Syndromes of Severe Insulin Resistance

AN exceedingly large number of studies have convincingly demonstrated that insulin resistance occurs in association with a variety of physiological and pathophysiological states, including obesity, noninsulin-dependent diabetes mellitus (NIDDM), polycystic ovary syndrome (PCOS), and the constellation of central obesity, hypertension, glucose intolerance, and hyperlipidemia known as metabolic syndrome or syndrome X (1, 2) (Table 1). In addition, a number of rare, albeit very interesting, syndromes characterized by extreme insulin resistance have been described over the past 20 yr (3, 4). These syndromes are not only clinically important, but have also significantly contributed to our knowledge of the mechanisms of insulin action and resistance. In this review, we focus on syndromes characterized by extreme insulin resistance. We present the tools and criteria for the diagnosis of severe insulin resistance and review the clinical phenotypes of type A and type B syndromes of insulin resistance, the HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, Rabson-Mendenhall syndrome, leprechaunism, and lipodystrophy (3, 4). Subsequently, we discuss our current knowledge of the underlying pathophysiological mechanisms and explore the current therapeutic approach to these syndromes as well as potential future directions for research in the area. Conditions and defects associated with insulin resistance Conditions and defects associated with insulin resistance Insulin resistance has been broadly defined as “a state (of a cell, tissue, or organism) in which a greater than normal amount of insulin is required to elicit a quantitatively normal response” (3). However, insulin resistance can be selective, i.e. involving only certain aspects of insulin action, a fact that complicates both the definition and its characterization in vitro or in vivo (1, 3). Currently, clinical assessment of insulin resistance (or, conversely, insulin sensitivity) relies on several tests, which, in order of increasing complexity, include determination of insulin levels, either at baseline (fasting) or after oral glucose tolerance testing (OGTT) (5), assessment of sequential plasma glucose levels after the iv administration of insulin (ITT) (5), estimation of an index of insulin sensitivity (Si) by applying the minimal model technique to data obtained from the frequently sampled iv glucose tolerance test (FSIVGTT) (6), and the measurement of in vivo insulin-mediated glucose disposal (M) by the euglycemic hyperinsulinemic clamp procedure (7). Although assessment of either fasting or peak insulinemia after OGTT provides a convenient, readily available means of classifying individuals into normal, mild to moderate, and severe insulin resistant (5), the results of this test must be interpreted in the context of plasma glucose levels, because the presence of any degree of hyperglycemia suggests the presence of defects in insulin secretion, further exacerbates insulin resistance, and invalidates the degree of insulinemia as an index of insulin resistance (5). Fasting insulin levels above 50–70 μU/mL or peak (post-OGTT) insulin levels above 350 μU/mL suggest severe insulin resistance, in contrast to the fasting serum insulin levels below 20 μU/mL or peak (post-OGTT) insulin levels below 150 μU/mL observed in normal individuals (5). Similarly, the rate and degree of plasma glucose fall in response to ITT are dependent not only on insulin sensitivity, but also on the presence and magnitude of the counterregulatory hormone response (including epinephrine, glucagon, cortisol, and GH) (5), thus decreasing the value of ITT in assessing insulin sensitivity per se. In contrast, the assessment of an index of insulin sensitivity (Si) by employing the minimal model kinetic analysis to data obtained from the FSIVGTT appears to represent a more accurate means of quantifying insulin sensitivity (6). In this test, an iv injection of a fixed amount of glucose is followed by frequent blood sampling over 180 min and subsequent modeling of the relevant plasma glucose and insulin data to derive the indexes of insulin sensitivity (Si) and glucose effectiveness (Sg) (6). Si index values below 2 × 104μ U/mL·min typically occur in the presence of severe insulin resistance, whereas values above 5 × 104μ U/mL·min are observed in normal subjects (4). The Si correlates well with the insulin-mediated glucose disposal rate (M), as determined by the euglycemic hyperinsulinemic clamp (7). The latter, considered to be the gold standard in the assessment of insulin resistance, involves the concurrent iv infusion of insulin at a fixed rate (usually raising plasma insulin levels to either 100 or 1000 μU/mL) and glucose at a variable rate, as necessary to maintain normoglycemia (8). Upon reaching steady state, the glucose disposal rate (M) is proportional to the exogenous glucose infusion rate (8). Patients with severe insulin resistance have M rates below 2 mg/kg·min, compared with M rates above 6 mg/kg·min in normal individuals (5). Intermediate values typify mild to moderate insulin resistance. Clinical findings associated with severe insulin resistance include acanthosis nigricans (1, 3–5), consisting of velvety hyperpigmented and hyperkeratotic patches in skin fold areas, such as the nape of the neck, the axillae, and the groins, and evidence of ovarian hyperandrogenism in postpuberatal females (1, 3–5), including hirsutism, oligoamenorrhea, and infertility. These manifestations apparently involve a selective effect of insulin on skin and ovaries, respectively, mediated at least in part through activation of the insulin-like growth factor I (IGF-I) receptor (1, 3–5, 9). All syndromes of severe insulin resistance share a number of laboratory findings. Among these, hyperinsulinemia, resulting from increased insulin secretion to compensate for the peripheral insulin resistance and (in many cases) reduced insulin clearance, is by far the most consistent finding (1, 3, 4). Additionally, impaired glucose tolerance or frank diabetes mellitus commonly, but not universally, occur at a later stage in the natural course of these syndromes (1, 3, 4). These manifestations depend on the ability of the pancreas to compensate for the peripheral insulin resistance by increasing insulin secretion (1, 3, 4). Unique features associated with each syndrome have been recognized as a result of extensive studies and have led to the classification of patients with severe insulin resistance into several distinct phenotypes. The term type A syndrome was originally applied to lean adolescent female patients with severe insulin resistance, acanthosis nigricans, severe ovarian hyperandrogenism, and decreased insulin binding to circulating leukocytes (4) and is currently used for both female and male patients with severe inherited insulin resistance and acanthosis nigricans in the absence of autoantibodies to the insulin receptor (IR) (3, 5). Postpubertal females also have evidence of mild to severe androgen excess of ovarian origin, ranging from hirsutism, acne, oligoamenorrhea, and infertility to frank virilism with markedly elevated testosterone levels (1, 3–5). Additional, but not invariable, features of the syndrome include short stature, acral hypertrophy, accelerated linear growth, muscle cramps, and retinitis pigmentosa (1, 3–5). In contrast to the typically early onset of the type A syndrome, patients afflicted with the type B syndrome are commonly middle-aged at presentation and, in addition to the common features of severe insulin resistance (i.e. abnormal glucose homeostasis, acanthosis nigricans, and ovarian hyperandrogenism), often demonstrate features associated with autoimmunity, including vitiligo, alopecia areata, arthritis, nephritis, and primary biliary cirrhosis, as well as Hodgkin’s disease and ataxia-telangiectasia (1, 3–5). These patients may present with fasting hypoglycemia (with or without postprandial hyperglycemia) or may develop hypoglycemia during the course of their disease, even subsequent to a period of hyperglycemia and diabetes (1, 3–5, 10). In addition to nonspecific laboratory findings, including elevated erythrocyte sedimentation rate, leukopenia, hypergammaglobulinemia, serum antinuclear antibodies, and proteinuria, these patients demonstrate the presence of anti-IR antibodies in the plasma (1, 3, 4). Commonly, anti-IR antibody titers are in proportion to the magnitude of insulin resistance (1, 3, 4). These anti-IR antibodies are the diagnostic hallmark of the type B syndrome and explain several of its manifestations, as will be discussed later. The type B syndrome is quite distinct from the resistance to exogenous (usually of animal origin) insulin, which occurs as a result of developing antiinsulin antibodies that bind insulin and prevent its interaction with IRs (3). In addition to the type A and B syndromes, the term HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) has been applied to women with all of the above features, often in association with obesity (5). However, it has not yet been fully clarified whether this syndrome represents a distinct entity from other syndromes of severe insulin resistance, such as the type A and B syndromes, or PCOS (5), and it will not be discussed in detail. Another very rare syndrome