Sindromes de Insulino Resistencia

Genetic Syndromes of Severe Insulin Resistance

Robert K. Semple, David B. Savage, Elaine K. Cochran, Phillip Gorden,and Stephen ORahilly

University of Cambridge Metabolic Research Laboratories (R.K.S., D.B.S., S.O.), Institute of Metabolic Science,Addenbrookes Hospital, Cambridge CB2 0QQ, United Kingdom; and Clinical Endocrinology Branch (E.K.C., P.G.),National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892

Insulin resistance is among themost prevalent endocrine derangements in theworld, and it is closely associatedwithmajor diseases of global reach including diabetesmellitus, atherosclerosis, nonalcoholic fatty liver disease,and ovulatory dysfunction. It is most commonly found in those with obesity but may also occur in an unusuallysevere form in rare patients with monogenic defects. Such patients may loosely be grouped into those withprimary disorders of insulin signaling and those with defects in adipose tissue development or function (lipo-dystrophy). The severe insulin resistanceofboth subgroupsputspatients at riskofacceleratedcomplicationsandposes severe challenges in clinical management. However, the clinical disorders produced by different geneticdefects are often biochemically and clinically distinct and are associatedwith distinct risks of complications. Thismeans that optimal management of affected patients should take into account the specific natural history ofeach condition. In clinical practice, they are often underdiagnosed, however, with low rates of identification ofthe underlying genetic defect, a problem compounded by confusing and overlapping nomenclature and clas-sification. We now review recent developments in understanding of genetic forms of severe insulin resistanceand/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlyingpathophysiology. (Endocrine Reviews 32: 498514, 2011)

I. IntroductionII. Definition and Prevalence of Severe IRIII. Generic Clinical Features of Severe IR

A. Abnormal glucose homeostasisB. Ovarian dysfunctionC. Acanthosis nigricans

IV. Clinical Features Limited to Some Severe IR SubtypesA. Dyslipidemia and hepatic steatosisB. Abnormal adipose development or topographyC. Growth disorders

V. Sexual Dimorphism in Severe IRVI. Biochemical Subphenotyping of Severe IRVII. Monogenic IR Classification/NomenclatureVIII. The INSR SpectrumIX. Downstream Insulin Signaling DefectsX. Disorders of Adipose Tissue Development/Function

(Lipodystrophies)XI. Digenic IRXII. Complex SyndromesXIII. Therapy

A. Dietary and lifestyle modificationB. Insulin sensitization and replacementC. Adipose tissue offloading

XIV. Summary

I. Introduction

Insulin resistance (IR), or more precisely the reduced re-sponsiveness of the body to the glucose-lowering ac-tivity of insulin, is closely associatedwith someof themostprevalent chronic clinical disorders, namely type 2 diabe-tes, atherosclerosis, polycystic ovarian syndrome, and he-patic steatosis. The population-wide toll of morbidity andmortality attributable to IR is large and growing, in par-ticular due to the consequences of coronary artery disease(1), type2diabetes (2), polycystic ovary syndrome (3), andfatty liver disease, and indeed IR is a cardinal feature of themetabolic syndrome itself (4).

Although IR is a traitwith significant heritability (58),it is usually only clinically expressed in the context of obe-sity, especially where this has a predominantly centripetaldistribution. In a small number of patients, however, IR ofan unusually severe degree developswithout obesity, or inassociation with generalized or regional lack of adiposetissue. Many such patients harbor pathogenic single gene

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright 2011 by The Endocrine Societydoi: 10.1210/er.2010-0020 Received October 1, 2010. Accepted March 28, 2011.First Published Online May 2, 2011

* R.K.S. and D.B.S. contributed equally to this work.Abbreviations:AR,Autosomal recessive;CIDEC,cell death-inducingDNAfragmentation factorA-like effector family-C; DS, Donohue syndrome; IGFBP1, IGF binding protein-1; INSR, insulinreceptor; IR, insulin resistance; mTORC1, mammalian target of rapamycin complex 1; PTRF,polymerase 1 and transcript release factor; RMS, Rabson Mendenhall syndrome.

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mutations, and several of these have been identified inrecent years. These genetic defects may currently begrouped into those affecting insulin signaling and thoseaffecting adipocyte development and/or function. De-tailed physiological study of such patients with definedgenetic defects has begun to identify distinct subpheno-types of IR and has yielded insights into the mechanisticbasis of more prevalent forms of IR.

Severe IR may also arise through acquired, immune-mediated mechanisms. These include antibodies againsteither insulin or the insulin receptor leading to blockade ofinsulin action (9) or autoimmune destruction of adi-pocytes leading to lipodystrophy (10, 11). Many, but notall, of these patients have coexisting autoimmune disease,alerting physicians to the possibility of acquired severe IR.These disorders have been recently reviewed (1215).

The prevailing clinical nomenclature in the field of se-vere IR dates from early work on these syndromes in the1970s (9, 16).Wenowdescribe the current state of knowl-edge of genetic forms of severe IR, suggest a refined clas-sification based on recent findings, and review currentlyavailable treatments.

