguchi CM, Emanuelli B, Kahn CR: Critical nodes in signalling pathways: Insights into insulin action. Nat Rev Mol Cell Biol ; — Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M: Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes.

Studies with a selective inhibitor wortmannin. J Biol Chem ; — Ikezu T, Okamoto T, Yonezawa K, Tompinks RG, Martyn JAJ: Analysis of thermal injury-induced insulin resistance in rodents: Implication of post-receptor mechanism. Franke TF, Kaplan DR, Cantley LC, Toker A: Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate.

Science ; —8. Datta SR, Brunet A, Greenberg ME: Cellular survival: A play in three Akts. Genes Dev ; — Yasuhara S, Perez ME, Kanakubo E, Yasuhara Y, Shin YS, Kaneki M, Fujita T, Martyn JA: Skeletal muscle apoptosis after burns is associated with activation of proapoptotic signals.

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Hotamisligil GS: Inflammation and metabolic disorders. Nature ; —7. If the liver becomes insulin-resistant, these processes are severely affected, resulting in significant metabolic consequences. When skeletal muscle develops insulin resistance, excess glucose in the blood is shunted to the liver.

When the liver tissue senses an excess of energy substrate, particularly in the form of diacylglycerol, a process similar to that in skeletal muscle occurs. In the liver, the diacylglycerol content activates protein kinase C epsilon PKC-epsilon , which decreases proximal insulin signaling.

Excess glucose enters hepatocytes via insulin-independent pathways stimulating DNL via substrate push, creating more fatty acids from the glucose surplus.

The excess fatty acid is deposited in the liver or as ectopic lipid throughout the viscera. Additionally, immune-mediated inflammatory changes contribute to excess lipolysis from adipose tissue, which is re-esterified by the liver and further adds to circulating fatty acid and ectopic lipid deposition.

Finally, normal insulin-mediated suppression of gluconeogenesis is defective, and the liver continues to create more glucose, adding to the circulating glucose surplus. Using the hyperinsulinemic-euglycemic clamp technique, researchers determined that lipolysis is sensitive to insulin.

The failure of insulin to suppress lipolysis in insulin-resistant adipose tissue, especially visceral adipose tissue, increases circulating free fatty acids FFAs. Higher levels of circulating FFAs directly affect both liver and muscle metabolism, further exacerbating insulin resistance in these tissues and contributing to lipotoxicity-induced beta-cell dysfunction.

The clinical presentation of insulin resistance is variable concerning both history and physical examination findings.

Common presentations include:. The gold standard for measuring insulin resistance is the hyperinsulinemic-euglycemic glucose clamp technique.

The amount of glucose required to reach a steady state reflects the exogenous glucose disposal needed to compensate for hyperinsulinemia. Insulin resistance calculation is based on whole-body glucose disposal and body size.

The associated risks and complexity of the glucose clamp method limit its clinical usefulness. As a result, multiple surrogate markers for insulin resistance have been developed and tested. The homeostatic model assessment for insulin resistance HOMA-IR , based on fasting glucose and fasting insulin levels, is a widely utilized measure of insulin resistance in clinical research.

Other measures based on fasting insulin include HOMA2, the Glucose to Insulin Ratio GIR , and the Quantitative Insulin Sensitivity Index QUICKI. The McAuley Index utilizes fasting insulin and triglycerides. Post-glucose challenge tests, done after an overnight fast, measure insulin and glucose response to a gram glucose load.

Methods include the Matsuda Index and Insulin Sensitivity Index ISI. Other surrogate markers involve triglycerides alone or in relation to HDL cholesterol. In general, a ratio greater than 3. More specifically, a ratio greater than or equal to 3. These correlations do not hold up in individuals who identify as Black.

Measures of insulin resistance have not been integrated into clinical guidelines. As a result, the presence of insulin resistance is generally inferred from the clinical presentation.

Metabolic syndrome MetS and insulin resistance syndrome IRS are considered to be clinical indicators of insulin resistance. Multiple criteria for metabolic syndrome MetS exist. In , a joint scientific statement harmonizing criteria for MetS was released. The American College of Endocrinology identifies specific physiologic abnormalities that increase IRS risk.

Lifestyle intervention represents the cornerstone of treatment for insulin resistance. Dietary intervention should include a combination of calorie restriction and high glycemic index carbohydrate reduction. Physical activity improves both calorie expenditure and insulin sensitivity in muscle tissue.

Individuals with insulin resistance are at high risk of developing T2D. While no medications are FDA approved for the treatment of insulin resistance, general approaches include the following:.

Surgical intervention in the form of gastric sleeves, banding, and bypass is available for qualified individuals with obesity.

The excess fat loss associated with bariatric surgery improves insulin sensitivity. The results of the STAMPEDE trial provide good evidence of the benefit of bariatric surgery on T2D.