associated with severe insulin resistance was initially described by Mendenhall (3, 11) and is currently known as the Rabson-Mendenhall syndrome. These patients present in childhood with severe insulin resistance and diabetes mellitus (commonly refractory to large doses of insulin), acanthosis nigricans, abnormal nails and dentition, accelerated linear growth, precocious pseudopuberty, and, ostensibly, pineal hyperplasia (3, 11). Prognosis is generally poor, mainly due to the development of severe microvascular complications of diabetes (3). Leprechaunism was first recognized in 1954 and is characterized by severe intrauterine and postnatal growth retardation and failure to thrive, lipoatrophy, dysmorphic features (globular eyes, large ears, and micrognathia), and acanthosis nigricans (3, 12). These infants have massive hyperinsulinemia, often associated with glucose intolerance or frank diabetes mellitus, in addition to fasting hypoglycemia (3, 12). Additionally, affected female infants commonly have hirsutism and clitoromegaly, whereas affected males commonly present with penile enlargement (3, 12). Other features of this syndrome include dysmorphic lungs, renal disease, and breast hyperplasia (3). Few of these infants live beyond the first year of life, although a few may survive until adolescence (3, 12). The lipodystrophy syndromes represent a diverse group of disorders characterized by severe insulin resistance and associated with severe hypertriglyceridemia leading to pancreatitis, and fatty infiltration of the liver leading to cirrhosis (3, 5). These syndromes have been conveniently subclassified according to the extent and the location of the lipodystrophy and the age of onset (3, 5). Specifically, newborns or infants with congenital generalized lipodystrophy (Berardinelli-Seip syndrome), an autosomal recessive condition, lack adipose tissue completely in both sc and visceral locations and commonly manifest impaired glucose tolerance or diabetes, accelerated linear growth, precocious puberty, muscular hypertrophy, and hypertriglyceridemia (3, 13). In contrast to the Berardinelli-Seip syndrome, patients with acquired total lipodystrophy (Lawrence syndrome) appear normal at birth, but develop lipoatrophy over days to weeks, sometimes after an infectious prodrome (3). Histological evidence of panniculitis has suggested an inflammatory etiology for this syndrome, although this remains to be demonstrated (3). In addition to the above variants of generalized lipodystrophy, several forms of partial lipodystrophy have been recognized and affect specific body areas. Thus, face-sparing lipodystrophy (Kobberling-Dunnigan syndrome), an X-linked (or, rarely, autosomal dominant) condition, spares the face, which is typically full, in contrast to the lipoatrophic trunk and extremities (3, 14). Another form of partial lipodystrophy occurs in association with mandibuloacral dysplasia and joint contractures and is termed lipodystrophy with other dysmorphic features (3). Additionally, a sporadic form of partial lipodystrophy, named cephalothoracic lipodystrophy, has been described predominantly in women and occurs in association with messangiocapillary glomerulonephritis, presumably as a result of complement activation (3). Another rare syndrome of severe insulin resistance that was recently described and characterized is insulin resistance in association with acromegaloidism (15). In addition to severe insulin resistance, these patients have features reminiscent of acromegaly, including coarse facies and bone thickening, despite a GH-IGF-I axis that appears to be normal (3, 15). However, whether these physical findings result from high insulin levels signaling through the IGF-I receptor or, alternatively, the IR per se remains to be established (3, 15). Finally, a number of rare genetic syndromes are associated with severe insulin resistance. Among them, Alstrom syndrome, an autosomal recessive disorder, presents with retinitis pigmentosa, sensorineural deafness, hypogonadism, and obesity and is commonly associated with severe insulin resistance and acanthosis nigricans (3). Myotonic dystrophy, an autosomal dominant condition that presents with progressive muscular dystrophy, myotonia, mild mental retardation, baldness, cataracts, and postpubertal testicular atrophy, has been associated with severe insulin resistance (3). Werner’s syndrome, a progeria syndrome, presents with bird-like facies, gray hair, cataract formation, slender extremities, and severe insulin resistance (16). Insulin binds to the extracellular (α) subunits of its heterotetrameric receptor, consisting of two (α) and two (β) subunits and