II. Definition and Prevalence of Severe IR

Plasma insulin, whether determined in the fasting state orafter a glucose challenge, is a continuous variable, and sothresholds used to diagnose IR and severe IR are arbi-trary. Furthermore, such thresholds are only reliable be-fore -cell decompensation has occurred. In entirely insu-lin-deficient individuals, severe IRmaybedefined solely interms of the body mass-adjusted requirements for exoge-nous insulin to maintain euglycemia, whereas in nondia-betic patients with compensated IR, severe IR may be de-fined solely in terms of plasma insulin levels before and/orafter a glucose challenge, with reference to data from acontrol population. However, between these extremes, inpatients with relative rather than absolute insulin defi-ciency, diagnosis of severe IR is based on semiquantitativeassessment of the biochemical abnormality coupled withclinical evidence of severe IR. A further complication isthat severe IR is most commonly seen in obese patients,and yet they are a group far less likely to harbor single genedefects. Similarly, puberty is a time of physiological IR,and so ideally biochemical assessment of possible severeIR should be made with reference to normative data de-rived from people of similar adiposity and developmentalstage. Subject to these caveats, a suggested working diag-nostic scheme for likely monogenic severe IR is shown inFig. 1. This emphasizes that, whereas numerical determi-nants of severe IR have utility in the settings of normal

glycemia and absolute insulin deficiency, diagnosis in thecontext of partial -cell decompensation, which is themost common scenario, relies heavily on interpretation ofphysical signs and clinical history. Although not widelyemployed in current clinical practice, we have also founda nomogram derived from a large, nondiabetic popula-tion, showing the relationship between body mass indexand insulin levels to be helpful in discriminating degrees ofIR in overweight/obese patients that are manifestly dispro-portionate to thedegreeof adiposity andare thusmore likelyto have a contribution from a single gene defect (Fig. 1B).

Thesediagnostic complexitiesmeanthat severe IR isoftennot recognized, especially in men. Furthermore, patientspresent to many different clinical services according to theirdominant clinical problem, and for these reasons no popu-lation-based prevalence figures exist. However, clinical ex-perience suggests that approximately 0.10.5% of patientsin hospital-based diabetes practices may have monogenicforms of severe IR.

III. Generic Clinical Features of Severe IR

A. Abnormal glucose homeostasisClinical awareness of IR is greatest among those car-

ing for patients with established diabetes mellitus, whereit is recognizedmost commonly by a requirement for large

Fig. 1. Diagnosis of possible monogenic severe IR. A, Suggested(arbitrary) diagnostic criteria. B, Relationship between body mass index(B.M.I.) and fasting plasma insulin in a healthy European nondiabeticpopulation (n 800). The solid line represents the 50th centile, andthe dashed lines the 5th and 95th centiles. [Figure courtesy of Prof.Nicholas J. Wareham.]

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doses of exogenous insulin. However, hyperglycemia isnot usually the earliest clinical manifestation of severe IR.It may be recognized much earlier by the presence of ac-anthosis nigricans and/or ovarian hyperandrogenism inwomen. Furthermore, symptomatic hypoglycemia oftenprecedes hyperglycemia, sometimes bymany years. Char-acteristically, hypoglycemia related to severe IR occurspostprandially, with autonomic symptoms sometimesprogressing toneuroglycopeniaandseizures ifnotabrogatedby oral carbohydrate. Such severe postprandial hypoglyce-miamaybeseen inpatientswith insulinreceptordefects (17),insulin signal transduction defects, or primary lipodystro-phies (18, 19). Its mechanism is unclear, but it most likelyrelates to severe impairment of hepatic insulin clearance dueprimarily to a insulin receptor defect or secondarily to theconsequences of hepatic steatosis (20).

Even in the context of severe loss of insulin receptorfunction, hyperplasia of pancreatic-cells, with attendantextreme hyperinsulinemia, may prevent hyperglycemiaformany years, indicating that the receptor on islets them-selves is not a prerequisite for -cell expansion, as sug-gested by some murine studies (21). However, in mostcases pancreatic -cell hyperplasia does eventually fail tocompensate for severe IR, and hyperglycemia ensues.Commonly, hyperglycemia diagnostic of diabetes is onlyseen after an oral glucose challenge, contrasting with fast-ing hypoglycemia or normoglycemia, making fasting glu-cose alone an inadequate diagnostic test for diabetes in thecontext of severe IR. Compounding this, glycosylated he-moglobin may be normal, or even low, at the time whenpostload glucose levels are diagnostic of diabetes. Al-though these observations suggest that the various currentdiagnostic criteria for diabetes may have different utilitiesin predicting risk of diabetic complications in severe IR,this has not yet been studied. The time taken to -celldecompensation varies substantially, with diabetes devel-oping in the neonatal period in the most severe cases andin the fourth decade or beyond at the milder end of thespectrum, especially in men.

B. Ovarian dysfunctionSevere IRmost commonly presents to clinical attention

first as oligomenorrhea and severe hyperandrogenism inyoung women after menarche, although the underlyinghyperinsulinemia is often not recognized. Ovarian ultra-sonography usually reveals multiple peripheral cysts asseen in idiopathic polycystic ovary syndrome. In severecases, cystsmay become very large and vulnerable to hem-orrhage or torsion, and surgical removal may be required,sometimes in infancy (Fig. 2). Hyperandrogenism in IRmaybe severe,with testosterone levels above 10nmol/litersometimes seen, well in excess of thresholds commonly

reported to discriminate virilizing tumors from nontu-moral hyperandrogenism (22).

The ovarian hyperandrogenism of IR is driven by syn-ergy between gonadotropin and insulin action on theovary (23, 24). Thus, it may be clinically apparent duringboth infancy and postpubertal life, when the hypothalam-ic-pituitary-gonadal axis is fully active, and it may alsoacceleratepuberty (25). Severeovarianhyperandrogenismmay occur postmenopausally, in which case ovarian his-tology characteristically reveals hyperthecosis, or hyper-plasia of the androgen-secreting theca cells (26).However,hyperandrogenism is not seen, despite extreme hyperin-sulinemia, when insulin receptor function is lost for thefirst time postmenopausally (12), suggesting that hyper-insulinemia around the time of the menopause may benecessary to sustain androgen-secreting theca cells.

