Version July 2025
INTRODUCTION —
Insulin resistance can be broadly defined as a subnormal biological response to normal insulin concentrations. By this definition, it may pertain to many biological actions of insulin in many tissues of the body. Typically, however, in clinical practice, insulin resistance refers to a state in which a given concentration of insulin is associated with a subnormal glucose response [1].
The term first came into use several years after the introduction of insulin therapy in 1922 to describe occasional patients with diabetes who required increasingly large doses of insulin to control hyperglycemia. Most of these patients developed insulin resistance secondary to antibodies directed against the therapeutic insulin, which at that time was both impure and derived from nonhuman species [2]. Anti-insulin antibodies in titers sufficient to impair insulin action are rare in patients treated with recombinant human insulin, and the broad spectrum of clinical disorders in which insulin resistance plays a major role has changed markedly (table 1).
This topic will review the definition, clinical features, and diagnosis of insulin resistance. Possible mechanisms for the development of insulin resistance are discussed elsewhere. (See "Pathogenesis of type 2 diabetes mellitus".)
The definition, prevalence, clinical implications, and therapy of the metabolic syndrome (a common syndrome that includes insulin resistance) are also reviewed separately. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)
DEFINITION AND CAUSES —
Insulin resistance may be defined as a subnormal glucose response to endogenous and/or exogenous insulin. It most commonly occurs in association with obesity but may result from multiple other underlying causes (table 1) [3].
●Obesity associated
●Lipodystrophy associated
●Stress induced (due to excess counterregulatory hormones cortisol, growth hormone, catecholamines, glucagon)
●Medications (eg, glucocorticoids, human immunodeficiency virus [HIV] antiretrovirals, oral contraceptives)
●Pregnancy (placental lactogen)
●Insulin antibodies
●Genetic defects in insulin-signaling pathways – Type A insulin resistance
●Blocking autoantibodies against the insulin receptor – Type B insulin resistance
CLINICAL FEATURES
Distribution of adipose tissue
●Obesity – In approximately 20 percent people with obesity, excess calories are stored as fat in the subcutaneous adipose tissue. Despite high body mass index (BMI) or overall fat mass, subcutaneous adiposity does not cause insulin resistance. As more fat accumulates, however, a relative deficiency of adipose tissue storage space in the usual fat depot sites develops. Fat is subsequently deposited intra-abdominally (central obesity) and in muscle, liver, and vasculature. This abnormal distribution of adipose tissue underlies the development of obesity-related insulin resistance [4-6]. It occurs in approximately 80 percent of people with obesity. At a local level, in organs where dystopic fat has been deposited, macrophages are attracted to the clear dystopic fat deposition areas through phagocytosis, and this initiates a chronic, low-grade inflammatory state, which can lead to fibrosis and over time, organ failure. (See "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults".)
The precise underlying molecular mechanisms leading to insulin resistance are under active investigation. Abnormal distribution of adipose tissue leads to decreasing levels of the protective adipocytokine, adiponectin. Adiponectin is an endogenous insulin sensitizer, and it reduces free fatty acids concentrations in blood. Low levels of adiponectin are associated with high circulating levels of insulin, insulin-like growth factor 1 (IGF-1), and proinflammatory cytokines, all of which lead to obesity and insulin resistance-related comorbidities in genetically predisposed individuals [7]. Adiponectin levels are decreased not only with intra-abdominal fat accumulation but also with abnormal sleep patterns, smoking, and unhealthy lifestyle whereas they are increased with healthy dietary patterns and exercise [8-10]. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Factors released from adipose tissue'.)
●Lipodystrophy – The lipodystrophy syndromes are a clinically diverse group of disorders characterized by either complete or partial lack of adipose tissue (lipoatrophy), sometimes in conjunction with apparent accumulation of fat in other regions of the body where fat should not exist (dystopic fat deposition in muscle and liver) [4]. Patients with lipodystrophy may have no excess adipose tissue, but since they are completely or partially lacking adipose tissue storage space, the energy they need to store as fat is deposited intra-abdominally and/or in organs it should not be deposited. Thus, the same mechanisms are activated as in central obesity. Adiponectin (indicating central or dystopic deposition of adipose tissue) and leptin levels (indicating overall fat mass) are low in some patients with lipoatrophy [4]. (See "Lipodystrophy syndromes: Clinical manifestations, classification, and diagnosis".)
●HIV-associated lipodystrophy – A syndrome of acquired lipodystrophy is associated with antiretroviral therapy (ART), including protease-inhibitors in patients with human immunodeficiency virus (HIV) infection. These patients develop lipoatrophy and/or dystopic fat deposition, as well as insulin resistance and metabolic abnormalities. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy".)