activates the intracellular tyrosine kinase in the transmembrane (β) subunits (17) (Fig. 1). Insulin receptor autophosphorylation and subsequent tyrosine phosphorylation of critical intracellular signaling intermediates ensue, including insulin-like substrates 1 and 2 (IRS-1 and -2), Shc, and Gab1 (17, 18). These activated intermediates bind to and activate other signaling molecules, including the adapter proteins Grb2 and Nck, the tyrosine phosphatase Syp, and the phosphoinositide 3-kinase, amplifying and diversifying the initial signal generated by the insulin binding to its receptor (17). A host of protein intermediates are subsequently activated, including the ras (Grb2-mSOS-Ras)-mitogen-activated protein kinase pathway, the pp70 kinase, the PKB/Akt (protein kinase B), and possibly other unidentified pathways, and ultimately lead to the well characterized insulin effects, such as stimulation of cellular glucose and amino acid uptake, glycogen synthesis, lipogenesis, and mitogenesis by mechanisms that have not been completely elucidated and are currently the focus of intense research (17). Overview of the insulin signaling cascade. Abbreviations used in text and figures: ESR, Erythrocyte sedimentation rate; IGT, impaired glucose tolerance;pY, phosphotyrosine; Shc, src homology 2 (SH2)-containing protein; Syp, SH2 protein tyrosine phosphatase; PI 3 K, phosphoinositide 3-kinase; GRB2, growth factor receptor-bound protein 2; GAB1, GRB2-associated binder 1; mSOS, mammalian son of sevenless; MAPK, mitogen-activated protein kinase; PKB/Akt, protein kinase B. Overview of the insulin signaling cascade. Abbreviations used in text and figures: ESR, Erythrocyte sedimentation rate; IGT, impaired glucose tolerance;pY, phosphotyrosine; Shc, src homology 2 (SH2)-containing protein; Syp, SH2 protein tyrosine phosphatase; PI 3 K, phosphoinositide 3-kinase; GRB2, growth factor receptor-bound protein 2; GAB1, GRB2-associated binder 1; mSOS, mammalian son of sevenless; MAPK, mitogen-activated protein kinase; PKB/Akt, protein kinase B. Abnormalities in any of the entire insulin signaling pathway molecules, from the IR until the final effectors, could potentially be implicated in the pathogenesis of severe insulin resistance (Fig. 1). Following the chronology of discovery of the messenger molecules involved in insulin signaling, the researchers’ attention was initially turned toward the IR, the first characterized and most obvious such candidate. Since 1988, over 50 mutations of the IR gene have been described, and have been shown to decrease IR synthesis (class I), interfere with intracellular trafficking of the IR (class II), decrease insulin binding (class III), impair IR tyrosine kinase activity (class IV), or lead to accelerated IR degradation (class V). IR mutations (in homozygous or compound heterozygous form) have been found in all patients with leprechaunism or the Rabson-Mendenhall syndrome (17, 18). In patients with the former condition, such IR mutations markedly curtail the availability of IR on the plasma membrane by interfering with IR synthesis or trafficking or by accelerating IR degradation (18). Similarly, in patients with the syndrome, the presence of severe defects of the IR gene results in IR synthesis and, markedly impaired insulin binding to the IR (18). studies an autosomal dominant or autosomal recessive of of the type A syndrome, with variable (1, 3–5). in vivo studies of such patients increased glucose and insulin-mediated glucose disposal rates (1, 3–5). findings are further by in vitro evidence of impaired insulin binding and action at the cellular (1, 3–5, Although several IR mutations have been associated with the type A syndrome it currently appears that most patients with this syndrome not such the presence of other critical primary defects in insulin signaling as to be the in patients with it appears that the and of patients with severe insulin resistance is as suggested by the presence of the of the IR gene in a with the type A syndrome and in with the Rabson-Mendenhall syndrome In addition to mutations of the IR a transmembrane protein named has been as the of the type A syndrome in possibly by interfering with IR tyrosine kinase activity (18). However, its in the pathogenesis of severe insulin resistance has not been demonstrated (18). Additionally, IR phosphorylation has been implicated as a potential for insulin resistance in a of PCOS patients anti-IR antibodies occur in association with the type B syndrome, presumably as a result of either of tolerance or of an response to an exogenous and through (3). These antibodies can lead to insulin resistance by interfering with insulin