Themain differential diagnosis of IR-related severe hy-perandrogenism is congenital adrenal hyperplasia or anandrogen-secreting tumor, but in these cases acanthosisnigricans is not usually prominent unless the patient is alsooverweight or obese.Although congenital adrenal hyperpla-sia is easily diagnosed biochemically, discriminating auton-omous androgen secretion and hence virilizing tumors maybe more challenging (27). A complicating consideration isthat ovarian tumors may arise in the context of sustainedsevere hyperinsulinemia, most likely due to chronic activa-tion of IGF-I receptor-mediated signaling (28).

C. Acanthosis nigricansAnother feature of nearly all known forms of severe IR

is acanthosis nigricans, a velvety thickening of the skin. It

Fig. 2. Ovarian appearances in severe IR. A, Ultrasound appearanceof an ovary in a 14-yr-old patient with severe IR due to a heterozygousmutation in the insulin receptor. B, Perioperative appearance of largeovarian and Fallopian tube cysts in a patient with digenic severe IR dueto heterozygous mutations in the PPARG and PPP1R3A genes (121). Cand D, Ovarian histology of the same patient, showing prominentsclerosis of the superficial ovarian cortex associated with multiplefollicle cysts (C) and stromal hyperthecosis with nests of eosinophilicluteinized cells (arrows) (D) embedded in hyalinized ovarian stroma.[Histological images courtesy of Dr. Merche Jimenez-Linan.]

500 Semple et al. Severe Insulin Resistance Syndromes Endocrine Reviews, August 2011, 32(4):498514


is usually found in the axillae, nape of the neck, and groin,but it can occur in any flexures and in the most extremecases may be periocular, perioral, perianal, or even occuron planar surfaces (Fig. 3). It is commonly associatedwithacrochordons (skin tags). Histologically, acanthosis nig-ricans is characterized by hyperkeratosis, sometimes withhyperpigmentation, as well as mild papillomatosis, sug-gesting that both keratinocytes and dermal fibroblasts areaffected (29). The precise pathogenesis is unclear, but itmay also rarely be found in congenital syndromeswithoutIR (29) or as a paraneoplastic syndrome (30), and severallines of evidence suggest that enhanced signaling throughmitogenic tyrosine kinase-type receptors including theIGF-I receptor plays a central role (29, 31). In IR, acan-thosis depends on hyperinsulinemia, and this is not seen inthe rare situation of pre receptor IR due to unusuallyhigh levels of anti-insulin antibodies in those receivingexogenous insulin therapy (32). Fading of acanthosis in-dicates a reduction in insulin levels either due to lesseningof IR or, conversely, worsening of -cell failure. Acantho-sis nigricans may become excoriated and/or infected, andin concert with IR-related hyperandrogenism may con-tribute to hydradenitis suppurativa (33).

IV. Clinical Features Limited to Some SevereIR Subtypes

All the above are seen in severe IR irrespective of under-lying etiology, whether congenital or acquired, and

whether due to a primary signaling defect or due to lipo-dystrophy. Some features of severe IR syndromes, in con-trast, are seen in only some subtypes.

A. Dyslipidemia and hepatic steatosis

Hypertriglyceridemia and lowhigh-density lipoproteincholesterol levels (hereafter designated metabolic dyslip-idemia) are closely associated with prevalent forms of IR(3437) and are seen in more severe form also in patientswith severe monogenic IR. Indeed, in some cases, hyper-triglyceridemia may be complicated by pancreatitis anderuptive xanthomata, and hepatic steatosis may progressto steatohepatitis, cirrhosis, andhepatocellular carcinoma(38). The presence of significant dyslipidemia and hepaticsteatosis is a sensitive but nonspecific clinical indicator ofunderlying lipodystrophy. Their absence in a patient withsevere IR is suggestive of a primary insulin receptoropathy(39, 40). Recently published mouse data (4143), sup-ported by our own observations in patients with severe IR(39), suggest that hepatic steatosis and dyslipidemia are aconsequence of selective postreceptor (or partial-) hepaticIR (44).

B. Abnormal adipose development or topography

Lipodystrophy is a common cause of severe IR andshould be considered in all cases. The fact that fat mass inlean women is close to double that in lean men, coupledwith the readily recognizable femorogluteal depot usuallypresent in women, generally means that lipodystrophy is

Fig. 3. Acanthosis nigricans (AN) in severe IR. A, Severe AN on the neck in a prepubertal patient with autosomal dominant IR of unknown cause.B, AN associated with exuberant axillary acrochordons in a 50-yr-old male with severe IR of unknown cause. CF, AN in abdominal skin flexures ofa 15-yr-old boy with severe IR due to a heterozygous INSR mutation (C), on the foot of a patient with congenital generalized lipodystrophy andsevere IR due to homozygous AGPAT2 mutations (D), on the knuckles in a prepubertal patient with severe IR of unknown cause (E), and on theneck of a prepubertal girl with RMS due to a homozygous INSR mutation (F). G, Histological appearances from a nuchal skin biopsy showingcharacteristic papillomatosis (solid arrows), hyperkeratosis, and some acanthosis (open arrow). [Histological image courtesy of Dr. Ed Rytina.]



more readily detected in women than men. Lean athleticmen can be very difficult to distinguish from lipodystro-phic men, particularly those with partial lipodystrophy.