The prognosis of insulin resistance depends on the subset of the disease, the severity of the disease, underlying pancreatic beta-cell function, the heritable susceptibility of the patient to the secondary complications from insulin resistance, and individual response to appropriate therapy.

The outcomes range from mildly insulin-resistant, asymptomatic individuals to those with catastrophic cardiovascular or cerebrovascular events and their resulting morbidity and mortality.

Statistically, coronary artery disease is the leading cause of mortality in the US, with diabetes as seventh. The common basis for diabetes and much of the resultant vascular disease is insulin resistance.

Additional mortality from insulin resistance occurs in the less common manifestations of the disease, including genetic syndromes and fatty deposition diseases. Finally, substantial morbidity manifests with the loss of reproductive function and associated features of PCOS.

Mitigation for the disease exists. Increased clinical awareness enables early diagnosis and treatment. Improved understanding of the disease process has resulted in more targeted, multi-faceted therapies.

Efforts to attain and maintain a healthy weight through improved dietary intake and increased physical activity can reduce insulin resistance and prevent associated complications.

More generalized lay recognition can increase the efficacy of preventative care, with the hope of an eventual downturn in epidemic obesity and resultant insulin resistance.

Most of the complications from insulin resistance are related to the development of vascular complications. The microvascular disease manifests as retinopathy, nephropathy, and peripheral neuropathy. In the central nervous system, dementia, stroke, mood disturbance, and gait instability may occur.

Cardiac microvascular disease can manifest as angina, coronary artery spasm, and cardiomyopathy. Renal microvascular disease is a significant cause of chronic kidney disease, renal failure, and dialysis. Ophthalmological small vessel disease is a leading cause of retinopathy and visual impairment.

Macrovascular disease, secondary to insulin resistance, causes PAD, CAD, and CVA. Non-alcoholic fatty liver disease NAFLD is intricately related to insulin resistance and T2D. Patients with T2D have a 2-fold increased risk for NAFLD.

With an increasing worldwide prevalence and incidence in children, NAFLD should be of great concern to clinicians treating patients with insulin resistance. Primary prevention promotes public education regarding the importance of regular health monitoring.

A healthy diet and increased activity level can prevent or delay the onset of insulin resistance, metabolic syndrome, and diabetes, along with the associated complications. The emphasis on behavior modification and a sustainable lifestyle is critical for long-term weight management.

Secondary prevention includes laboratory screening for insulin resistance, diabetes, and further subspecialist referral to manage the early intervention for insulin resistance.

Public acceptance of tertiary prevention, such as intensive medical intervention and bariatric surgery for weight reduction, can lead to decreased morbidity and mortality associated with the consequent complications of insulin resistance. Intensive lifestyle intervention should be the first line of therapy for patients with metabolic syndrome or insulin resistance syndrome.

The benefits of exercise cannot be understated in treating patients with insulin resistance. Barriers to exercise should be discussed, and a well-formulated plan, including moderate-intensity cardiovascular exercise like walking, should be provided in accordance with the physical activity guidelines.

Discussion of dietary modification following the dietary guidelines should also be provided with individualization to the patient's preferences, with particular attention to reducing sugar, refined grain products, and high glycemic index carbohydrates.

Over the past few decades, the incidence of insulin resistance has skyrocketed primarily due to our lifestyle and the rising incidence of obesity. Without treatment, the condition is associated with numerous complications, including fatal cardiac events. Therefore, the management of insulin resistance is best done with an interprofessional team.

The consultations and coordination of care most indicated for the treatment of insulin resistance include:. There is limited evidence in favor of continuous glucose monitoring CGM. Remote monitoring for healthcare teams shows benefits in the management of T2D.

More research is needed to show the effects of CGM on those with prediabetes or insulin resistance without T2D. The key to the management of insulin resistance is encouraging lifestyle changes.

Dietary intervention should include a combination of calorie restriction and reduction of high glycemic index carbohydrates. The outcomes of well-managed insulin resistance are good for those who remain adherent to therapy.

Unfortunately, many patients struggle with adherence to therapy, with consequential progression to T2D and subsequent risk of adverse cardiac or CNS events.

Early identification and intervention with an interprofessional team approach are essential in managing these patients. Disclosure: Andrew Freeman declares no relevant financial relationships with ineligible companies.

Disclosure: Luis Acevedo declares no relevant financial relationships with ineligible companies. Disclosure: Nicholas Pennings declares no relevant financial relationships with ineligible companies. This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.

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Search term. Insulin Resistance Andrew M. Author Information and Affiliations Authors Andrew M. Affiliations 1 Southeastern Regional Medical Center.

Continuing Education Activity Insulin resistance, identified as an impaired biologic response to insulin stimulation of target tissues, primarily involves liver, muscle, and adipose tissue. Introduction Insulin resistance is identified as the impaired biologic response of target tissues to insulin stimulation.