●Insulin receptor dysfunction – In patients with type A (insulin receptor mutations) and type B (anti-insulin receptor antibodies) insulin resistance, the amount and distribution of adipose tissue may be normal since the underlying mechanism involves dysfunction of the insulin receptors rather than abnormal distribution of adipose tissue.
Presentations — Insulin resistance can present in a variety of ways depending on the underlying etiology and severity. Although obesity-related and other forms of insulin resistance share similar clinical features, patients with the genetic syndromes typically have extreme insulin resistance and therefore more severe phenotypes (table 2). Presentations of insulin resistance may include:
●Metabolic syndrome
●Abnormal glucose metabolism (prediabetes, type 2 diabetes, increased insulin requirements in type 1 diabetes)
●Cardiovascular disease and coronary artery disease
●Chronic kidney disease (CKD)
●Cutaneous findings (eg, acanthosis nigricans)
●Polycystic ovary syndrome (PCOS)
●Metabolic dysfunction-associated steatotic liver disease (MASLD, previously termed nonalcoholic fatty liver disease), MASLD with metabolic dysfunction-associated steatohepatitis (MASH, previously termed nonalcoholic steatohepatitis)
●Certain obesity-related malignancies (eg, endometrial cancer)
●Neurodegenerative diseases (eg, Alzheimer)
●Certain rare genetic syndromes
Metabolic syndrome — In patients with obesity, particularly abdominal obesity, insulin resistance, the associated hyperinsulinemia and hyperglycemia, and adipocyte cytokines (adipokines) may lead to vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease (CVD). The metabolic syndrome is defined as the co-occurrence of metabolic risk factors for both type 2 diabetes and CVD (abdominal obesity, hyperglycemia, dyslipidemia, and hypertension). There are several definitions for the metabolic syndrome. This topic is reviewed in more detail elsewhere. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)
Abnormal glucose metabolism — The spectrum of abnormalities in glucose homeostasis is variable and depends upon the underlying etiology and severity and on the ability of beta cells to respond to insulin resistance with increased insulin secretion, which differs widely among patients.
●Many patients with insulin resistance initially have normal or only slightly high blood glucose concentrations, particularly during the early phases of developing insulin resistance since normal glucose levels are maintained at the expense of rising insulin levels. Initially, patients may have only postprandial hyperglycemia (or abnormal oral glucose tolerance testing) well before they develop sustained hyperglycemia. Subsequently, however, pancreatic beta cells eventually fail to compensate for insulin resistance and hyperglycemia develops in most patients.
●In patients with genetic syndromes of severe insulin resistance, significant hyperglycemia despite large doses of insulin is the classical presentation since very high insulin levels may not be effective given the dysfunctional insulin receptor [11].
●A small percentage of patients may initially present with hypoglycemia due to developing activating autoantibodies to the insulin receptor or postprandial hypoglycemia due to reactive hyperinsulinemia in response to the carbohydrate load of a meal [3,12-14].
●Abnormalities in glucose metabolism related to glucocorticoid therapy and in response to infection or critical illness (stress hyperglycemia) are reviewed elsewhere. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'Differential diagnosis' and "Glycemic control in critically ill adult and pediatric patients" and "Major adverse effects of systemic glucocorticoids", section on 'Metabolic and endocrine effects'.)
Acanthosis nigricans — Acanthosis nigricans and skin tags are commonly associated with insulin resistance, regardless of its cause. Acanthosis nigricans is a skin lesion characterized by brown, velvety, hyperkeratotic plaques. The lesions are usually found on the back of the neck, the axilla (picture 1), the groin, and over the elbows, but they may cover the entire surface of the skin, sparing only the palms and soles. The lesions may be papillomatous. Histologic hallmarks are hyperkeratosis, epidermal papillomatosis, and increased numbers of melanocytes. (See "Acanthosis nigricans".)
The common denominator in all cases of acanthosis nigricans, with the possible exception of tumor-induced lesions, is insulin resistance and, more specifically, elevated insulin and IGF-1 levels due to insulin resistance [15]. It may vary in severity and may be inherited or acquired.
Hyperandrogenism and reproductive abnormalities — Women with insulin resistance commonly present with reproductive abnormalities, whereas men with insulin resistance are not known to have disorders of the reproductive system.
As an example, most women with severe tissue resistance to insulin, regardless of cause, have marked hyperandrogenism. This association has been described in women with the type B syndrome (caused by insulin-receptor autoantibodies) [16,17] or the type A syndrome (caused by genetic defects in the insulin-signaling system, such as mutations in the insulin receptor gene) [18,19]. Affected women can present with overt virilization or hirsutism, amenorrhea, and infertility. The ovaries show a polycystic pattern on ultrasound.
