Insulin Resistance

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Background

Insulin resistance is a state in which a given concentration of insulin produces a less-than-expected biologic 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 immunologic 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.

Obesity-related insulin resistance or metabolic syndrome is typically characterized by central adiposity, glucose intolerance, dyslipidemia, and hypertension. Prevalence of hypertension rises with exacerbation of stages of impaired glucose metabolism; however, it seems that only in the early stages of impaired insulin metabolism do hyperglycemia and hyperinsulinemia appear to be significant contributors to the presence of hypertension.[10]  Other features may include acanthosis nigricans, polycystic ovary syndrome, and the metabolic dysfunction-associated steatotic liver disease, previously known as nonalcoholic fatty liver disease.

There are other forms of insulin resistance, including those with unique phenotypes such as lipodystrophy, and those due to insulin receptor dysfunction (type A and type B syndromes) with different amounts or patterns of fat distribution.

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, the thiazolidinediones, sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists.[11, 12, 13, 14]  

See Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus for complete information on these topics.

Pathophysiology

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. Individuals with obesity 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:

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 predicted 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; 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 patients with type 1 diabetes. Uruska et al found that an independent relationship existed between insulin resistance and the risk of microangiopathy in 81 patients with type 1 diabetes 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.

Etiology

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 2764 Europeans, with replication in an additional 2860 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 body mass index (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:

Receptor causes include the following:

Postreceptor causes include the following:

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:

Specific causes of insulin resistance

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

Epidemiology

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 2017-2018 data, 41.8% 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 growth of the obesity epidemic and insulin resistance in children, no clear diagnostic criteria and surrogate markers have been identified for childhood insulin resistance. 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 White populations. However, prevalence rates of the various components of the metabolic syndrome tend to be higher among non-White 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

Prognosis depends on the type of insulin resistance syndrome. The prognosis is guarded with 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 five-fold increased risk of developing type 2 diabetes.

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

In 2021, diabetes was the eighth leading cause of US deaths.[45]  Using an adult cohort, a study by Raghavan et al suggested that in the United States the risk of cardiovascular disease (CVD) mortality is increased by 18% in persons with diabetes.[46]  Diabetes is also a common source of blindness and kidney failure in the United States.[47]  Moreover, individuals with diabetes have a higher risk of stroke, neuropathy, and gangrene. Additionally, diabetes is associated with acute metabolic complications.

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

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.

Complications

Potential complications of insulin resistance include the following:

Patient Education

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.

History

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:

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

A study by Raju et al indicated that a relationship exists between insulin resistance and lung disease. The investigators found an association between an increased insulin resistance measure and the presence, radiographically, of qualitative emphysema, interstitial lung abnormalities, “and modest increases in airway wall thickness and wall area percentage.” A positive association determined between the homeostatic model assessment for insulin resistance (HOMA-IR) and incident lung disease corroborated the radiographic evidence.[49]

Physical Examination

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 BMI may indicate insulin resistance syndrome. It has been predicted that for the foreseeable future the assessment of adiposity risk will continue to rely on the cost-effective and easily available measures of height, weight, and waist circumference.[50]  The risk assessment informs the implementation of appropriate treatment plans and weight management goals.

Cardiovascular system

Cardiovascular findings associated with insulin resistance may include the following:

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, 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:

Approach 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.

Laboratory Studies

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

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 the interstitium. Endothelial dysfunction is an important component of insulin resistance syndrome and includes reduced capillary formation, reduced surface area, and abnormal reactivity of endothelium.[62]

Serum WNT1-inducible signaling pathway protein 1 (WISP-1, also known as CCN4), a novel pro-inflammatory adipokine, has been proposed as a suitable biomarker of obesity, and the levels correlate with anthropometric indices of obesity.[63]

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:

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). The tool is designed to estimate risk in adults aged 20 years or older who do not have heart disease or diabetes. The American College of Cardiology/American Heart Association (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).[71]

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.

Approach Considerations

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.[72, 73]

Patients should avoid physical inactivity.[74] Exercise improves insulin sensitivity via the following[75, 76] :

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.

Medical Care

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.[77]

Long-term follow-up data from the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS) found that metformin is associated with vitamin-B12 deficiency, and routine measurement of vitamin B12 should be considered in patients receiving metformin.[78]

Thiazolidinediones lower plasma insulin levels and treat type 2 diabetes associated with insulin resistance.[79, 80, 81] In a multicenter, double-blind trial of 3876 insulin-resistant patients who had had a recent ischemic stroke or transient ischemic attack (TIA), those receiving pioglitazone (45 mg daily) had a reduced risk of stroke, myocardial infarction, and diabetes compared with those receiving placebo. However, pioglitazone increased the risk for weight gain, edema, and fracture.[82]

Newer drugs such as the SGLT2 inhibitors, incretin-based therapy with the glucagon-like peptide 1 receptor agonists, and a dual-acting GIP/GLP-1 receptor agonist are increasingly favored because of their higher efficacy and proven cardiovascular disease benefits[83, 84, 51, 52, 53]

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.[83]

Surgical Care

Improvement in insulin resistance occurs after bariatric surgery, such as gastric banding, sleeve gastrectomy, and gastric bypass, when carried out in carefully selected patients with morbid obesity.[84] Bariatric surgery may be appropriate for patients with a 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).

