Insulin Resistance

Insulin resistance is a state in which a given concentration of insulin produces a less-than-expected biological effect. Insulin resistance has also been arbitrarily defined as the requirement of 200 or more units of insulin per day to attain glycemic control and to prevent ketosis. The syndromes of insulin resistance actually make up a broad clinical spectrum, which includes obesity, glucose intolerance, diabetes, and the metabolic syndrome, as well as an extreme insulin-resistant state.[1] Many of these disorders are associated with various endocrine, metabolic, and genetic conditions. These syndromes may also be associated with immunological diseases and may exhibit distinct phenotypic characteristics.[2, 3, 4, 5, 6, 7, 8, 9]  The metabolic syndrome —a state of insulin-resistance that is also known as either syndrome X or the dysmetabolic syndrome—has drawn the greatest attention because of its public health importance.

The prevalence of hypertension rises with exacerbation of stages of impaired glucose metabolism; however, only in the early stages of impaired insulin metabolism do hyperglycemia and hyperinsulinemia appear to be significant contributors to the presence of hypertension.[10] In addition to hypertension, findings can include central obesity, peripheral arterial disease, type A syndrome, type B syndrome, ancanthosis nigricans, polycystic ovary syndrome, and other insulin-resistant states.

In clinical practice, no single laboratory test is used to diagnose insulin resistance syndrome. Diagnosis is based on clinical findings corroborated with laboratory tests. Individual patients are screened based on the presence of comorbid conditions. Laboratory tests include the plasma glucose level, the fasting insulin level, and a lipid profile, among others.

Treatment involves pharmacologic therapy to reduce insulin resistance, along with surgical management of underlying causes if appropriate. Comorbid conditions should be evaluated and addressed; this is generally feasible on an outpatient basis, though some patients will require admission. The metabolic syndrome requires aggressive control of cardiovascular and metabolic risk factors. Modifications of diet and activity are recommended. Medications that reduce insulin resistance (insulin-sensitizing and antihyperglycemic effects) include metformin and the thiazolidinediones.[11]

Go to Diabetes Mellitus, Type 1 and Diabetes Mellitus, Type 2 for complete information on these topics.

In insulin resistance, various clinical entities of this state are evident. The clinical heterogeneity can be explained, at least in part, on a biochemical basis. Insulin binds and acts mainly through the insulin receptor and also acts via the insulinlike growth factor–1 (IGF-1) receptor; cellular actions of insulin involve a wide variety of effects on postreceptor signaling pathways within target cells.

The b subunit of the insulin receptor is a tyrosine kinase, which is activated when insulin binds to the a subunit; the kinase activity autophosphorylates and mediates multiple actions of insulin. Ambient insulin levels, various physiologic and disease states, and drugs regulate insulin receptor concentration or affinity.

Insulin sensitivity and secretion are reciprocally related; thus, insulin resistance results in increased insulin secretion to maintain normal glucose and lipid homeostasis.[12, 13] The mathematical relation between sensitivity and secretion is curvilinear or hyperbolic. Several mediators are thought to signal the pancreatic B cells to respond to insulin resistance; failure of the signals or of the B cells to adapt adequately in relation to insulin sensitivity results in inappropriate insulin levels, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes.

These potential signaling mediators include glucose, free fatty acids, autonomic nerves, fat-derived hormones (eg, adiponectin), and the gut hormone glucagonlike peptide-1 (GLP-1). GLP-1 is an incretin hormone that stimulates insulin secretion, causes B-cell mitosis while inhibiting apoptosis, inhibits glucagon secretion, and delays gastric emptying with overall antidiabetic effects.

The mechanisms responsible for insulin resistance syndromes include genetic or primary target cell defects, autoantibodies to insulin, and accelerated insulin degradation.[14] Given that glucose and lipid metabolism largely depend on mitochondria to generate energy in cells, mitochondrial dysfunction may play an important role in the development of insulin resistance and associated complications.[15]

Obesity, the most common cause of insulin resistance, is associated with a decreased number of receptors and with postreceptor failure to activate tyrosine kinase. Although adiposity and insulin resistance are related, they are not necessarily synonymous, and each may make independent and different contributions to increasing the risk of cardiovascular disease.[16]  Moreover, "in obesity, inflammation, with increased accumulation and inflammatory polarization of immune cells, takes place in various tissues, including adipose tissue, skeletal muscle, liver, gut, pancreatic islet, and brain, and may contribute to obesity-linked metabolic dysfunctions, leading to insulin resistance and type 2 diabetes."[17]

Leptin and ghrelin are two hormones that have a major influence on energy balance. Leptin is a long-term regulator of energy balance, suppressing food intake and thereby inducing weight loss, while ghrelin is a fast-acting hormone, seemingly playing a role in meal initiation. Obese individuals tend to be leptin resistant; their circulating levels of the anorexigenic hormone leptin are increased, but the levels of the orexigenic hormone ghrelin are decreased. Potential exists for both hormones as drug targets.[18]

Insulin resistance plays a major pathogenic role in the development of the metabolic syndrome, which may include any or all of the following:

• Hyperinsulinemia

• Type 2 diabetes or glucose intolerance

• Central obesity[2]

• Hypertension

• Dyslipidemia that includes high triglyceride levels

• Low HDL-C level and small, dense low-density lipoprotein (LDL) particles

• Hypercoagulability characterized by an increased plasminogen activator inhibitor–1 (PAI-1) level