Etiology The etiologies of insulin resistance may be acquired, hereditary, or mixed. Medications glucocorticoids, anti-adrenergic, protease inhibitors, selective serotonin reuptake inhibitors, atypical antipsychotics, and some exogenous insulins. Type-A insulin resistance: Characterized by severe insulin resistance abnormal glucose homeostasis, ovarian virialization, and acanthosis nigricans caused by abnormalities of the insulin receptor gene.

Type-B insulin resistance: Characterized severe impairment of insulin action triggered by the presence of insulin receptor autoantibodies with resultant abnormal glucose homeostasis, ovarian hyperandrogenism, and acanthosis nigricans.

Epidemiology Epidemiologic assessment of insulin resistance is typically measured in relation to the prevalence of metabolic syndrome or insulin resistance syndrome.

Pathophysiology The 3 primary sites of insulin resistance are the skeletal muscle, liver, and adipose tissue. History and Physical The clinical presentation of insulin resistance is variable concerning both history and physical examination findings. Common presentations include: Associated Diseases Non-alcoholic fatty liver disease NAFLD.

Evaluation The gold standard for measuring insulin resistance is the hyperinsulinemic-euglycemic glucose clamp technique. Elevated blood pressure greater than or equal to mm Hg systolic or greater than or equal to 85 mm Hg diastolic or on antihypertensive medication.

Metformin is a common first-line therapy for medication treatment of T2D and is approved for use in PCOS. Despite the concerns about using metformin in mild to moderate renal dysfunction, several organizations, including the American Geriatric Society and the Kidney Disease Improving Global Outcomes guidelines, endorse use as long as the GFR exceeds Glucagon-like peptide one GLP-1 receptor agonists stimulate the GLP-1 receptors in the pancreas, thereby increasing insulin release and inhibiting glucagon secretion.

The use of GLP-1 agonists is associated with weight loss, which may reduce insulin resistance. Liraglutide and semaglutide are FDA-approved for the treatment of T2D and obesity. Another agent, tirzepitide, is a dual GLP-1 and gastric inhibitory polypeptide GIP agonist, has effects similar to semaglutide, and is also FDA-approved for treating T2D.

Sodium-glucose cotransporter 2 SGLT2 inhibitors increase urinary glucose excretion, thereby reducing plasma glucose levels and exogenous insulin requirements. The use of SGLT2 inhibitors has also been associated with weight loss, which may reduce insulin resistance.

Thiazolidinediones improve insulin sensitivity and glucose control by increasing insulin-dependent glucose disposal in skeletal muscle and adipose tissue and decreasing hepatic glucose output. Though effective, associated secondary weight gain and fluid retention, with associated cardiovascular concerns, limit their use.

Dipeptidyl peptidase-4 DPP-4 inhibitors prolong the activity of endogenous GLP-1 and GIP by preventing their breakdown. Differential Diagnosis Lipodystrophy acquired, localized or generalized : Loss of adipose tissue that results from either genetic or acquired causation and can result in the ectopic deposition of fat in either hepatic or muscular tissue [56].

Obesity: Excess body weight is categorized as overweight BMI of 25 to Other forms of glucose intolerance impaired fasting glucose, impaired glucose tolerance, and gestational diabetes. Prognosis The prognosis of insulin resistance depends on the subset of the disease, the severity of the disease, underlying pancreatic beta-cell function, the heritable susceptibility of the patient to the secondary complications from insulin resistance, and individual response to appropriate therapy.

Complications Most of the complications from insulin resistance are related to the development of vascular complications. Deterrence and Patient Education Primary, secondary, and tertiary prevention have distinct roles in managing insulin resistance. Pearls and Other Issues Intensive lifestyle intervention should be the first line of therapy for patients with metabolic syndrome or insulin resistance syndrome.

Enhancing Healthcare Team Outcomes Over the past few decades, the incidence of insulin resistance has skyrocketed primarily due to our lifestyle and the rising incidence of obesity.

The consultations and coordination of care most indicated for the treatment of insulin resistance include: Obesity medicine specialist: medical management for obesity treatment. Bariatric surgeon: bariatric surgery is effective for obesity treatment in individuals who satisfy the criteria for surgery.

Cardiology and cardiac surgery: management of the cardiovascular complications of insulin resistance.

Neurology: management of the cerebrovascular and peripheral neurologic complications of insulin resistance. Pharmacist: educates the patient on the importance of medication adherence, instructing the patient on the proper use of medications, potential drug-drug interactions, and side effects.

Review Questions Access free multiple choice questions on this topic. Comment on this article. Figure Acanthosis Nigricans Contributed by Scott Dulebohn, MD. References 1.

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