binding although anti-IR antibodies appear to lead to IR the fasting hypoglycemia that may occur in these patients (1, 3–5, 10). Additionally, defects of signaling intermediates to the IR are demonstrated in a of patients with severe insulin resistance, including the presence of an in such a although its remains (18). selective of phosphoinositide activity was demonstrated in patients with severe insulin resistance and Although an autosomal recessive of has been suggested for the Berardinelli-Seip syndrome (3, the pathogenesis of associated insulin resistance is and it remains whether insulin resistance is primary or occurs to analysis in with congenital lipodystrophy to the IR, and IGF-I to plasma may lead to insulin resistance by decreasing peripheral glucose and increasing (3). In addition, the of insulin resistance in and adipose adipose tissue was completely suggests that insulin resistance may be to the lack of adipose tissue and the that the for lipodystrophy may be elucidated The pathogenesis of severe insulin resistance in patients with the rare genetic syndromes is although impaired insulin binding has been demonstrated in insulin from patients with and impaired insulin signaling has been shown in patients with Werner’s syndrome (16). available for the syndromes of severe insulin resistance are as the pathogenesis of these syndromes is and in addition to have been the of for diabetes glucose intolerance in patients with diabetes mellitus by both peripheral insulin resistance and insulin secretion However, short term severe not the response to exogenous insulin in a of women with severe insulin resistance Additionally, although may the glucose tolerance of patients with it is whether the peripheral insulin sensitivity in patients with severe insulin resistance. Thus, the of and in patients with these syndromes further although it appears that the commonly individuals will significantly from and for patients with severe insulin resistance syndromes is currently Insulin is often in very high but to (3, Similarly, administration of to patients with severe insulin resistance has to because these by insulin secretion, which is increased in patients with severe insulin resistance of which may by binding to either the IGF-I receptor or a IR, has been in patients with several syndromes of severe insulin resistance, including the type A or B syndromes, the Rabson-Mendenhall syndrome, leprechaunism, and lipodystrophy and and has led to in and decrease in fasting insulin levels in short term studies and However, of these not in a IGF-I administration is associated with such as syndrome, and In addition, is that IGF-I administration may the development of microvascular in patients with diabetes and IGF-I has recently been associated with breast and Thus, its in patients with severe insulin resistance remains that insulin sensitivity present for the of individuals with severe insulin resistance. Specifically, a that glucose and insulin-mediated glucose has been shown to in patients with the type B syndrome or lipoatrophic diabetes but not the insulin resistance in patients with a that insulin sensitivity in was shown to insulin resistance in patients with Werner’s syndrome and is currently in individuals with other syndromes of severe insulin resistance, including the HAIR-AN syndrome. administration of or to patients with has led to in and peripheral insulin resistance although the of these in patients with severe insulin resistance data suggest an in insulin sensitivity in response to administration of to patients with the type A syndrome Additionally, activation of a IR, obtained from a with the Rabson-Mendenhall syndrome, by a antibody in vitro led to IR autophosphorylation and glycogen synthesis in raising that such may patients with severe insulin resistance studies suggest in insulin sensitivity of patients with diabetes in response to administration of or with fatty possibly by interfering with (3). Finally, and have been in patients with the type B syndrome with results (3). Although has been in our of the syndromes associated with severe insulin resistance, remains to be Thus, the critical defects in insulin signaling for the severe syndromes to be Additionally, the clinical of syndromes, such as the HAIR-AN syndrome, must be from more common phenotypes associated with moderate insulin resistance. studies must the of currently available at insulin resistance, such as and and the of other such as IGF-I at the underlying defects in a specific are very is that the in our of insulin signaling will lead to such including gene for both the common associated with insulin resistance as well as these rare but