Inflammation and adipocytokines probably play some role in the etiopathogenesis of metabolic syndrome.[3, 17, 19, 20]  Increased levels of the acute-phase inflammatory marker C-reactive protein (CRP) are related to insulin resistance and the metabolic syndrome, suggesting a role for chronic, low-grade inflammation.[4] In a number of prospective studies, increased levels of CRP predict the development of diabetes and cardiovascular disease.[16, 21, 22]  Indeed, insulin resistance is not only predictive for type 2 diabetes and associated with myriad metabolic derangements in fasting conditions, but nondiabetic insulin-resistant individuals are subjected to a similar adverse postprandial metabolic setting and cardiometabolic risk as those with type 2 diabetes.[1]

Reduced serum levels of adiponectin (a hormone made by fat tissue) and elevated leptin concentration are also features of conditions associated with the metabolic syndrome or cardiovascular disease.[23, 24, 25, 26]

Omentin, a novel adipokine, is a protein expressed and secreted from visceral but not subcutaneous adipose tissue that increases insulin sensitivity in adipocytes. Plasma levels of omentin-1, the major circulating isoform, are inversely correlated with body mass index (BMI), waist circumference, leptin levels, and insulin resistance syndrome and are positively correlated with adiponectin and high-density lipoprotein (HDL) levels.[27, 28, 29, 30]

Insulin resistance, the compensatory hyperinsulinemia, and other components are associated with increased risk of cardiovascular disease; endothelial dysfunction is a prominent feature of insulin resistance syndrome.[5] Type 2 diabetes is characterized by increased hepatic glucose output, increased peripheral resistance to insulin action (due to receptor and postreceptor defects), and impaired insulin secretion.[31]

In skeletal muscle, various abnormalities, including defective glucose transport, may cause insulin resistance. Glucose transporter 4 (GLUT-4) is the main insulin-responsive transporter.[32] Insulin and IGFs are important regulators of ovarian function. Insulin resistance and hyperinsulinemia are thought to be responsible for the hyperandrogenism that is characteristic of the polycystic ovary syndrome (PCOS). Other distinct manifestations of insulin resistance syndrome or related conditions involve various organs, as well as the skin.

Two major variants of insulin receptor abnormalities associated with acanthosis nigricans have been described—the classic type A insulin resistance syndrome, which is due to an absent or dysfunctional receptor, and type B insulin resistance syndrome, which results from autoantibodies to the insulin receptor. Both syndromes are associated with hyperinsulinemia.

Hypoglycemia may still occur in some individuals with insulin resistance syndrome because of an agonist effect of autoantibodies on the insulin receptor. In some patients with insulin-binding antibodies, hypoglycemia may occur when insulin dissociates from the antibodies several hours after a meal.

Insulin resistance may also develop in some type 1 diabetic patients. Uruska et al found that an independent relationship existed between insulin resistance and the risk of microangiopathy in 81 patients with diabetes type 1 who began receiving intensive insulin therapy right after their diagnosis.[33] The authors determined that insulin resistance indicators, including waist circumference, waist-to-hip ratio, and triglyceride levels, were greater in cohort members with microangiopathy than in those without it. In addition, the estimated glucose disposal rate was lower in the microangiopathy patients than in the others.

Insulin resistance results from inherited and acquired influences. Hereditary causes include mutations of insulin receptor, glucose transporter, and signaling proteins, although the common forms are largely unidentified.

In a genome-wide association study for direct measures of insulin sensitivity in 2,764 Europeans, with replication in an additional 2,860 individuals, the presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI.[34]

Acquired causes include physical inactivity, diet, medications, hyperglycemia (glucose toxicity), increased free fatty acids, and the aging process.[35]

Classification of prereceptor, receptor, and postreceptor causes

The underlying causes of insulin-resistant states may also be categorized according to whether their primary effect is before, at, or after the insulin receptor (see below).

Prereceptor causes of insulin resistance include the following:

• Abnormal insulin (mutations)

• Anti-insulin antibodies

Receptor causes include the following:

• Decreased number of receptors (mainly, failure to activate tyrosine kinase)

• Reduced binding of insulin

• Insulin receptor mutations

• Insulin receptor–blocking antibodies

Postreceptor causes include the following:

• Defective signal transduction

• Mutations of GLUT4 (in theory, these mutations could cause insulin resistance, but polymorphisms in the GLUT4 gene are rare.

Combinations of causes are common. For example, obesity, the most common cause of insulin resistance, is associated mainly with postreceptor abnormality but is also associated with a decreased number of insulin receptors.

Other conditions that are categorized as receptor or postreceptor insulin-resistant states include the following:

• Type A syndrome

• Type B syndrome

• Leprechaunism

• Lipodystrophic states

• Ataxia-telangiectasia

• Werner syndrome

• Rabson-Mendenhall syndrome

• Pineal hypertrophic syndrome

Specific causes of insulin resistance

Specific conditions and agents that may cause insulin resistance include the following:

• Aging: This may cause insulin resistance through a decreased production of GLUT-4.

• Increased production of insulin antagonists: A number of disorders are associated with this effect, such as Cushing syndrome, acromegaly, and stress states, such as trauma, surgery, diabetes ketoacidosis, severe infection, uremia, and liver cirrhosis.

• Medications: Agents associated with insulin resistance syndrome include glucocorticoids (Cushing syndrome), cyclosporine, niacin, and protease inhibitors. Glucocorticoid therapy is a common cause of glucose intolerance; impairment of glucose tolerance may occur even at low doses when administered long term.[36]

• Sodium: High sodium intake has been associated with increased glucocorticoid production and insulin resistance.[37]

• Anti-HIV therapy[38] : Protease inhibitor–associated lipodystrophy is a recognized entity.[39] Nucleoside analogues have also been implicated in the development of insulin resistance.

