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Insulin resistance: Definition and clinical spectrum

Insulin resistance: Definition and clinical spectrum
Literature review current through: Jan 2024.
This topic last updated: Mar 14, 2022.

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 diabetic patients 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

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)

Lipodystrophy associated

Insulin antibodies

Genetic defects in insulin-signaling pathways – Type A insulin resistance

Blocking autoantibodies against the insulin receptor – Type B insulin resistance

CLINICAL FEATURES — Insulin resistance can present in a variety of ways depending on the underlying etiology and severity. Consequences of obesity-related insulin resistance include:

Impaired glucose tolerance, impaired fasting glucose, type 2 diabetes mellitus, increased insulin requirements in type 1 diabetes

Coronary artery disease

Metabolic syndrome

Polycystic ovary syndrome (PCOS)

Nonalcoholic fatty liver disease

Certain obesity-related malignancies (eg, endometrial cancer)

The genetic syndromes of severe insulin resistance are a clinically diverse group. 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).

In most cases, the precise basis for the link between insulin resistance and the clinical findings is not yet identified. 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 insulin-like growth factor-1 (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).

Distribution of adipose tissue — In obesity-related insulin resistance, central or abdominal obesity as well as ectopic fat deposition (eg, in muscle and liver) are common. There is a relative deficiency of adipose tissue storage space in the usual fat depot sites, resulting in fat deposited in muscle and liver and an abnormal distribution of adipose tissue that underlies the development of insulin resistance, although the precise mechanism is not fully understood. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Role of diet, obesity, and inflammation'.)

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, in these cases, the underlying mechanism involves dysfunction of the insulin receptors per se.

Abdominal obesity – An increasing number of individuals in Western societies have general obesity and/or abdominal obesity. High serum free fatty acid concentrations in the circulation and/or excess fat deposition in muscle or liver (derived from enlarged adipose cells, the storage capacity of which has been exceeded) have been implicated in the pathogenesis of obesity-related metabolic disorders, including insulin resistance [4-6]. Macrophages are attracted to the dystopic fat deposition areas to phagocytose adipocytes, and this initiates a chronic, low-grade inflammatory state. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Role of diet, obesity, and inflammation'.)

Increased release of adipocytokines, such as tumor necrosis factor (TNF)-alpha, or decreased production of protective adipocytokines, such as adiponectin [7], are thought to mediate the effects of obesity in the pathogenesis of insulin resistance and, subsequently, the metabolic syndrome and type 2 diabetes. Adiponectin levels are decreased with intraabdominal fat accumulation and increased with healthy dietary patterns and exercise [8-10]. Low adiponectin levels are associated with high circulating levels of insulin, IGF-1, and proinflammatory cytokines, all of which lead to obesity and insulin resistance-related comorbidities in genetically predisposed individuals. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Role of diet, obesity, and inflammation'.)

Lipoatrophy – 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). The patients often have severe tissue resistance to insulin and may have some of the other clinical features of insulin resistance, such as acanthosis nigricans. The syndromes can be congenital or acquired, and atrophy of adipose tissue can be total or partial [4]. The results of studies of the pathogenesis of insulin resistance in the context of lipoatrophy have varied regarding the presence or absence of defects at the level of insulin receptor expression, function, and signaling, as well as in genes involved in adipogenesis. Adiponectin and leptin levels are low in some patients with lipoatrophy [4]. (See "Lipodystrophic syndromes", section on 'Lipodystrophies and insulin resistance'.)

A syndrome of acquired lipodystrophy is associated with antiretroviral therapy (ART), including protease-inhibitors in patients with human immunodeficiency virus (HIV) infection. These patients have insulin resistance and develop lipoatrophy and/or dystopic fat deposition, as well as metabolic abnormalities. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy".)

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.

Obesity related – Obesity, particularly abdominal obesity, is associated with resistance to the effects of insulin on peripheral glucose and fatty acid utilization, often leading to type 2 diabetes mellitus. Many patients with obesity-related insulin resistance initially have normal or only slightly high blood glucose concentrations. In many cases, however, pancreatic beta cells eventually fail to compensate for insulin resistance and hyperglycemia develops. Patients may have impaired fasting glucose or impaired glucose tolerance prior to developing overt type 2 diabetes. Some patients require large doses of insulin to control hyperglycemia. (See "Pathogenesis of type 2 diabetes mellitus".)

Genetic syndromes of severe insulin resistance – In patients with genetic syndromes of severe insulin resistance, hyperglycemia despite large doses of insulin is the classical presentation since very high insulin levels may not be effective given the dysfunctional insulin receptor. However, certain patients with extreme resistance to insulin may not present with overt hyperglycemia, particularly during the early phases of developing insulin resistance since normal glucose levels are maintained at the expense of rising insulin levels. Not infrequently, patients may initially have only postprandial hyperglycemia (or abnormal oral glucose tolerance testing) well before they develop sustained hyperglycemia.

Other patients may develop postprandial hypoglycemia due to rising insulin levels well before they develop sustained hyperglycemia. It has been hypothesized that this results from impairment of hepatic insulin clearance in patients with insulin receptor defects or secondarily as a consequence of hepatic steatosis. In addition, a small percentage of patients may initially present with hypoglycemia due to developing activating autoantibodies to the insulin receptor [3,11-13].

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'.)

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)".)

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 [14]. 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) [15,16] or the type A syndrome (caused by genetic defects in the insulin-signaling system, such as mutations in the insulin receptor gene) [17,18]. Affected women can present with overt virilization or hirsutism, amenorrhea, and infertility. The ovaries show a polycystic pattern on ultrasound.

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) [19]. The basis for the association between insulin resistance and ovarian hyperandrogenism is not entirely clear [20,21]. 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 (figure 1) [22]. 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" and "Metformin for treatment of the polycystic ovary syndrome", section on 'Potential uses'.)

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 [3,23,24]. 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 [25]. 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):

Hyperglycemia

Dyslipidemia

Abdominal obesity

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 [26], 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 [27]. 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 [28].

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 [29,30]. However, these techniques are impractical for routine clinical use.

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 [31]. 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 [32,33], none are recommended for routine assessment of insulin resistance in the clinical setting.

Severe phenotype of insulin resistance — In patients with 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) or with lipodystrophy phenotypes, 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 "Lipodystrophic syndromes".)

SUMMARY

Insulin resistance is a state in which a given concentration of insulin is associated with a subnormal glucose response. Important long-term consequences of insulin resistance include the development of type 2 diabetes, cardiovascular disease (CVD), and certain malignancies associated with obesity and insulin resistance. (See 'Definition and causes' above and 'Clinical features' above.)

Insulin resistance is associated with a variety of clinical presentations based on its severity (table 2). Some of these features include acanthosis nigricans, ovarian hyperandrogenism (polycystic ovary syndrome [PCOS]), lipodystrophy, accelerated or impaired linear growth, autoimmunity, and muscle cramps. (See 'Clinical features' above.)

For patients with obesity, the diagnosis of insulin resistance is based upon clinical findings (eg, 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.)

In patients with severe phenotypes suggesting an inherited state of target cell resistance (eg, Leprechaunism, Rabson-Mendenhall syndrome) or with lipodystrophy phenotypes, 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 "Lipodystrophic syndromes".)

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Topic 1762 Version 18.0

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