C. Growth disordersSevere IR per se may be associated with a range of

growth disorders, including linear growth impairment(40, 45), prepubertal linear growth acceleration (46), orpseudoacromegalic soft tissue overgrowth in adult-hood (4750).Although the precisemolecular basis of thisclose association between severe IR and growth abnor-malities has yet to be determined, it may well relate toperturbation of the cross talk between the endocrine axiscontrolling growth and insulin action, or perhaps to ab-normal paracrine action of IGF-I or IGF-II (45). BothIGF-I, themajor hormone driving linear growth, and IGF-II, which is an important determinant of growth in utero,but which remains present at high levels in serum in post-natal life in humans but not rodents, exert mitogenic ef-fects through the IGF-I receptor and also have significantability to stimulate the insulin receptor. Insulin, con-versely, is able to stimulate the IGF-I receptor at concen-trations seen in extreme hyperinsulinemia (51, 52). Addedto this direct cross talk, insulin or IR has been shown in avariety of contexts to influence action of IGF through al-terations in expression of the ligands themselves, of theirbinding proteins, or of their receptors (53). These obser-vations have yet to be synthesized into a coherent modelaccounting for growth abnormalities in severe IR; how-ever, improving understanding of these phenomena willnot only be of relevance to these rare conditions, but mayalso give mechanistic insights into the link between com-mon obesity/IR and both the prevalence and prognosis ofa variety of different cancers (52, 54, 55).

V. Sexual Dimorphism in Severe IR

Aprominent feature of severe IR is the earlier presentationand more severe metabolic derangement seen in affectedwomen (56). Amajor contributor to this is hyperinsuline-mia-driven ovarian dysfunction, with hyperandrogenismand oligomenorrhea serving as clinical red flags that leadto early presentation (57). Men, in contrast, exhibit onlyacanthosis nigricans, and sometimes symptomatic post-prandial hypoglycemia. Even if noticed, these are muchless likely to lead to medical consultation. However,women also havemuchmore severe hyperinsulinemia anddyslipidemia than men. In lipodystrophy, this is almostcertainly explained at least in part by the larger amount ofwhite adipose tissue as a proportion of total body mass inhealthy women.

VI. Biochemical Subphenotyping of Severe IR

Growing evidence suggests that some syndromes of se-vere IR exhibit different patterns of IR among insulin-responsive tissues and pathways. Thus, the generalized IRof insulin receptor (INSR) defects is associatedwith a nor-mal lipid profile and relative lack of fatty liver (39, 40),suggesting that some insulin signaling is needed to drivehepatic fat synthesis and secretion. This is quite unlike thesituation in patients with lipodystrophy or with defects inthe insulin signal transducer AKT2, all of whom showsevere dyslipidemia and fatty liver (39).

The mechanisms linking hyperinsulinemia in prevalentforms of IR and fatty liver/dyslipidemia are of particularimportance, given the enormous associated prevalence ofatherosclerosis, and are the subject of intense investiga-tion. Full consideration of progress in the field is beyondthe scope of this article; however, recent cell-based studieshave strongly implicated activation of themammalian tar-get of rapamycin complex 1 (mTORC1), hitherto widelyperceived to be predominantly a mediator of insulinsactions on cell growth, in driving hepatic de novo lipo-genesis in response to insulin (5860). Such up-regu-lation of hepatic lipogenesis has been suggested to be asignificant contributor to fatty liver and atherogenicdyslipidemia in humans (61, 62), whereas aberrant ac-tivation of mTORC1 is well documented in IR (63),potentially explaining why lipogenesis appears to be in-creased in these states. However, many critical questionsremain to be answered, including whether enhanced denovo lipogenesis in IR may truly be explained as a hepa-tocyte autonomous phenomenon related to resistance toonly some of insulins cellular effects, or whether it mayinstead reflect parallel hyperactivation of mTORC1 byincreased delivery to hepatocytes of, for example,branched chain amino acids, which have been reported tobe elevated in many forms of IR (59, 64, 65).

INSR defects may also be discriminated from otherforms of IR by unexpectedly high adiponectin (6668),SHBG (69), and IGF binding protein-1 (IGFBP1) (70) lev-els, providing further evidence that in prevalent forms ofIR (7173), in lipodystrophies (15, 67), and in nonrecep-toropathy severe IR (70, 74), where the levels of theseproteins are usually reduced, hyperinsulinemia is able toexert effects through intact elements of the cellular insulinsignal transduction network to suppress gene expressionin both adipose tissue and liver (62, 75). Parenthetically,because adiponectin is nearly exclusively expressed in ad-ipose tissueandbecause circulatingSHBGand IGFBP1areproducts of hepatic expression, determination of thesemarkers in states of IR may also allow assessment to bemade of the insulinization of distinct insulin target tissues



in future, enhancing clinical ability to discern any organ-selective forms of severe IR.

This concept of IR subphenotypes has been exploiteddiagnostically by using it to subclassify IR and target ge-netic screening, greatly enhancing efficiency of moleculardiagnosis of INSR defects (68, 70). Thus, in the context ofsevere IR, we have found that adiponectin levels above 7mg/liter have a 97% positive predictive value for insulinreceptoropathy (70), although the precise cutoff is assay-specific. SHBG and IGFBP1 levels have lesser, althoughstill significant, utility.