• Androgen-deprivation therapy: This therapy causes severe hypogonadism with unfavorable metabolic changes.[40]

• Insulin therapy: Low-titer immunoglobulin G (IgG) anti-insulin antibody levels are present in most patients who receive insulin. Rarely, the antibodies result in significant prereceptor insulin resistance. Patients with a history of interrupted exposure to beef insulin treatment are particularly prone to this resistance. Clinically significant resistance usually occurs in patients with preexisting, significant tissue insensitivity to insulin. Enhanced destruction of insulin at the subcutaneous injection site has also been implicated in resistance.

United States statistics

In the United States, the frequency of insulin resistance is observed to be 3% in the general population; a several-fold increase occurs in individuals with glucose intolerance.  On the basis of National Health and Nutrition Examination Survey 2003-2006 data, about one-third of men and women have metabolic syndrome.[41]

International statistics

A quarter of the world’s adults are considered to have the metabolic syndrome.[6, 42]  Worldwide, early studies indicated a more significant association between insulin resistance and the various components of the metabolic syndrome in white persons than in members of other ethnic groups. Prevalence rates of insulin resistance syndrome reported for white populations ranged from 3-16%; a rate of less than 2% was reported among Japanese populations.

Subsequent findings, however, have suggested a similar relationship in many minority populations. Nevertheless, available systematic data apply mainly to white populations. Marked variations exist in methodologies and diagnostic criteria.

Age distribution for insulin resistance

Type A insulin resistance typically occurs in younger patients, while type B insulin resistance occurs more often in older women. Women with polycystic ovary syndrome (PCOS) usually present in their mid-20s. Many rare disorders of insulin resistance present in early life (eg, leprechaunism [first year of life], lipodystrophic states [ages 6-9 y until early puberty]).

The strongest relationship between insulin resistance and cardiovascular risk factors is observed in middle-aged persons rather than in older individuals, although cardiovascular morbidity and mortality increase with age.

Despite the growing obesity epidemic and insulin resistance in children, no clear diagnostic criteria and surrogate markers have been identified. An international consensus group recommended against screening for insulin resistance in children based on existing methodology and criteria.[43]

Sex distribution for insulin resistance

The metabolic syndrome is more evident in middle-aged men. Women tend to assume increased cardiovascular risk after menopause. PCOS is a disease limited to women. Type A and type B syndromes are typically found in women but can occur in men. Hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome has also been proposed as an alternative to type A in describing females with congenital forms of insulin resistance and acanthosis nigricans with ovarian hyperandrogenism but no other phenotypic changes such as growth retardation or lipodystrophy.

Prevalence of insulin resistance by race

Insulin resistance syndrome is found in all races. The degree of clustering of the risk variables of the metabolic syndrome is generally considered to be higher among whites. However, prevalence rates of the various components of the metabolic syndrome tend to be higher among nonwhite populations.[44]

Acanthosis nigricans, a common physical sign of insulin resistance syndrome, occurs in all ethnic groups, but the prevalence is higher in Hispanics and blacks than it is in whites.

Prognosis depends on the type of insulin resistance syndrome. The prognosis is guarded in regard to many of the disorders related to insulin resistance syndrome early in life. For instance, in leprechaunism, the clinical course is often characterized by growth retardation, abnormal glucose homeostasis (especially occurrence of hypoglycemia), and fatality within the first year of life. In other conditions, progression of insulin resistance and manifestation of related disorders continue into adulthood.

In the metabolic syndrome, the prognosis is often affected by the number and severity of comorbid conditions and by the institution of appropriate therapy. People with the metabolic syndrome are twice as likely to die from, and three times as likely to have, a myocardial infarction (MI) or stroke than are people without the syndrome. They also have a 5-fold increased risk of developing type 2 diabetes.

Insulin resistance is a common basis for development of glucose intolerance, including diabetes and coronary artery disease (CAD).

Diabetes mellitus is the sixth leading cause of death by disease and the seventh leading cause of death in the United States. Globally, up to 80% of the 200 million people with diabetes will die of cardiovascular disease. Diabetes is the leading cause of end-stage renal disease and blindness in the United States. Individuals with diabetes have a much higher risk of heart disease and a higher risk of stroke; they also have a high risk of neuropathy and gangrene. Diabetes is also associated with acute metabolic complications.

CAD is the leading cause of death in the United States and in most developed countries. Coronary artery disease is responsible for 500,000 deaths annually in the United States. Nearly 1.5 million myocardial infarctions, approximately one third of which are fatal, occur annually. The total annual economic cost of CAD in the United States is nearly $60 billion.

Mortality and morbidity related to other conditions associated with insulin resistance include the following:

• PCOS - Infertility, menstrual irregularity, androgen excess

• Rare conditions -Lipodystrophic states (fatty liver [Liver cirrhosis is a major cause of morbidity and mortality.])

The availability of newer modalities of treatment specifically targeted at primary and secondary prevention of complications has improved survival and quality of life significantly in patients with insulin resistance syndrome. However, morbidity and mortality rates are still considerable in the general population.

Educate patients who have insulin resistance on the nature of the disease, treatment, risk of complications, and primary and/or secondary preventive measures, including adoption of a healthier lifestyle. Educate family members on various issues related to the management and screening of persons at risk.

For patient education information, see the Diabetes Center.

The presentation of insulin resistance depends on the type and stage of the insulin-resistant state. Most patients have one or more clinical features of the insulin-resistant state. Many patients do not develop overt diabetes despite extreme insulin resistance. Other patients present with cases of severe hyperglycemia that require large quantities of insulin (>200 units); these people may manifest the classic symptoms of diabetes mellitus, such as polyuria, polydipsia, polyphagia, and weight loss.