The basis for the association between insulin resistance and ovarian hyperandrogenism is not entirely clear [20,21]. It is likely that high serum insulin concentrations generated largely in response to the rising glucose levels overstimulate specific insulin-responsive pathways that are less impaired than those affecting glucose transport. This may occur from pathway-specific differences in insulin sensitivity or via activation of IGF-1 receptors or hybrid receptors formed by covalent linkage of subunits of the homologous receptors for insulin and IGF-1, as is hypothesized to occur in PCOS (figure 1).
Most women with ovarian hyperandrogenism have tissue resistance to insulin that is identified by fasting hyperinsulinemia or subnormal insulin-mediated glucose uptake (from euglycemic clamp studies) [22]. Studies in cultured skin fibroblasts suggest that approximately 50 percent of them have a defect in phosphorylation of the insulin receptor [20]. Insulin receptors, and the closely related receptors for IGF-1, are present on ovarian cells, and stimulation of these receptors in the presence of adequate luteinizing hormone (LH) increases androgen production [23]. Excess androgens in turn produce insulin resistance by direct effects on insulin action in skeletal muscle and adipose tissue, altering adipokine secretion, and increasing visceral adiposity [21]. (See "Clinical manifestations of polycystic ovary syndrome in adults" and "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults".)
Metabolic dysfunction-associated steatotic liver disease — When dystopic fat is deposited in the liver, macrophages are attracted to the fat deposition areas through phagocytosis, and this initiates a chronic, low-grade inflammatory state, which can lead to fibrosis and over time, organ failure. Liver steatosis is reviewed in detail separately. (See "Pathogenesis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease)" and "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults".)
Linear and acral growth — Linear growth is normal in most patients with insulin resistance. There are, however, two pediatric disorders with severe insulin resistance; leprechaunism, which almost universally results in a fatal outcome soon after birth, and the Rabson-Mendenhall syndrome, in which growth is impaired [3,24,25]. These syndromes are due to mutations in the insulin receptor gene (INSR), which result in complete or nearly complete absence of insulin receptor function [3]. They are associated with markedly delayed linear growth and failure to thrive due to the cross reactivity of insulin and IGF-1 with each other's receptors as well as the existence of hybrid insulin-IGF-1 receptors that mediate growth.
Pseudoacromegaly, in contrast, is a syndrome in which severe insulin resistance is associated with accelerated linear growth [26]. In these patients, hyperinsulinemia probably promotes linear growth by activating skeletal IGF-1 receptors.
DIAGNOSIS
Obesity-related insulin resistance — The diagnosis of insulin resistance in most patients is based upon clinical findings (eg, metabolic syndrome traits):
●Abdominal obesity
●Hyperglycemia
●Dyslipidemia
●Hypertension
In a clinical setting, it would be useful to quantify insulin resistance in patients with obesity as they are at highest risk for the development of type 2 diabetes mellitus and its complications [27], cardiovascular disease (CVD), and certain malignancies associated with obesity and insulin resistance (eg, colon, breast, and endometrial cancers). However, there is currently no acceptable test for measuring insulin resistance in a clinical setting.
In nondiabetic, normotensive overweight individuals, the following tests are sometimes used, but none have been fully validated in the clinical setting.
●Triglycerides, HDL, fasting insulin – Serum triglyceride concentration, the ratio of triglyceride to high-density lipoprotein (HDL) cholesterol concentrations, and fasting insulin concentration are useful markers for identifying those who may be insulin resistant (as measured by an insulin suppression test). Optimal cutoff points were identified as 130 mg/dL (1.47 mmol/L), 3.0 (1.8 SI units), and 15.7 microU/mL (109 pmol/L) for triglycerides, triglyceride-to-HDL ratio, and insulin, respectively [28]. Sensitivity and specificity for these thresholds were 67, 64, and 57 percent, respectively, and 71, 68, and 85 percent, respectively, which are not in the range that would make these tests clinically recommended.
●Insulin-to-glucose ratio – Some clinicians use a fasting plasma insulin-to-glucose ratio to assess the degree of insulin resistance. This is of value at early stages of insulin resistance when pancreatic beta cells continue to secrete appropriate amounts of insulin. In this setting, higher insulin-to-glucose ratios indicate higher levels of insulin resistance. As the pancreatic beta cells begin to fail, however, insulin levels decline, and the ratio is less useful.
●SHBG – Infrequently, serum sex hormone-binding globulin (SHBG) is used as a marker for insulin resistance. A low serum SHBG concentration has been associated with insulin resistance and an increased incidence of type 2 diabetes [29].
In the research setting, several techniques are used to measure insulin resistance:
●Euglycemic clamp/IVGTT/ITT – The euglycemic insulin clamp technique has been considered to be the gold standard (figure 2), and an intravenous glucose tolerance test (IVGTT) and/or insulin tolerance test (ITT)/insulin suppression test are most frequently used because they are easier to perform [30,31]. However, these techniques are impractical for routine clinical use, although they are extremely useful in research settings.