VII. Monogenic IR Classification/Nomenclature

The nomenclature in the field of severe IR dates from the1970s. Then, in seminal publications, Kahn and col-leagues (9, 16) designated severe IR in nonobese patientsas type A or type B, the latter discriminated by thepresence of anti-insulin receptor antibodies. In a series ofindependent publications around the same time, the termHAIR-AN came to be used commonly (76). However,HAIR-AN (hyperandrogenism, insulin resistance, andacanthosis nigricans) is an entirely generic description ofsevere IR inwomen. If it has anyutility, it iswhere it is usedto discriminate women with severe IR who also have abodymass index above 30 kg/m2,who aremuch less likelyto harbor pathogenic single gene defects than their nono-bese counterparts. However, the imprecise and overlap-ping usage of these different diagnostic terms and increas-ing understanding of subgroups of severe IR suggest thata reclassification of syndromes of severe IRmay be timely.Based on the above observations, such a classification issuggested in Table 1.

The key subdivision in this proposedmechanism-basedclassification is between those disorders in which there isa primary defect in canonical insulin signal transductionand those in which severe IR is a consequence of adiposetissue abnormalities, or adipose failure. Primary IR isthen subdivided into generalized IR, in which there is adefect at the level of the insulin receptor, and biochemi-cally distinguishable partial IR, in which there is a sig-naling defect that is limited either to only some parts of thepostreceptor signal transduction pathway or to some tis-sues. Few examples of this group currently exist, but it isto be anticipated that increased recognition of this group,allied tomodern sequencing technologies, will lead to fur-ther examples and refinement of this subgroup.

Adipose failure may also be subdivided into a groupwithmanifest lipodystrophy, inwhich there is a deficiencyin generating adipose tissue, leading to severe IR despitelow or normal adipose tissue mass, and a group in whichthe dominant defect is unrestrained accumulation of ad-ipose tissue, most commonly due to hyperphagia, suchthat even a relatively normal capacity safely to accrue tri-glyceride in adipose tissue is overcome.

Severe IR is also seen in a groupof complex disorders(see Table 3), in association with other defects; however,because the IR in these conditions is subjected to mecha-nistic study with the above framework in mind, we antic-ipate that they may be accommodated within one of thetwo main groups.

VIII. The INSR Spectrum

The first defects in the INSR were reported in 1988 (77,78), shortly after cloning of the human gene (79), and

TABLE 1. Proposed new classification for syndromes of severe IR

Discriminating features

I. Primary insulin-signaling defectsA. Generalizeda INSR mutations (40) or anti-INSR antibodies (12) Extreme hyperinsulinemia but normal lipid profile (39, 40),

preserved or elevated adiponectin, SHBG, and IGFBP1 (70)B. Partialb AKT2 (19), AS160 (91, 169), others to be defined Likely to depend upon precise signaling defect

II. Secondary to adipose tissue abnormalitiesc

A. Severe obesity e.g., MC4R (170), POMC (171), LEP (126), LEPR (172),SH2B1 (173)

Early onset severe, hyperphagic obesityTall stature (MC4R)Hypogonadotropic hypogonadism (LEP)Red hair and hypoadrenalism (POMC)Disproportionate IR SH2B1 (173)

B. Lipodystrophy (generalized or partial, Table 2) Congenitally absent adipose tissue, or regional deficiency ofadipose tissue

Usually severe dyslipidemia, fatty liverLow adiponectin and leptin levels

a An alternative term for this cluster of disorders is insulin receptoropathies.b Affecting only some intracellular arms of the insulin signaling pathway, or variable among tissues.c In addition to frank obesity or lipodystrophy, there is a less well-defined group of disorders having clinical and biochemical evidence of adipose tissue failure andsevere dyslipidemia despite grossly normal whole body adipose tissue mass.



more than 100 allelic variants have now been described.These genetic insulin receptoropathies form a continuumof clinical severity but are best divided into two groups(Fig. 4). The first consists of rare and severe autosomalrecessive (AR) disorders presenting in the first decade oflife and usually classified, arbitrarily, as Donohue syn-drome (DS; formerly leprechaunism) or Rabson Men-denhall syndrome (RMS), based on the original clinicaldescriptions (80, 81). These syndromes have been welldescribed (40, 82). As well as fasting hypoglycemia, post-prandial hyperglycemia, and extreme hyperinsulinemia,their dominant features are markedly retarded lineargrowth, impairedmuscle and adipose tissue development,and overgrowth or precocious development of sex hor-mone-dependent tissues such as genitalia and nipples, andof other tissues including hair, skin, and viscera (Fig. 4).When -cells decompensate, hyperglycemia may becomerefractory to treatment. InDS, deathusually occurs duringintercurrent infection in infancy, whereas in RMS, ad-vanced microvascular complications or diabetic ketoaci-dosis are the commonest modes of death, usually in thesecond or third decade (40).

Some aspects of the DS phenotype remain to be fullyexplained. In particular, it remains to be determined de-finitivelywhy affected infants are resistant to ketoacidosisat least in the first year of life, even in those with no func-tional insulin receptor, although suggestions include con-tinued action of extremely elevated insulin on persistinghepatic IGF-I receptors in the immature liver or deficiencyof GH secretion or action (83).

More commonly, INSR defects present peripubertallyas oligomenorrhea and hyperandrogenism with acantho-sis nigricans (40). At presentation, hyperglycemia has of-ten yet to develop. In the prediabetic phase, males exhibitonly acanthosis nigricans and sometimes hypoglycemia,and they often remain undiagnosed even after the devel-opment of symptomatic diabetes, which may not occuruntil the fourth decade or beyond.

In some patients with DS or RMS, loss of INSR ex-pression from one allele has been identified and has beeninferred to be due to a mutation in a regulatory sequencesuch as the promoter (84). However, four patients withsevere IR and extremely low expression of both alleles ofthe INSR gene have also been described harboring eithera heterozygous deletion ormutation of theHMGA1 gene,but no mutations in the INSR gene (85). HMGA1 is anarchitectural transcription factor that binds to key sites inthe promoter of the INSR gene to facilitate its transcrip-tion. Based on the single report to date, these patientsappeared to share many characteristics of patients withINSR defects, consistent with the notion that a key func-tion for HMGA1 is the stimulation of INSR expression.