Patients may present with the following:

• Metabolic syndrome (syndrome X) – Note that a patient with the metabolic syndrome may be asymptomatic in spite of the presence of some, or even most, of the components of insulin resistance syndrome.

• Obesity (most common cause of insulin resistance) or history of excessive body weight.

• Type 2 diabetes mellitus (chronic or acute [during severe decompensation] presentation [ie, the classic symptoms of diabetes]).

• A diagnosis of IGT or of IFG levels.

• History of biochemical abnormalities, such as dyslipidemia, detected during routine screening or workup for a cardiovascular disease.

• History of hypertension.

• Symptoms of coronary artery disease.

• Symptoms related to other macrovascular disease (eg, stroke, peripheral vascular disease).

• Microvascular angina.

• Combination of hyperglycemia and virilization occurs in several syndromes of insulin resistance.

• Type A, which affects young women, is characterized by severe hyperinsulinemia, usually present with obesity and features of hyperandrogenism.

• Polycystic ovary syndrome (PCOS) - Patients usually present with infertility associated with anovulation; menstrual irregularity, typically chronic; and symptoms related to androgen excess, such as acne, frontal baldness, and hirsutism, but rarely features of virilization.

• Type B syndrome - Some patients present with symptoms of hypoglycemia, such as sweating, tremulousness, irritability, and an altered level of consciousness. Hypoglycemia results from interaction between insulinomimetic antibodies and the insulin receptor. Some patients have insulin-binding antibodies directed against insulin, which, upon dissociation, can cause hypoglycemia. Symptoms related to immunologic disease (eg, arthralgia, swollen salivary glands, hair loss) may occur.

Other indicators of insulin-resistant states that may be elicited in the history include the following:

• Leprechaunism - Abnormal facial appearance, early life growth retardation

• Lipodystrophic states - Insulin resistance, usually during childhood, with progression to diabetes over several years

• Werner syndrome - Features of premature aging

• Rabson-Mendenhall syndrome - Dental and nail abnormalities, skin lesions

• Pineal hypertrophic syndrome - Dental and nail abnormalities, sexual precocity

• Alstrom syndrome - Childhood blindness, impaired hearing

• Ataxia-telangiectasia - Movement disorder and symptoms related to immune deficiency, such as increased proneness to pulmonary infections

• Myotonic dystrophy - Muscle weakness and visual symptoms (cataract)

In addition to elevated blood pressure (hypertension), the physical examination findings may include the features listed below.

Anthropometry

Central obesity, not peripherally distributed fat, is a strong marker of insulin resistance syndrome. Waist or waist-to-hip ratio, height, weight, and body mass index (BMI) may indicate insulin resistance syndrome. This notion was supported by an Argentinian study that found waist circumference and BMI to be the anthropometric indexes that best correlate with the presence of insulin resistance.[45]

The Argentinian investigators examined the association between insulin resistance and the following indexes: waist circumference, BMI, waist circumference/height, weight/(sitting height)(2), and waist circumference/sitting height of 625 children, 91 of whom were overweight and another 96 of whom were classified as obese.

Cardiovascular system

Cardiovascular findings associated with insulin resistance may include the following:

• Signs of heart disease

• Peripheral vascular disease - Abnormalities in pulses and arterial wall

• Stigmata of lipid disorders - Suggests the possibility of underlying hyperlipidemia

• Premature arcus cornealis - Deposits of cholesterol and phospholipid

• Xanthelasma - Indicates that lipid status should be investigated

• Lipemia retinalis - Retinal vessels with milky, chylomicron-rich plasma commonly observed in acute, uncontrolled diabetes

• Skin xanthomata - Eruptive xanthomas found most commonly on the buttocks

• Tendon xanthomata - Usually over the patellar and Achilles tendon

Type A syndrome

Patients with type A syndrome are usually tall and have features of hirsutism and abnormalities of the female reproductive tract related to hyperandrogenism (eg, polycystic ovary syndrome [PCOS]). The patient may have either a thin or a muscular body build. Acral enlargement, a form of pseudoacromegaly, is not uncommon.

Acanthosis nigricans

Acanthosis nigricans is common in patients with type A syndrome; it causes patchy, velvety-brown hyperpigmentation plaques that are usually found in flexural areas, especially in the axillae and the nuchal region. Lesions may be due to the effect of high circulating levels of insulin on insulinlike growth factor (IGF) receptors in the skin. These eruptions have been reported in nearly one tenth of women evaluated for PCOS.

Acanthosis nigricans is found in a wide variety of clinical conditions that are associated with insulin resistance. It is occasionally a marker of malignant neoplasm.

Polycystic ovary syndrome

Patients with PCOS may have masculine habitus, such as coarse or greasy skin and acne, frontal alopecia, breast atrophy, hypertrophy of the clitoris, and obesity; varying degrees of hirsutism or virilization may be present. These manifestations are due to hyperandrogenism.

Type B syndrome (autoantibodies to insulin receptor)

Patients with type B syndrome usually have symptomatic diabetes mellitus, although ketoacidosis is unusual. Patients occasionally present with hypoglycemia. Agonist activity (hypoglycemia) or antagonist effect (insulin resistance) can occur, depending on the site of binding to the insulin receptor.

Other insulin-resistant states

Findings characteristic of other insulin-resistant states include the following:

• Leprechaunism - Elfin appearance of the face, hirsutism, lack of subcutaneous fat, and thickened skin

• Lipodystrophic states - Variable phenotypic expression (features include a total or partial lack of adipose tissue, metabolic dysfunction, such as abnormal glucose homeostasis, hypertriglyceridemia, and increased metabolic rate.)

