AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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 comprise a broad clinical spectrum, which includes obesity, glucose intolerance, diabetes, and syndrome X, as well as an extreme insulin-resistant state. 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.

Syndrome X, the insulin-resistance state also known as metabolic or dysmetabolic syndrome, has drawn the greatest attention because of the public health importance. 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).

• NCEP/ATP III criteria for the diagnosis of metabolic syndrome include the following (diagnosis is made when 3 or more are present):
• • Waist circumference of more than 102 cm in men or more than 88 cm in women
  • Fasting triglyceride (TG) 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 the revised American Diabetes criteria for impaired fasting glucose [IFG])
• The World Health Organization (WHO) criteria for the diagnosis of metabolic syndrome include the following:
• • Type 2 diabetes
  • Impaired fasting  glucose 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 2 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
• The American Association of Clinical Endocrinologists (AACE) clinical criteria for diagnosis of insulin resistance syndrome (IRS) include the following:
• • 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
  • Additional risk factors include the following:
  • • Family history of type 2 diabetes
    • Hypertension
    • Coronary heart disease (CHD)
    • Polycystic ovary disease
    • Sedentary lifestyle
    • Advanced age
    • Ethnic groups at high risk for type 2 diabetes or for CHD

The ATP III criteria use fasting glucose level as the only measurement of glucose tolerance, while 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, since impaired glucose tolerance has been shown to be independently associated with endothelial dysfunction and, hence, cardiovascular risk.

Recently, an International Diabetes Federation (IDF) panel issued a global consensus statement that presents a new worldwide definition of the metabolic syndrome, aiming at facilitating early detection and more intensive management, with the hope of reducing the long-term risk of cardiovascular disease (CVD) and diabetes.

• According to the definition of the IDF panel, the new diagnostic criteria for 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 impaired glucose tolerance

Recently, the scientific basis for the definition of the metabolic syndrome and its clinical utility have been debated. The debate was accentuated by a joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. However, both sides of this debate 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. For additional resources, please visit Cardiometabolic Risk Factor Management.

Pathophysiology

Various clinical entities of the insulin-resistant 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 physiological and disease states, and drugs regulate insulin receptor concentration or affinity.

The mechanisms responsible for insulin resistance syndromes include genetic or primary target cell defects, autoantibodies to insulin, and accelerated insulin degradation. Obesity, the most common cause of insulin resistance, is associated with a decreased number of receptors and with postreceptor failure to activate the tyrosine kinase. While 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. 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
• 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. Increased levels of the acute-phase inflammatory marker C-reactive protein (CRP) are related to insulin resistance and metabolic syndrome, suggesting a role for chronic low-grade inflammation. In a number of prospective studies, increased levels of CRP predict the development of diabetes and cardiovascular disease. Reduced serum levels of adiponectin (a novel hormone made by fat tissue) and elevated leptin concentration are also features of conditions associated with metabolic syndrome or cardiovascular disease.¹

Insulin sensitivity and secretion are reciprocally related, such that insulin resistance is adapted by increased insulin secretion to maintain normal glucose and lipid homeostasis. The mathematical relationship between insulin sensitivity and secretion is curvilinear or hyperbolic. Several potential mediators are thought to be signals for the pancreatic b cells to respond to insulin resistance; these potential 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.

Failure of the signals or of the pancreatic b cells to adapt adequately to insulin secretion in relation to the sensitivity results in inappropriate insulin levels, impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes.

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. 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. In skeletal muscle, various abnormalities, including defective glucose transport, may cause insulin resistance. Glucose transporter 4 (GLUT-4) is the main insulin-responsive transporter. 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 polycystic ovary disease (PCOD). 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.

Frequency

United States

A frequency of 3% is observed in the general population; a several-fold increase occurs in individuals with glucose intolerance.

International

Early studies indicated a more significant association between insulin resistance and the various components of the metabolic syndrome in whites compared with other ethnic groups. However, recent findings suggest a similar relationship in many minority populations. Systematic data available apply mainly to white populations. Marked variations exist in methodologies and diagnostic criteria. Prevalence rates of insulin resistance syndrome reported for white populations ranged from 3-16%; a much lower rate of less than 2% was reported among Japanese populations. A quarter of the world's adults are considered to have the metabolic syndrome.