Prevention

A study by Jun et al found that handgrip strength in young children was inversely related to the presence of metabolic syndrome and insulin resistance in adolescence. Handgrip was measured at ages 7-9 years, and the occurrence of metabolic syndrome and insulin resistance, at ages 13-15 years. According to the investigators, their results indicate that working to increase muscle strength in younger children decreases the likelihood of the metabolic syndrome and insulin resistance in adolescence.[85]

Medication Summary

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 the 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 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,  SGLT2 inhibitors, incretin mimetics) and insulin sensitivity (metformin, thiazolidinediones).

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.[86, 87, 88, 89, 90]

Other currently available drugs, more potent than orlistat but with increased risk of some adverse effects, include phentermine, phentermine/topiramate extended release (ER), and naltrexone ER/bupropion ER. 

Most recently, the incretin-based drugs, the GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonists, have increasingly been used because of their higher efficacy and reasonable safety profile.[83, 84, 51, 52, 53]

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.[91]

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 levels of physical activity, whereas pharmacotherapy is reserved for selected cases.[43]

Metformin (Glucophage (DSC), Glucophage XR (DSC), Glumetza)

Clinical Context:  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 patients with obesity 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.

Exenatide injectable suspension (Bydureon (DSC), Bydureon BCise)

Clinical Context:  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 the 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 (Saxenda, Victoza)

Clinical Context:  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 and, 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.

Semaglutide (Ozempic, Rybelsus, Wegovy)

Clinical Context:  This is a longer-acting GLP-1 agonist. More efficacious than liraglutide, it is administered once weekly.

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.

Tirzepatide (Mounjaro, Zepbound)

Clinical Context:  A GIP/GLP-1 receptor agonist, it is very efficacious. The weight reduction achieved is comparable to that obtainable through some bariatric procedures.

It is administered once weekly.

Insulin lispro (Admelog, Admelog Solostar, Humalog)

Clinical Context:  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.

Empagliflozin (Jardiance)

Clinical Context:  It is administered by mouth once daily.

Pioglitazone (Actos)

Clinical Context:  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 the pancreas. It decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and, possibly, in liver and adipose tissue.

Rosiglitazone (Avandia)

Clinical Context:  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 patients with PCOS. 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.

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. The FDA required a restricted access program to be developed for rosiglitazone under a risk evaluation and mitigation strategy (REMS) other thiazolidinedione.

The results of  a large-scale, phase III trial (RECORD) designed to study cardiovascular outcomes of rosiglitazone were inconclusive.

Rosiglitazone is no longer available in the United States.

What is insulin resistance?What is the pathophysiology of insulin resistance?What is the pathophysiology of metabolic syndrome?What is the role of genetics in the etiology of insulin resistance?What causes acquired insulin resistance?How are the causes of insulin resistance classified?Which specific conditions or agents may cause insulin resistance?What is the prevalence of insulin resistance in the US?What is the global prevalence of insulin resistance?Which age groups have the highest prevalence of insulin resistance?What are the sexual predilections of insulin resistance?What are the racial predilections of insulin resistance?What is the prognosis of insulin resistance?What is included in patient education about insulin resistance?Which clinical history findings are characteristic of insulin resistance?Which blood pressure findings are characteristic of insulin resistance?How is obesity characterized in insulin resistance?Which cardiovascular findings are characteristic of insulin resistance?Which physical findings are characteristic of type A syndrome–caused insulin resistance?Which physical findings are characteristic of acanthosis nigricans in patients with insulin resistance?Which physical findings are characteristic of polycystic ovary syndrome (PCOS) in patients with insulin resistance?Which physical findings are characteristic of type B syndrome caused insulin resistance?Which physical findings are characteristic of insulin-resistant states?What are the possible complications of insulin resistance?What are the most commonly used diagnostic criteria for insulin resistance?What are the NCEP/ATP III criteria for metabolic syndrome?What are the WHO diagnostic criteria for metabolic syndrome?What are the AACE clinical criteria for insulin resistance syndrome?What are the differences between the NCEP/ATPIII, WHO, and AACE criteria for insulin resistance?What are the IDF diagnostic criteria for metabolic syndrome?What are the differential diagnoses for Insulin Resistance?How is insulin resistance diagnosed?How is cardiovascular risk assessed in the workup of insulin resistance?What is the role of lab tests in the workup of insulin resistance?How is insulin sensitivity assessed in the workup of insulin resistance?How is insulin resistance treated?Which specialist consultations are beneficial to patients with insulin resistance?Which medications are used in the treatment of insulin resistance?What is the role of surgery in the treatment of insulin resistance?What is the role of medications in the treatment of insulin resistance?Which medications in the drug class Antidiabetics, Thiazolidinediones are used in the treatment of Insulin Resistance?Which medications in the drug class Antidiabetics, SGLT2 Inhibitors are used in the treatment of Insulin Resistance?Which medications in the drug class Antidiabetics, Insulins are used in the treatment of Insulin Resistance?Which medications in the drug class Antidiabetics, Glucose-dependent Insulinotropic Polypeptides are used in the treatment of Insulin Resistance?Which medications in the drug class Antidiabetics, Glucagon-like Peptide-1 Agonists are used in the treatment of Insulin Resistance?Which medications in the drug class Antidiabetics, Biguanides are used in the treatment of Insulin Resistance?

Author

Samuel T Olatunbosun, MD, FACP, FACE, Associate Professor of Medicine, University of California, Davis, School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

David S Schade, MD, Chief, Division of Endocrinology and Metabolism, Professor, Department of Internal Medicine, University of New Mexico School of Medicine and Health Sciences Center

Disclosure: Nothing to disclose.

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