• Werner syndrome - Cataract, atrophic skin, and early osteopenia

• Rabson-Mendenhall syndrome - Dystrophic nails, dental dysplasia, and acanthosis nigricans

• Pineal hypertrophic syndrome - Early dentition with malformed teeth, hirsutism, thick nails, and skin dryness

• Alstrom syndrome - Nerve deafness, hypogonadism (males), and retinal degeneration that results in blindness

• Ataxia telangiectasia - Cerebellar ataxia, oculocutaneous telangiectases, immune deficiency, and increased proneness to pulmonary infections

• Myotonic dystrophy - Weakness of limb and cranial muscles, cataract

Potential complications of insulin resistance include the following:

• Acute metabolic complications, including severe hyperglycemia and hypoglycemia

• Angina

• Myocardial infarction

• Stroke

• Transient ischemic attack

• Peripheral vascular disease

• Renal disease[46]

• Ocular complications

In clinical practice, no single laboratory test is used to diagnose insulin resistance syndrome. Diagnosis is based on clinical findings corroborated with laboratory tests. Individual patients are screened based on the presence of comorbid conditions.

Routine laboratory measurements in the evaluation of patients with insulin resistance syndrome include the following:

• Plasma glucose level (fasting, random, and oral glucose tolerance test) - Diagnosis and monitoring of glucose intolerance (diabetes mellitus, impaired glucose tolerance [IGT], impaired fasting glucose [IFG]).

• Insulin resistance - May also be associated with hypoglycemia (autoimmune conditions).

• Glycohemoglobin level – Used to assess chronic hyperglycemia.

• Fasting insulin level - A measure of the degree of insulin resistance in many patients with insulin resistance syndrome.

• Lipid profile (fasting total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], cholesterol, triglyceride) - Insulin resistance syndrome characterized by elevated LDL-B levels (small, dense, pattern B), high triglyceride levels, and reduced HDL-C levels.

• Combined use of insulin and lipid markers in atherosclerosis - Fasting insulin, apolipoprotein B, and small LDL levels are more biologically significant than are standard lipid tests. Elevations in the 3 markers increase the risk of coronary artery disease by nearly 20-fold.

• Electrolyte levels (BUN [blood urea nitrogen], creatinine, and uric acid levels) - Hyperuricemia is common and is often considered a component of the metabolic syndrome.

• Urinalysis - Microalbuminuria is a marker of endothelial dysfunction.

• Homocysteine (H[e]) - An elevated level is a risk factor for atherosclerosis, which predicts macrovascular disease. levels are regulated by insulin.

• Plasminogen activator inhibitor (PAI)-1 - An elevated level is associated with insulin resistance syndrome and is correlated with obesity, waist-to-hip ratio, hypertension, fasting and postprandial insulin levels, proinsulin levels, fasting glucose levels, and elevated triglyceride and LDL levels.[53] An increased PAI-1 level signifies impaired fibrinolysis, thus indicating increased risk of atherosclerosis.

Other laboratory studies include measurement of fibrinogen levels and testing of endothelial function. An increased fibrinogen level is a feature of insulin resistance syndrome. Endothelium plays an important role in insulin action, including in the regulation of tissue blood flow and in insulin delivery to interstitium. Endothelial dysfunction is an important component of insulin resistance syndrome and includes reduced capillary formation, reduced surface area, and abnormal reactivity of endothelium.[54]

Most recently, serum WISP-1/CCN4 level (WNT1 inducible signaling pathway protein 1), a novel pro-inflammatory adipokine, was proposed as a suitable biomarker of obesity, and the levels correlate with anthropometric indices of obesity.[55]

Biochemical changes associated with endothelial dysfunction include (1) reduced nitric oxide and prostacyclin levels, (2) increased endothelin and angiotensin activity, and (3) increased local and systemic inflammation (increased C-reactive protein [CRP] levels).[4] Blood testing for CRP measurement is widely available. Smoking and abnormal lipids are major contributors to endothelial dysfunction.

In theory, insulin sensitivity can be assessed through the following methods:

• Fasting insulin level - This provides an indirect assessment of insulin sensitivity. The limitation of this study is inaccuracy in a patient with mutant insulin in which the hormone measured by radioimmunoassay is not fully bioactive.

• Measurement of response to direct intravenous infusion of insulin - The limitations of this measurement are a confounding factor in data interpretation and a variation in secretion of antagonist hormones in response to hypoglycemia.

• Euglycemic insulin clamp technique - Plasma glucose levels are held constant, with variable glucose infusion. Biochemical responses that are surrogate estimates of insulin resistance, such as glucose disposal and antilipolysis, are determined. This method is considered the criterion standard.

• The latter two tests are more accurate, but they are research tools and are not routinely used in clinical practice.

• Homeostatic model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) - These are the most widely used simple indices for assessing insulin resistance in clinical research and practice. Both indices are based on fasting glucose and insulin measurements; they differ mainly in the log transformation of these variables in QUICKI.[56, 57, 58]

• HOMA-IR is derived from the product of the insulin and glucose values divided by a constant--that is, calculated by using the following formula: fasting glucose (mg/dL) X fasting insulin (µU/mL) / 405 (for SI units: fasting glucose (mmol/L) X fasting insulin (µU/L) / 22.5). A value greater than 2 indicates insulin resistance.

• QUICKI is derived by calculating the inverse of the sum of the logarithmically expressed values of fasting insulin and glucose: 1/[log(fasting glucose) + log(fasting insulin)] . It measures insulin sensitivity, which is the inverse of insulin resistance. A value of less than 0.339 indicates insulin resistance.