IX. Downstream Insulin Signaling Defects

Rapid progress in elucidating the key components of theinsulin signaling pathway in the early 1990s raised hopethat defects may be found in the genes encoding thesesignaling elements in patients with severe IR but withoutINSR mutations. However, few such sequence variantshave been reported in severe IR, and in most cases theresulting signaling defects in vitro have been subtle at best(8690).

One exceptionwas a single family in which threemem-bers carried a nonfunctional, heterozygous mutation inAKT2, encoding a critical serine/threonine kinase down-stream from the INSR in the signal transduction pathway(19). Clinical features seen in affected family membersincluded acanthosis nigricans, ovarian hyperandro-genism, diabetes mellitus presaged by several years ofpostprandial hypoglycemia, metabolic dyslipidemia, andfatty liver (19). The female proband also exhibited partiallipodystrophy, highlighting the role of insulin in adipo-genesis and the need for awareness that primary defects inthe insulin signaling cascade may impair adipose tissuegeneration in vivo. However, although a generalized de-ficiency in adipose tissue development is seen in severeinsulin receptoropathies, the metabolic characteristics ofthis differ dramatically fromthefat failurephenotypeofprimary generalized lipodystrophy, and they may moreappropriately be regarded as states of nonlipidated ratherthan absent adipose tissue.

More recently, a heterozygous nonsense mutation inAS160, a smallGTPase-activatingprotein that formsakeylink between insulin signaling and glucose uptake by theGLUT4 transporter, has been described in a family inwhomaffectedmembers had acanthosis nigricans anddis-proportionate hyperinsulinemia after a glucose challenge(91). Surprisingly, no other mutations have been found to

Fig. 4. Clinical spectrum of insulin receptoropathies.



date in other, more distal signaling components involvedin GLUT4 transporter translocation to the cell membranein response to insulin.

X. Disorders of Adipose Tissue Development/Function (Lipodystrophies)

Far more success has been had in identifying primary de-fects in adipose tissue that lead to severe IR as a secondaryconsequence. This probably reflects the fact that lipodys-trophy, in contrast to many other forms of severe IR, isrelatively easily recognized clinically, facilitating identifi-cation of extended families with multiple affected mem-bers for genetic studies (9296). The possibility of lipo-dystrophy should be carefully considered in all severelyinsulin-resistant patients with dyslipidemia and/or nonal-coholic fatty liver disease.

Lipodystrophy is a heterogeneous disorder character-ized by pathological adipose tissue deficiency. The lack offatmay be partial or generalized and inherited or acquiredin origin. Themolecular pathogenesis and clinical featuresof lipodystrophy have recently been reviewed (15, 97

101), are not covered in detail here, but are summarized inTable 2. Within the past 2 yr, three novel subtypes ofcongenital lipodystrophy were identified by a candidategene approach. Biallelic nonsense mutations in CAV1(102) and PTRF (103106) were identified in patientswith generalized lipodystrophy and inCIDEC in a patientwith partial lipodystrophy (107). Caveolins are essentialfor the formation of caveolae, which are abundant in adi-pocytes and appear to play a role in fatty acid uptake,insulin receptor signaling (108), and lipid droplet forma-tion (109). PTRF (polymerase 1 and transcript release fac-tor) stabilizes caveolins 13 and is required for the for-mation of caveolae (110, 111). CAV3 mutations areknown to cause muscular dystrophy (112), which prob-ably explains why PTRF mutations were also associatedwith a muscular dystrophy phenotype.

One female patient with partial lipodystrophy (affect-ing limb, femorogluteal, and sc abdominal fat), white adi-pocytes with multiloculated lipid droplets, and insulin-resistant diabetes was found to be homozygous for apremature truncation mutation in the lipid droplet pro-tein,CIDEC (cell death-inducingDNA fragmentation fac-

TABLE 2. Classification and clinical features of lipodystrophies

Inheritance Major clinical features Ref.

CGL Common features: severe IR, T2DM, severe dyslipidemia,fatty liver, pseudoacromegaly, PCOS

15

AGPAT2a AR Adiponectin levels are particularly low in this form ofCGL, whereas they are slightly higher (although stilllower than the reference range) in BSCL2-associatedCGL

67, 174

BSCL2a AR See note above 174CAV1a AR (single case) Short stature 102PTRFa AR Muscular dystrophy, modest metabolic disturbance (?) 103106

Familial partial lipodystrophy Common features: IR, T2DM, dyslipidemia, fatty liver,PCOS

LMNAa AD Preserved/excess facial and neck fat 15, 175PPARGa AD Preserved abdominal fat, hypertension (?) 18, 176, 177179ZMPSTE24a AR Mandibuloacral dysplasiaAKT2a AD (single family) 19CIDECa AR (single case) Preserved facial and neck fat, multiloculated lipid

droplets107

Acquired generalizedlipodystrophy

Common features: severe IR, T2DM, severe dyslipidemia,fatty liver, pseudoacromegaly, PCOS

14, 15

Associated with otherautoimmune diseases;commonly alsoassociated with low C4complement levels

N/A May be associated with juvenile dermatomyositis, SLE,autoimmune hemolytic anemia, autoimmunehepatitis. The low C4 complement subgroup isparticularly associated with autoimmune hepatitis andautoimmune hemolytic anemia.