●HOMA – In large, population-based epidemiology studies, simple ratios derived from fasting insulin and glucose (eg, glucose-to-insulin ratios, homeostasis model assessment of insulin resistance [HOMA-IR or HOMA]) have been extensively employed. There are limitations to their use, including changes in beta cell function over time, lack of a standardized universal insulin assay, and lack of data demonstrating that markers of insulin resistance predict response to treatment. In addition, there are rare cases of mutations in the insulin gene resulting in the production of insulin that has subnormal bioactivity but normal immunoactivity. These insulins circulate at high concentrations, simulating insulin resistance, but the response to exogenous insulin is normal [32]. Therefore, although indexes such as HOMA and quantitative insulin sensitivity check index (QUICKI) or other tests of insulin resistance have been proposed and cutpoints identified [33,34], none are recommended for routine assessment of insulin resistance in the clinical setting.
Lipodystrophy or severe phenotype of insulin resistance — In patients with lipodystrophy phenotypes or severe phenotypes suggesting an inherited state of target cell resistance (eg, leprechaunism, which is extremely rare since most patients die in utero or soon after birth, or Rabson-Mendenhall syndrome), fasting serum insulin should be measured. The finding of marked hyperinsulinemia (with normal or high blood glucose) should prompt further studies to evaluate for the presence of insulin receptor mutations, circulating anti-insulin receptor antibodies, or other disorders (table 1). (See "Lipodystrophy syndromes: Clinical manifestations, classification, and diagnosis".)
SUMMARY AND RECOMMENDATIONS
●Definition and causes – Insulin resistance is a state in which a given concentration of insulin is associated with a subnormal glucose response. It most commonly occurs in association with obesity but may result from multiple other underlying causes (table 1).
●Clinical features
•Distribution of adipose tissue – When excessive fat accumulates, a relative deficiency of adipose tissue storage space in the usual fat depot sites develops. Fat is subsequently deposited intra-abdominally (central obesity) and in other regions of the body where fat should not exist (dystopic fat deposition in muscle, liver, and vasculature). This abnormal distribution of adipose tissue underlies the development of obesity-related insulin resistance.
Patients with lipodystrophy may have no excess adipose tissue, but since they are completely or partially lacking adipose tissue storage space, the energy they need to store as fat is deposited intra-abdominally and/or in organs it should not be deposited. Thus, insulin resistance develops similarly as in central obesity. In contrast, patients with type A (insulin receptor mutations) and type B (anti-insulin receptor antibodies) insulin resistance, the amount and distribution of adipose tissue may be normal since the underlying mechanism involves dysfunction of the insulin receptors rather than abnormal distribution of adipose tissue. (See 'Distribution of adipose tissue' above.)
•Presentations – Insulin resistance can present in a variety of ways depending on the underlying etiology and severity. Although obesity-related and other forms of insulin resistance share similar clinical features, patients with the genetic syndromes typically have extreme insulin resistance and therefore more severe phenotypes (table 2). Common presentations of insulin resistance include metabolic syndrome, abnormal glucose metabolism (eg, prediabetes, type 2 diabetes), cardiovascular disease (CVD), steatotic liver disease, and ovarian hyperandrogenism (polycystic ovary syndrome [PCOS]). (See 'Presentations' above.)
●Diagnosis
•Obesity-related insulin resistance – For patients with obesity, the diagnosis of insulin resistance is based upon clinical findings (eg, abnormal fat distribution (or lipodystrophy), hyperglycemia, dyslipidemia, abdominal obesity, hypertension). There currently is no validated test for measuring insulin resistance in a clinical setting. As a result, we do not routinely measure insulin resistance in patients without severe phenotypes. (See 'Diagnosis' above and "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Definition'.)
In research settings, the euglycemic insulin clamp technique has been considered to be the gold standard, although easier to perform intravenous glucose tolerance testing (IVGTT) and/or insulin tolerance test (ITT)/insulin suppression testing are most frequently performed to identify patients who are insulin resistant. However, these techniques are impractical for routine clinical use. (See 'Diagnosis' above.)
•Lipodystrophy or severe phenotypes of insulin resistance – In patients with lipodystrophy phenotypes or severe phenotypes suggesting an inherited state of target cell resistance (eg, leprechaunism, Rabson-Mendenhall syndrome), fasting insulin should be measured. The finding of marked hyperinsulinemia should prompt further studies to evaluate the presence of insulin receptor mutations, circulating anti-insulin receptor antibodies, and other disorders (table 1). (See 'Diagnosis' above and "Lipodystrophy syndromes: Clinical manifestations, classification, and diagnosis".)