• They both compensate for fasting hyperglycemia, and the results for the indices correlate reasonably well with the euglycemic clamp technique. Some investigators believe that QUICKI is superior to HOMA-IR (for instance, in reproducibility), but the two indices correlate very well.[59, 60, 61]

• One study suggests fasting insulin sensitivities are not better than routine clinical variables in predicting insulin sensitivity in black Africans.[62]

Other cardiac tests include echocardiography and stress testing, depending on the presentation.

A risk-assessment calculator, based on data from the Framingham Heart Study for estimating 10-year cardiovascular risk, is available. This calculator estimates the 10-year risk for hard coronary heart disease outcomes (myocardial infarction and coronary death). The tool is designed to estimate risk in adults aged 20 years and older who do not have heart disease or diabetes. The ACC/AHA Pooled Cohort Equations CV Risk Calculator was developed as a 10-year risk assessment tool for atherosclerotic cardiovascular disease from multiple community-based cohorts (including the Framingham Heart study).[63]

For patients with insulin resistance without overt diabetes, the metabolic syndrome criteria for cardiovascular risk stratification are less sensitive than those of the Framingham Risk Score, which takes into account age, total cholesterol, tobacco use, HDL-C, and blood pressure, but not diabetes.

Evaluate patients for comorbid conditions; this is generally feasible on an outpatient basis. Admission for laboratory studies and treatment of acute complications may be warranted for patients whose conditions require urgent or emergent intervention. The metabolic syndrome requires aggressive control of cardiovascular and metabolic risk factors. Tailor therapy for optimal benefits.

Weight reduction improves insulin sensitivity in cases of obesity and in most of the obesity-related insulin-resistant states. Restriction of caloric intake is indicated. Dietary indiscretion, such as consumption of a diet high in cholesterol and sodium, should be avoided. Alcohol use should be limited. Smoking cessation is indicated.[64, 65]

Patiends should avoid physical inactivity.[66] Exercise improves insulin sensitivity via the following[67, 68] :

• Increased oxidative enzymes

• Increased GLUT-4

• Increased capillarity

• Reduced central adiposity

In patients with insulin resistance, diligent monitoring of metabolic profile, general status, medications, and side effects is indicated. Transfer may be indicated for diagnostic evaluation and for the treatment of major primary conditions and complications.

Consultation with an endocrinologist is indicated in insulin resistance. Referral to a medical weight management program is usually needed. Consultation with a cardiologist is also usually indicated. Other specialists, such as a dermatologist, gynecologist, cardiothoracic surgeon, and ophthalmologist, may need to be consulted based on the nature of the disease and the prevailing pathology.

Medications that reduce insulin resistance (insulin-sensitizing and antihyperglycemic effects) include metformin and the thiazolidinediones.[11]

Metformin is a biguanide; it reduces hepatic glucose output and increases the uptake in the peripheral tissues (muscle and adipocytes). Metformin is a major drug in the treatment of patients who are obese and have type 2 diabetes. The drug enhances weight reduction and improves lipid profile and vascular integrity.[69]

Long-term follow-up data from the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS) found metformin is associated with vitamin B12 deficiency, and routine measurement of vitamin B12 should be considered in patients receiving metaformin.[70]

Thiazolidinediones lower plasma insulin levels and treat type 2 diabetes associated with insulin resistance.[71, 72, 73]  In a multicenter, double-blind trial of 3876 insulin-resistant patients who had had a recent ischemic stroke or transient ischemic attack (TIA), those receiveing pioglitazone  (45 mg daily) had a reduced the risk of stroke, myocardial infarction, and diabetes compared to those receiving placebo. However, pioglitazone increased the risk for weight gain, edema, and fracture.[74]

Successful treatment of severe type B insulin resistance has been reported with rituximab, cyclophosphamide, and prednisone following failure of immunosuppressive therapy and plasmapheresis to control glucose levels or reduce insulin dosage.[75]

Improvement in insulin resistance occurs after bariatric surgery, such as gastric banding, sleeve gastrectomy, and gastric bypass, when carried out in carefully selected morbidly obese patients.[76] Bariatric surgery may be appropriate for patients with a body mass index (BMI) greater than 40 kg/m2 or greater than 35 kg/m2 in combination with high-risk comorbidities. It is the most effective treatment for obesity that is currently available, but it is reserved for patients who are unable to attain weight reduction after attempting noninvasive or less intense options. In severe cardiovascular disease, procedures such as coronary artery bypass graft and peripheral vascular surgery may be necessary.

Cosmetic and palliative treatments may be indicated in the treatment of many patients with insulin resistance syndrome, depending on the type and severity of physical anomalies (eg, epilation and electrolysis for hirsutism in patients with PCOS).

In an effort to clinically identify patients with insulin resistance, various organizations have developed diagnostic criteria. The most commonly used criteria in the United States are those of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III).[77, 78, 79]

NCEP/ATP III criteria for metabolic syndrome

NCEP/ATP III criteria for the diagnosis of the metabolic syndrome include the following (diagnosis is made when three or more are present):

• Waist circumference of more than 102 cm in men or more than 88 cm in women

• Fasting triglyceride level of 150 mg/dL or higher

• Blood pressure level of 130/85 mm Hg or higher

• High-density lipoprotein cholesterol (HDL-C) level of less than 40 mg/dL in men or less than 50 mg/dL in women

• Fasting glucose level of 110 mg/dL or higher (which has been changed to 100 mg/dL to reflect revised criteria for impaired fasting glucose [IFG])

WHO criteria for metabolic syndrome

The World Health Organization (WHO) has also developed criteria for the diagnosis of the metabolic syndrome, as follows[79] :

• Type 2 diabetes

• IFG level of 101-125 mg/dL

• Impaired glucose tolerance (IGT) (glucose level of 140-199 mg/dL 2 h after administration of 75 g of glucose)

