Insulin Resistance 

Insulin resistance is a state in which a given concentration of insulin produces a less-than-expected biological effect. (See Pathophysiology.) 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. 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. (See Etiology and Clinical Presentation.)

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. (See Diagnostic Considerations.)

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. (See Workup.)

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. (See Treatment and Management.)

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 physiological 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.^{[1, 2]} 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.^[3] 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.^[4]

Obesity, the most common cause of insulin resistance, is associated with a decreased number of receptors and with postreceptor failure to activate 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.^[5]

Leptin and ghrelin are 2 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 subjects 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.^[6]

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^[7]
• 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.^{[8, 9, 10]} 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.^[11] In a number of prospective studies, increased levels of CRP predict the development of diabetes and cardiovascular disease.^{[5, 12, 13]}

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.^{[14, 15, 16, 17]}

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.^{[18, 19, 20, 21]}

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.^[22] 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.^[23]

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 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; in a recent study, 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.^[24] 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. Acquired causes include physical inactivity, diet, medications, hyperglycemia (glucose toxicity), increased free fatty acids, and the aging process.^[25]

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.^[26]
• Anti-HIV therapy^[27] : Protease inhibitor–associated lipodystrophy is a recognized entity.^[28] Nucleoside analogues have also been implicated in the development of insulin resistance.
• 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.

International statistics

A quarter of the world’s adults are considered to have the metabolic syndrome.^{[29, 30]} 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 children for insulin resistance in children based on existing methodology and criteria.^[31]

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.^[32]

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 3 times as likely to have, a myocardial infarction (MI) or stroke than are with 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 MIs, 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.