11, 13, 14

Acquired partial lipodystrophy 14HIV-associated

lipodystrophyN/A Not typically associated with severe IR but is

associated with IR, dyslipidemia, fatty liver180

C3 nephritic factorassociated

N/A Cephalocaudal pattern of fat loss, low C3 complementlevels, MPGN, not usually insulin resistant, althoughmay become so if overweight

14

AD, Autosomal dominant; CGL, congenital generalized lipodystrophy; C3/4, complement factor 3/4; T2DM, type 2 diabetes mellitus; PCOS, polycystic ovary syndrome;MPGN, mesangioproliferative glomerulonephritis; N/A, not applicable; SLE, systemic lupus erythematosus.a Genetic subtype.



torA-like effector family-C) (107).Cidecknockdowncellsmanifest multiloculated lipid droplets with increased mi-tochondria (113), and in mice, Cidec deficiency also re-duces fat mass and induces the formation of white adi-pocytes with multilocular lipid droplets (114, 115).However, in contrast to the human phenotype associatedwith a homozygous loss of function mutation in CIDEC,Cidec null mice are protected against diet-induced obesityand IR (114116).BSCL2, an enigmatic geneof unknownfunction in which homozygous mutations were the firstidentified cause of congenital lipodystrophy (95), has alsorecently been implicated in lipid droplet biogenesis (117119) and adipocyte differentiation (120).

XI. Digenic IR

In 2002 (121),we described a family inwhich five severelyinsulin-resistant subjects and no unaffected relativeswere doubly heterozygous for frameshift/premature stopmutations in two unlinked genes, namely PPARG, a keyregulator of adipocyte biology, and PPP1R3A, a muscle-specific protein involved in regulating glycogen turnover(122125). This report was of particular interest becausethe observation that genetic defects inmolecules primarilyinvolved in either lipid or carbohydrate metabolism cancombine to result in an extreme phenotype of IR providesa model for the type of metabolic interaction that mayunderlie common forms of IR/type 2 diabetes.

XII. Complex Syndromes

Several genetic syndromes feature severe IR as part of awider constellation of abnormality (Table 3). In many of

these, the IR is related to severe obesity. However, thisgroup may roughly be divided into those conditions inwhich IR does not seem to be disproportionate to the de-gree of excess adiposity, such as genetically severe hy-perphagia due to congenital leptin deficiency (126), andthose in which IR appears unusually severe, suggesting arole for the defective genes concerned in systemic insulinsensitivity as well as in hypothalamic appetite control.However, in most cases this issue has not been rigorouslystudied. One well-established example is Alstrom syn-drome, which is due to genetic defects in the large centro-somal ALMS1 protein, where predominantly centripetaladiposity is associated with severely disproportionate IRand dyslipidemia (127).

Although the molecular pathogenesis of severe IR inAlstrom syndrome is not clear, it is notable that defects inthepericentrosomalproteinpericentrin, causingosteodys-plastic primordial dwarfism of Majewski type 2, are alsoassociated with highly penetrant severe IR (128), whichmay also be true in many cases of Bardet Biedl syndrome(129), caused by defects in a variety of proteins involvedin basal body/centrosomal function (130). Collectively,these observations hint at an important role for the cen-trosome or basal body, or the cellular functions they sub-serve, in maintaining metabolic homeostasis.

Another notable group of disorders that feature dis-proportionate and often severe IR are associated withDNA repair defects and/or progeria, including Wernersyndrome (131, 132), Bloom syndrome (133), and man-dibuloacral dysplasia (97, 134). In further DNA repairdefects such as ataxia telangiectasia, severe IR has beenreported in several molecularly defined cases (135, 136).However, the precise mechanism of severe IR in these set-tings has yet to be established.

TABLE 3. Selected complex genetic disorders associated with severe IR

Syndrome Gene(s)Adipose tissuephenotype

IR disproportionateto adiposity?

Cellular component orfunction affected

Alstrm ALMS1 Centripetal obesity Yes (127) Centrosome/ basal bodyMOPDII PCNT Centripetal fat

distributionYes (128) Centrosome/basal body

Bardet Biedl BBS1, BBS2, ARL6, BBS4, BBS5,MKKS, BBS7, BBS8, BBS9,BBS10, BBS11, BBS12,MKS1, CEP290

Obesity Unclear (129) Centrosome/basal body (130)

Bloom RECQ2 Lipodystrophy Yes (133) DNA repairWerner RECQL2 Lipodystrophy Yes (131132) DNA repair

LMNAMandibuloacral

dysplasiaLMNA Lipodystrophy Yes (97, 134) Involved in formation of nuclear

laminaZMPSTE24

Myotonicdystrophy

DMPK None Yes (181) Transcriptional/splicing regulationon chromosome 19, includingthe INSR (182)

MOPDII, Osteodysplastic primordial dwarfism of Majewski type II.



XIII. Therapy

The rarity and underdiagnosis of severe IR means thatalmost all therapeutic decisions are based on rational tar-geting of underlying defects and anecdotal evidence ratherthan randomized controlled trials. Therapy aims to reducehyperglycemia, to ameliorate dyslipidemia, and to lessenthe sometimes debilitating reproductive and cosmetic con-sequences of hyperinsulinemia. This is achieved firstthrough mitigation of the underlying signaling defect,through minimizing secretory demands on the pancreatic-cells, and throughoptimal delivery of exogenous insulinwhen required. In the context of adipose tissue absence ordysfunction, offloading adipose tissue by reducing lipiddelivery to it is also critical, and, finally, countering hy-perandrogenism, ovulatory dysfunction, and acanthosisnigricans by measures targeted at the relevant end organsis also often of value. The treatment of such secondarymanifestations of the IR state has been reviewed elsewhere(137, 138).