• Glucose uptake level of less than the lowest quartile for ethnic population under hyperinsulinemic, euglycemic conditions if the fasting glucose level is normal

In addition to the aforementioned criteria, the diagnosis must also include two of the following:

• Use of antihypertensive medication; blood pressure of 140 mm Hg systolic or higher, 90 mm Hg diastolic or higher, or both

• Triglyceride level of 150 mg/dL or higher

• HDL-C level of less than 35 mg/dL in men or less than 39 mg/dL in women

• Body mass index (BMI) of more than 30 kg/m2, waist-to-hip ratio of more than 0.9 in men or more than 0.85 in women, or both

• Urinary albumin excretion level of 20 mcg/min or higher or albumin-creatinine ratio of 30 mg/g or higher

AACE clinical criteria for insulin resistance syndrome

The American Association of Clinical Endocrinologists (AACE) has formulated clinical criteria for the diagnosis of insulin resistance syndrome, as follows[7] :

• BMI of 25 kg/m2 or higher

• Triglyceride level of 150 mg/dL or higher

• HDL-C level of less than 40 mg/dL in men or less than 50 mg/dL in women

• Blood pressure of 130/85 mm Hg or higher

• Glucose level of more than 140 mg/dL 2 hours after administration of 75 g of glucose

• Fasting glucose level of 110-126 mg/dL

Differences in diagnostic criteria

Whereas the NCEP/ATP III criteria use fasting glucose level as the only measurement of glucose tolerance, the WHO and AACE criteria include the option of performing a 2-hour oral glucose tolerance test (OGTT). The OGTT better identifies individuals at risk for endothelial damage due to hyperglycemia, because IGT has been shown to be independently associated with endothelial dysfunction and, hence, cardiovascular risk.[16]

IDF global consensus statement on metabolic syndrome

In a global consensus statement, an International Diabetes Federation (IDF) panel presented a worldwide definition of the metabolic syndrome aimed at facilitating early detection and more intensive management of the condition, with the hope of reducing the long-term risk of cardiovascular disease (CVD) and diabetes.

According to the definition by the IDF panel, the diagnostic criteria for the metabolic syndrome include central obesity (defined as waist circumference ≥94 cm in men or ≥80 cm in women in Europid persons and in ethnic-specific levels in Chinese, Japanese, and South Asian persons) together with 2 of the following:

• Triglyceride level of 1.7 mmol/L (150 mg/dL) or higher

• Low HDL-C level (defined as < 1.04 mmol/L [40 mg/dL] in men or < 1.29 mmol/L [50 mg/dL] in women)

• Blood pressure of 130/85 mm Hg or higher

• Fasting hyperglycemia (defined as glucose level ≥5.6 mmol/L [100 mg/dL]) or previous diagnosis of diabetes or IGT.

The scientific basis for the definition of the metabolic syndrome and its clinical utility have been debated.[50, 51, 52] The debate was accentuated by a joint statement from the American Diabetes Association and the European Association for the Study of Diabetes.[8]

Both sides of the debate, however, generally agree that the risk factors commonly coexist in the same patient and that insulin resistance is the major underlying mechanism. Moreover, the metabolic syndrome serves as a clinical tool to raise awareness among health care providers, thus assisting in identifying high-risk individuals.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Medications that reduce insulin resistance include biguanides and thiazolidinediones, which have insulin-sensitizing and antihyperglycemic effects. Large quantities of insulin are also used in overcoming insulin resistance. Response to usual dosage of insulin is observed in instances in which the resistance is due to enhanced destruction at the subcutaneous injection site.

The treatment of type 2 diabetes and impaired glucose tolerance (IGT)—conditions that are strongly associated with insulin resistance and significant cardiovascular morbidity and mortality—should aim at restoring the normal relationship between insulin sensitivity and secretion.

For diabetes, this involves pharmacotherapy, which includes stimulation of insulin secretion (sulfonylureas, meglitinides, incretin mimetics) and insulin sensitivity (metformin, thiazolidinediones), as well as treatment intended to support the signals that mediate the islet adaptation (incretin mimetics).[11, 69]

Pramlintide (an amylin analogue) acts as an amylinomimetic agent by modulating gastric emptying, preventing postprandial increases in plasma glucagon, and promoting satiety, leading to decreased caloric intake and potential weight loss. Antiobesity drugs, such as orlistat, may reduce insulin resistance and related cardiovascular risk factors through weight reduction and other mechanisms.[80, 81, 82, 83, 84]

Other currently available drugs include liraglutide, phentermine, phentermine/topiramate extended release (ER), lorcaserin, and naltrexone ER/bupropion ER. Weight-loss medications are prescribed as an adjunct to lifestyle measures and to help achieve a greater degree of weight loss than that produced by dietary changes and physical activity alone. In selecting the optimal weight-loss medication for each patient, the clinician needs to consider differences in efficacy, side effects, precautions, and warnings that characterize the medications approved for chronic management of obesity.[85]

In most patients, the administration of insulin is also crucial in the treatment of diabetes.

Most experts recommend early preventive strategies in children, especially lifestyle changes such as diet and increased level of physical activity, whereas pharmacotherapy is reserved for selected cases.[43]

Class Summary

Biguanides are insulin sensitizers useful in type 2 diabetes and related insulin resistance. They reduce hepatic glucose output and peripheral resistance to insulin action and lower plasma insulin levels.

Metformin (Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet)

Metformin reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in the peripheral tissues (muscle and adipocytes). It is a major drug used in obese patients who have type 2 diabetes. It enhances weight reduction and improves lipid profile and vascular integrity. Individualize metformin treatment with monotherapy, or administer it in combination with insulin or sulfonylureas.