Mortality/Morbidity

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

• People with metabolic syndrome are twice as likely to die from, and 3 times as likely to have, a myocardial infarction or stroke compared with people without the syndrome.
• People with metabolic syndrome have a 5-fold increased risk of developing type 2 diabetes.
• 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.
• Coronary artery disease 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 occur annually, of which approximately one third are fatal. The total annual economic cost of Coronary artery disease in the United States is nearly $60 billion.
• Mortality and morbidity related to other conditions associated with insulin resistance include the following:
• • Polycystic ovary disease - Infertility, menstrual irregularity, androgen excess
  • Rare conditions - Lipodystrophic states (fatty liver [Liver cirrhosis is a major cause of morbidity and mortality.])
  • Leprechaunism - Growth retardation, abnormal glucose homeostasis (especially occurrence of hypoglycemia), early death

Race

Insulin resistance syndrome is found in all races. The degree of clustering of the risk variables of syndrome X is generally considered to be higher among whites. However, prevalence rates of the various components of syndrome X tend to be higher among nonwhite populations.²

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 in whites.

Sex

Metabolic syndrome is more evident in middle-aged men. Women tend to assume increased cardiovascular risk after menopause. Polycystic ovary disease is a disease limited to women. Type A syndrome and type B syndrome are typically found in women.

Age

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

• Women with polycystic ovary disease usually present in their mid twenties.
• 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]).
• Type A insulin resistance typically occurs in the younger patients, while type B insulin resistance occurs more often in older women.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Presentation 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:

• Hypoglycemia (Some patients present with hypoglycemia symptoms such as sweating, tremulousness, irritability, and 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.)
• Metabolic syndrome (syndrome X)
• Obesity (most common cause of insulin resistance) or history or excessive body weight
• Type 2 diabetes mellitus (chronic or acute [during severe decompensation] presentation [ie, the classic symptoms of diabetes])
• A diagnosis of impaired glucose tolerance (IGT) or impaired fasting glucose (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 (CAD)
• Symptoms related to other macrovascular disease (eg, stroke, peripheral vascular disease)
• Microvascular angina
• Polycystic ovary disease (PCOD: Patients usually present with infertility associated with anovulation; menstrual irregularity, typically chronic; and symptoms related to androgen excess, such as frontal baldness and deepening of the voice.)
• Type B syndrome (Symptoms related to immunologic disease [eg, arthralgia, swollen salivary glands, hair loss] may occur.)
• Other insulin-resistant states
• • 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)
• Immune insulin resistance
• • Low titer immunoglobulin (Ig) G anti-insulin antibodies are present in most patients receiving insulin.
  • 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 (eg, obesity).

Physical

• Blood pressure (hypertension)
• Anthropometry
• • Waist or waist-to-hip ratio, height, weight, and BMI may indicate insulin resistance syndrome.
• • Central obesity, not peripherally distributed fat, is a strong marker of insulin resistance syndrome.
• Cardiovascular system
• • 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 buttocks
• • Tendon xanthomata - Usually over the patellar and Achilles tendon
• Type A syndrome
• • Patients are usually tall and have features of hirsutism and abnormalities of the female reproductive tract related to hyperandrogenism (eg, polycystic ovary disease).
  • 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 and 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 IGF receptors in the skin.
  • Acanthosis nigricans is found in a wide variety of clinical conditions that are associated with insulin resistance.
  • These eruptions have been reported in nearly one tenth of women evaluated for polycystic ovary disease.
  • Acanthosis nigricans is occasionally a marker of malignant neoplasm.
• Polycystic ovary disease: Patients may have masculine habitus, such as coarse or greasy skin and acne, frontal alopecia, breast atrophy, hypertrophy of clitoris, and obesity; varying degrees of hirsutism or virilization may be present. These manifestations are due to hyperandrogenism. 
• Type B insulin resistance (autoantibodies to the insulin receptor): Patients 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
• • Leprechaunism - Elfin appearance of the face, hirsutism, lack of subcutaneous fat, and thickened skin
  • Lipodystrophic states - Variable phenotypic expression (Features include 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 - Retinal degeneration that results in blindness, nerve deafness, hypogonadism (males)
  • Ataxia telangiectasia - Cerebellar ataxia, oculocutaneous telangiectases, immune deficiency, and increased proneness to pulmonary infections
  • Myotonic dystrophy - Weakness of limb and cranial muscles, cataract