A. Dietary and lifestyle modificationIn severe IR, whether or not a single gene defect is iden-

tified, weight gain inevitably exacerbates metabolic de-rangement and either worsens hyperglycemia in patientswith overt diabetes or increases -cell stress, so restrictingenergy intake and maximizing aerobic exercise are essen-tial elements of management. This is particularly impor-tant in lipodystrophy where the apparent leanness of pa-tients frequently results in a failure of caregivers to placesufficient emphasis on dietary modification. Indeed, fail-ure to restrict energy intake in patientswith lipodystrophymakes it almost impossible to obtain good glycemic andlipidemic control.

B. Insulin sensitization and replacementInsulin-sensitizing agents also play a key role in man-

agement. Metformin is often effective, and in some casesthiazolidinediones also exert markedly beneficial effects,but no comparative studies exist to guide the choice oftherapy in different subgroups of severe IR. When -celldecompensation occurs in severe IR to produce diabetes,this is only relative to the very high insulin requirements,and plasma insulin levels remain extremely elevated. Thismeans that insulin secretagogues such as sulfonylureas of-ten produce little benefit. When insulin is required, thismay need to be used in concentrated form to achieve met-abolic control (139), and limited evidence suggests thatdelivery by sc infusion may be efficacious (140). Use ofrecombinant human IGF-I has been reportedmostly in thesetting of severe insulin receptoropathies and appears toimprove glycemia and perhaps survival in some infantilecases (141151). It may exert activity by acting as an in-

sulin mimetic, as a trophic factor for pancreatic -cells, orby enhancing insulin sensitivity through postreceptorcross talk between insulin and IGF-I signaling pathways.However, its dominant mode of action, optimal dosing,and clinical indications remain unclear.

C. Adipose tissue offloading

Minimizing caloric intake and hence strain on adiposestorage capacity is particularly difficult in lipodystrophybecause either absoluteor relative leptindeficiency, in gen-eralized and partial lipodystrophy, respectively, leads tohyperphagia (152). Recombinant leptin therapy substan-tially reduces food intake in this setting and dramaticallyimproves dyslipidemia, hepatic steatosis, and glycemiccontrol (153157). The response to leptin and dose titra-tion is largely based on clinical criteria because many pa-tients develop antibodies that interfere with leptin assays(158) but do not, on the whole, appear to reduce its long-term efficacy (159). Leptin has been used in all prevalentforms of generalized and familial partial lipodystrophy,with particularly dramatic results in the former (157). Ini-tial reports also suggest that it may be useful in at leastsome cases ofHIV-associated partial lipodystrophy (160),whereas a single study has also reported benefits in RMS(161). In principle, increasing oxidative catabolism of ex-cess calories may achieve the same benefits as limitingintake, as illustrated by the dramatically beneficial effectof suppressive doses of T4 in a patientwith an INSR defectwho also had a papillary thyroid carcinoma (162), but thisstrategy has yet to be developed safely for more wide-spread application.

Given the importance of restricting energy intake, par-ticularly in patients with lipodystrophy, other weight losstherapies used in obese diabetic patients, including gluca-gon-like peptide-1 agonists and appetite suppressants,have the potential to produce clinical benefits (163), andscattered reports have even suggested that bariatric sur-gery can be helpful in severe cases (164).

A complementary strategy to reducing the energy inputinto adipose tissue is to increase its storage capacity byusing insulin-sensitizing thiazolidinedione peroxisomeproliferator-activated receptor agonists. These were anobvious choice, particularly in lipodystrophywhere it washoped that they might restore fat mass. However, thiazo-lidinediones are not helpful in generalized lipodystrophyand exacerbate hepatic steatosis in animal models (165),and reports of their use in partial lipodystrophy conflict(166168).Our ownexperience is similar to that of Simhaet al. (167), who noted that fat tended to accumulate inresidual adipose depots, with modest metabolic benefits.



XIV. Summary

Genetic syndromes of severe IR, with or without lipodys-trophy, are underrecognized conditions that exact an im-mense toll of early morbidity and mortality for those af-fected. Considerable progress over the past 20 yr inidentifying the molecular basis of these disorders nowpresents the opportunity for trials or therapy targeted atspecific subgroups of these patients. It is anticipated thatthis will not only improve clinical outcomes for these rarepatients but will also give insights into the pathophysiol-ogy and therapy of more prevalent forms of IR.

Acknowledgments

Address all correspondence and requests for reprints to:Dr.R.K. Sempleor Dr. D. B. Savage, Metabolic Research Laboratories, Institute of Met-abolic Science, University of Cambridge, Addenbrookes Hospital, HillsRoad, Cambridge CB2 0QQ, United Kingdom. E-mail: [email protected] or [email protected].

This work was supported by research grants from the WellcomeTrust (Intermediate Clinical Fellowship 080952/Z/06/Z, to R.K.S.; Pro-gramme Grant 078986/Z/06/Z, to S.O.), GlaxoSmithKline (to D.B.S.),the UK National Institute for Health Research Cambridge BiomedicalResearch Centre, and the UKMedical Research Council Centre forObe-sity and Related Metabolic Disease.

Disclosure Summary: R.K.S., D.B.S., E.K.C., and P.G. have nothingto disclose. S.O. acts as a consultant in drug discovery for GlaxoSmith-Kline, Pfizer, and OSI Pharmaceuticals, Inc.

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Sindromes de Insulino Resistencia