Class Summary

Thiazolidinediones are insulin-sensitizing drugs that increase the disposal of glucose in peripheral tissues and act by activating a specific nuclear receptor, the peroxisome proliferator-activated receptor gamma (PPAR-gamma). Thiazolidinediones have a major effect in the stimulation of glucose uptake, skeletal muscle, and adipose tissue. They lower plasma insulin levels and are used to treat type 2 diabetes associated with insulin resistance. They appear to benefit patients with PCOS. Thiazolidinediones include rosiglitazone and pioglitazone.[11, 71]

Pioglitazone (Actos)

Pioglitazone may be used in monotherapy and in combination with metformin, insulin, or sulfonylureas. It improves target cell response to insulin without increasing insulin secretion from pancreas. It decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and, possibly, in liver and adipose tissue.

Rosiglitazone (Avandia)

Rosiglitazone is an insulin sensitizer with a major effect in stimulating glucose uptake in skeletal muscle and adipose tissue. It lowers plasma insulin levels. Rosiglitazone is used for treatment of type 2 diabetes associated with insulin resistance and may benefit polycystic ovary syndrome (PCOS) patients. It may be used as monotherapy or in combination with metformin.

Rosiglitazone is highly selective and a potent agonist for PPAR-gamma. The activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby lowering blood glucose concentrations and reducing hyperinsulinemia. Potent PPAR-gamma agonists have been shown to increase the incidence of edema. A large-scale, phase III trial (RECORD) is currently underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.

On May 21, 2007, following the online publication of a meta-analysis, the US Food and Drug Administration (FDA) issued an alert to patients and health care professionals warning that rosiglitazone can potentially increase the risk for myocardial infarction and heart-related deaths.

As of September 2010, the FDA is requiring a restricted access program to be developed for rosiglitazone under a risk evaluation and mitigation strategy (REMS). Patients currently taking rosiglitazone and benefiting from the drug will be able to continue if they choose to do so. Rosiglitazone will only be available to new patients if they are unable to achieve glucose control on other medications and are unable to take pioglitazone, the only other thiazolidinedione.

For more information, see FDA's Safety Alert on Avandia. The meta-analysis, entitled Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes, can be viewed online. Additionally, responses to the controversy—including the articles Rosiglitazone increases MI and CV death in meta-analysis and The rosiglitazone aftermath: legitimate concerns or hype? —can be viewed at the Heartwire news site (the heart.org), from WebMD.

Class Summary

Corticosteroids are immunosuppressants used for the treatment of immune insulin resistance due to anti-insulin antibodies.

Prednisone (Rayos)

Prednisone is an immunosuppressant used for the treatment of autoimmune disorders. It may decrease inflammation by suppressing key steps of the immune reaction process.

Class Summary

Insulin is given to overcome insulin resistance, but large quantities are often required.

Insulin (Humulin, Novolin, Humalog)

Insulin stimulates proper utilization of glucose by the cells and reduces blood sugar levels. Various preparations are currently available. There are rapid-acting, intermediate acting, and long-acting formulations. Insulin mixes are also available that provide a rapid onset and an intermediate duration of action.

Class Summary

Lipase inhibitors inhibit nutrient absorption. Lipase inhibitors such as orlistat may reduce insulin resistance and related cardiovascular risk factors through weight reduction and other mechanisms.

Orlistat (Xenical, Alli)

Orlistat is a gastrointestinal lipase inhibitor that induces weight loss by inhibiting nutrient absorption. Its effectiveness in producing weight loss does not depend on systemic absorption. May reduce absorption of some fat-soluble vitamins (A, D, E, K) and beta-carotene. Administer a daily oral multivitamin supplement containing fat-soluble vitamins 2 hours before meals or 1 hour after meals. Rare cases of severe liver injury have been reported with use so caution should be taken when administering orlistat.

Class Summary

These agents are incretin mimetics. They are analogues of human glucagonlike peptide-1 (GLP-1) and they act as GLP-1 receptor agonists to increase insulin secretion in the presence of elevated blood glucose. These agents delay gastric emptying to decrease postprandial glucose and they also decrease glucagon secretion.

Exenatide (Bydureon, Byetta)

Exenatide, a 39-amino acid incretin mimetic peptide derived from Gila monster hormone exendin-4, is structurally similar to GLP-1. Approved by the FDA for treatment of type 2 diabetes, it enhances glucose-mediated insulin secretion in the beta cell, decreases the pathologic hypersecretion of glucagon in the alpha cell, slows gastric emptying, and induces satiety. It improves postprandial and fasting hyperglycemia without a significant risk of hypoglycemia and promotes weight loss, resulting in increased insulin sensitivity.

The suspension form of exenatide allows once-weekly dosing by subcutaneous administration. Clinical trials observed a statistically significant improvement in HBA1c levels and fasting plasma glucose levels with the long-acting exenatide once-weekly subcutaneous injection compared with the twice-daily subcutaneous injection.

Liraglutide (Victoza)

Liraglutide is an incretin mimetic agent that elicits GLP-1 receptor agonist activity. It activates the GLP-1 receptor by stimulating G-protein in pancreatic beta cells. It also increases intracellular cyclic AMP, leading to insulin release in the presence of elevated glucose concentrations. It produces weight loss, hence an increase in insulin sensitivity.

Liraglutide was originally approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

In December 2014, the FDA approved the drug liraglutide (Saxenda) for the treatment of obesity. It is approved for use in adults with a BMI of 30 or greater (obesity) or adults with a BMI of 27 or greater (overweight) who have at least one weight-related condition such as hypertension, type 2 diabetes, or dyslipidemia.