Causes

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

The underlying causes of insulin-resistant states can be categorized as follows:

• Prereceptor
• • Abnormal insulin (mutations)
• • Anti-insulin antibodies
• Receptor
• • Decreased number of receptors (mainly, failure to activate tyrosine kinase)
• • Reduced binding of insulin
• • Insulin receptor mutations
• • Insulin receptor–blocking antibodies
• Postreceptor
• • Defective signal transduction
• • Mutations of GLUT4 (In theory, these mutations could cause insulin resistance, but polymorphisms in the GLUT4 gene are rare.)
• Combinations of defects are common. Obesity is associated mainly with postreceptor abnormality and is also associated with a decreased number of insulin receptors. Obesity is the most common cause of insulin resistance.
• Other conditions that are categorized as receptor and 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
• Aging: This may be due to decreased production of GLUT-4
• Increased production of insulin antagonists: A number of disorders are associated with increased production of insulin antagonists, such as Cushing syndrome and acromegaly, and stress states, such as trauma, surgery, diabetes ketoacidosis, severe infection, uremia, and liver cirrhosis.
• Medications associated with insulin resistance syndrome: These include glucocorticoids (Cushing syndrome), cyclosporine, niacin, and protease inhibitors.
• HIV: Protease inhibitor–associated lipodystrophy is a recognized entity.
• Insulin treatment
• • Low titer IgG anti-insulin antibody levels are present in most patients who receive insulin. In rare instances, the antibodies result in significant prereceptor insulin resistance.
  • Enhanced destruction of insulin at the site of subcutaneous injection has also been implicated.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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, LDL, high-density lipoprotein [HDL], cholesterol, triglyceride [TG]) - 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 standard lipid tests. Elevations in the 3 markers increase risk of coronary artery disease [CAD] by nearly 20-fold.)
• • Electrolyte levels (BUN, 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]) - Elevated level a risk factor for atherosclerosis, which predicts macrovascular disease (levels are regulated by insulin.)
• • Plasminogen activator inhibitor 1 (Elevated level is associated with insulin resistance syndrome and correlated with obesity, waist-to-hip ratio, hypertension, fasting and postprandial insulin levels, proinsulin levels, fasting glucose levels, and elevated triglyceride and LDL levels. Increased PAI-1 level signifies impaired fibrinolysis, thus indicating increased risk of atherosclerosis.)
• Other laboratory studies include the following:
• • Fibrinogen level: Increased fibrinogen level is a feature of insulin resistance syndrome.
• • Endothelial function: Endothelium plays an important role in insulin action, including regulation of tissue blood flow and 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. Biochemical changes include (1) reduced nitric oxide and prostacyclin levels, (2) increased endothelin and angiotensin activity, and (3) increased local and systemic inflammation (increased CRP levels). 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 is 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.
  • The latter 2 tests are more accurate, but they are research tools and are not routinely used in clinical practice.

Other Tests

• 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). This tool is designed to estimate risk in adults aged 20 years and older who do not have heart disease or diabetes. For patients with insulin resistance without overt diabetes, the metabolic syndrome criteria for cardiovascular risk stratification is less sensitive than that of the Framingham Risk Score, which takes into account age, total cholesterol, tobacco use, HDL cholesterol, and blood pressure, but not diabetes.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Evaluate patients for comorbid conditions; this is generally feasible on an outpatient basis. Admission for laboratory studies may be warranted for patients whose conditions require urgent or emergent intervention.

Syndrome X requires aggressive control of cardiovascular and metabolic risk factors. Tailor therapy for optimal benefits.

Surgical Care

• In severe cardiovascular disease, procedures such as coronary artery bypass graft and peripheral vascular surgery may be necessary.
• Wedge resection has largely been abandoned, but it was once thought to be beneficial in polycystic ovary disease (PCOD).
• 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 polycystic ovary disease).

Consultations

• Consultation with an endocrinologist is indicated.
• Consultation with a cardiologist is indicated.
• Other specialists, such as a dermatologist, gynecologist, cardiothoracic surgeon, and ophthalmologist, may need to be consulted based on the nature of disease and the prevailing pathology.

Diet

• Weight reduction improves insulin sensitivity in patients who are obese and in patients with most of the obesity-related insulin-resistant states.
• Restriction of caloric intake is indicated.

Activity

• Exercise improves insulin sensitivity via the following:
• • Increased oxidative enzymes
  • Increased glucose transporters (GLUT-4)
  • Increased capillarity
  • Reduction of central adiposity

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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), of which both 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).

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 and sibutramine may reduce insulin resistance and related cardiovascular risk factors through weight reduction and other mechanisms. Administration of insulin is also crucial in the treatment of diabetes in most patients.

Drug Category: Biguanides

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 lowers plasma insulin levels.

Drug Category: Thiazolidinediones

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

The US Food and Drug Administration issued an alert on May 21, 2007 to patients and health care professionals of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis. Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by improving insulin sensitivity. The drug is highly selective and a potent agonist for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing 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.
 
For more information, see FDA's Safety Alert on Avandia. The online published meta-analysis entitled Effect of "Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news (the heart.org from WebMD) including the following articles: 1) Rosiglitazone increases MI and CV death in meta-analysis and 2) The rosiglitazone aftermath: Legitimate concerns or hype?

Drug Name	Rosiglitazone (Avandia)
Description	Insulin sensitizer with major effect in stimulation of glucose uptake in skeletal muscle and adipose tissue. Lowers plasma insulin levels. Used for treatment of type 2 diabetes associated with insulin resistance. May benefit PCOD patients. May use as monotherapy or in combination with metformin.
Adult Dose	4-8 mg/d PO or divided bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active liver disease; ketoacidosis; type 1 diabetes
Interactions	In combination with insulin or oral hypoglycemics (eg, sulfonylureas) may increase risk for hypoglycemia
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Monitor transaminases; discontinue if ALT rises above 3 times the upper limit of the reference range; caution in edema and CHF; may decrease hemoglobin, hematocrit, and white blood cell counts

Drug Category: Glucocorticoids

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

Drug Category: Antidiabetic agent, insulin

This is used to overcome insulin resistance, but large quantities are often required.

Drug Category: Lipase inhibitors

These agents inhibit nutrient absorption.

Drug Category: Anorexiants

These agents reduce appetite and may increase metabolism.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admission for testing and treatment of acute complications, as needed

Further Outpatient Care

• Diligent monitoring of metabolic profile, general status, medications, and side effects

In/Out Patient Meds

• Medications that reduce insulin resistance (insulin-sensitizing and antihyperglycemic effects) include metformin and the thiazolidinediones.
• • Metformin is a biguanide, which 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. 
  • Thiazolidinediones lower plasma insulin levels and treat type 2 diabetes associated with insulin resistance.

Transfer

• Transfer may be indicated for diagnostic evaluation and treatment of major primary conditions and complications.

Deterrence/Prevention

• Reduce caloric intake (and avoid dietary indiscretion, such as high cholesterol and high sodium diet).
• Avoid physical inactivity.
• Stop smoking.
• Limit alcohol use.

Complications

• Acute metabolic complications, including severe hyperglycemia and hypoglycemia
• Angina
• Myocardial infarction
• Stroke
• Transient ischemic attack
• Peripheral vascular disease
• Renal disease
• Ocular complications

Prognosis

• Prognosis depends on the type of insulin resistance syndrome (IRS).
  
  
  • Syndrome X: Prognosis is often affected by the number and severity of comorbid conditions and institution of appropriate therapy.
  • 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.
  • 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 hypoglycemia and fatality within the first year of life. In other conditions, progression of insulin resistance and manifestation of related disorders continue into adulthood.

Patient Education

• Educate patients on the nature of the disease, treatment, risk of complications, and primary and/or secondary preventive measures, including a healthier lifestyle.
• Educate family members on various issues related to management and screening of those at risk.
• For excellent patient education resources, visit eMedicine's Diabetes Center.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize the related conditions—insulin resistance, glucose intolerance, obesity, hypertension, atherosclerosis, hypercoagulability, and dyslipidemia
• Failure to make use of appropriate and effective treatment
• Failure to exclude malignancy-related acanthosis nigricans in a small group of patients

Special Concerns

• A patient with syndrome X may be asymptomatic in spite of presence of some, or even most, of the components of insulin resistance syndrome.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jun 19, 2007