Sindromes de Insulino Resistencia

R E V I E W
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 the most prevalent endocrine derangements in the world, and it is closely associated
with major diseases of global reach including diabetes mellitus, atherosclerosis, nonalcoholic fatty liver disease,
and ovulatory dysfunction. It is most commonly found in those with obesity but may also occur in an unusually
severe form in rare patients with monogenic defects. Such patients may loosely be grouped into those with
primary disorders of insulin signaling and those with defects in adipose tissue development or function (lipodystrophy). The severe insulin resistance of both subgroups puts patients at risk of accelerated complications and
poses severe challenges in clinical management. However, the clinical disorders produced by different genetic
defects are often biochemically and clinically distinct and are associated with distinct risks of complications. This
means that optimal management of affected patients should take into account the specific natural history of
each condition. In clinical practice, they are often underdiagnosed, however, with low rates of identification of
the underlying genetic defect, a problem compounded by confusing and overlapping nomenclature and classification. We now review recent developments in understanding of genetic forms of severe insulin resistance
and/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlying
pathophysiology. (Endocrine Reviews 32: 498 514, 2011)
I. Introduction
II. Definition and Prevalence of Severe IR
III. Generic Clinical Features of Severe IR
A. Abnormal glucose homeostasis
B. Ovarian dysfunction
C. Acanthosis nigricans
IV. Clinical Features Limited to Some Severe IR Subtypes
A. Dyslipidemia and hepatic steatosis
B. Abnormal adipose development or topography
C. Growth disorders
V. Sexual Dimorphism in Severe IR
VI. Biochemical Subphenotyping of Severe IR
VII. Monogenic IR Classification/Nomenclature
VIII. The INSR Spectrum
IX. Downstream Insulin Signaling Defects
X. Disorders of Adipose Tissue Development/Function
(Lipodystrophies)
XI. Digenic IR
XII. Complex Syndromes
XIII. Therapy
A. Dietary and lifestyle modification
B. Insulin sensitization and replacement
C. Adipose tissue offloading
XIV. Summary
nsulin resistance (IR), or more precisely the reduced responsiveness of the body to the glucose-lowering activity of insulin, is closely associated with some of the most
prevalent chronic clinical disorders, namely type 2 diabetes, atherosclerosis, polycystic ovarian syndrome, and hepatic steatosis. The population-wide toll of morbidity and
mortality attributable to IR is large and growing, in particular due to the consequences of coronary artery disease
(1), type 2 diabetes (2), polycystic ovary syndrome (3), and
fatty liver disease, and indeed IR is a cardinal feature of the
metabolic syndrome itself (4).
Although IR is a trait with significant heritability (5 8),
it is usually only clinically expressed in the context of obesity, especially where this has a predominantly centripetal
distribution. In a small number of patients, however, IR of
an unusually severe degree develops without obesity, or in
association with generalized or regional lack of adipose
tissue. Many such patients harbor pathogenic single gene
ISSN Print 0021-972X ISSN Online 1945-7197

Printed in U.S.A.
Copyright 2011 by The Endocrine Society
doi: 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-inducing DNA fragmentation factor
A-like effector family-C; DS, Donohue syndrome; IGFBP1, IGF binding protein-1; INSR, insulin
receptor; IR, insulin resistance; mTORC1, mammalian target of rapamycin complex 1; PTRF,
polymerase 1 and transcript release factor; RMS, Rabson Mendenhall syndrome.
498
edrv.endojournals.org
I. Introduction
Endocrine Reviews, August 2011, 32(4):498 514
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 25 September 2014. at 12:56 For personal use only. No other uses without permission. . All rights reserved.
mutations, and several of these have been identified in

recent years. These genetic defects may currently be
grouped into those affecting insulin signaling and those
affecting adipocyte development and/or function. Detailed physiological study of such patients with defined
genetic defects has begun to identify distinct subphenotypes of IR and has yielded insights into the mechanistic
basis of more prevalent forms of IR.
Severe IR may also arise through acquired, immunemediated mechanisms. These include antibodies against
either insulin or the insulin receptor leading to blockade of
insulin action (9) or autoimmune destruction of adipocytes leading to lipodystrophy (10, 11). Many, but not
all, 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 severe IR dates from early work on these syndromes in the
1970s (9, 16). We now describe the current state of knowledge of genetic forms of severe IR, suggest a refined classification based on recent findings, and review currently
available treatments.
II. Definition and Prevalence of Severe IR

Plasma insulin, whether determined in the fasting state or
after a glucose challenge, is a continuous variable, and so
thresholds used to diagnose IR and severe IR are arbitrary. Furthermore, such thresholds are only reliable before -cell decompensation has occurred. In entirely insulin-deficient individuals, severe IR may be defined solely in
terms of the body mass-adjusted requirements for exogenous insulin to maintain euglycemia, whereas in nondiabetic patients with compensated IR, severe IR may be defined solely in terms of plasma insulin levels before and/or
after a glucose challenge, with reference to data from a
control population. However, between these extremes, in
patients with relative rather than absolute insulin deficiency, diagnosis of severe IR is based on semiquantitative
assessment of the biochemical abnormality coupled with
clinical evidence of severe IR. A further complication is
that severe IR is most commonly seen in obese patients,
and yet they are a group far less likely to harbor single gene
defects. Similarly, puberty is a time of physiological IR,
and so ideally biochemical assessment of possible severe
IR should be made with reference to normative data derived from people of similar adiposity and developmental
stage. Subject to these caveats, a suggested working diagnostic scheme for likely monogenic severe IR is shown in
Fig. 1. This emphasizes that, whereas numerical determinants of severe IR have utility in the settings of normal
499
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 nondiabetic
population (n 800). The solid line represents the 50th centile, and
the dashed lines the 5th and 95th centiles. [Figure courtesy of Prof.
Nicholas J. Wareham.]
glycemia and absolute insulin deficiency, diagnosis in the

context of partial -cell decompensation, which is the
most common scenario, relies heavily on interpretation of
physical signs and clinical history. Although not widely
employed in current clinical practice, we have also found
a nomogram derived from a large, nondiabetic population, showing the relationship between body mass index
and insulin levels to be helpful in discriminating degrees of
IR in overweight/obese patients that are manifestly disproportionate to the degree of adiposity and are thus more likely
to have a contribution from a single gene defect (Fig. 1B).
These diagnostic complexities mean that severe IR is often
not recognized, especially in men. Furthermore, patients
present to many different clinical services according to their
dominant clinical problem, and for these reasons no population-based prevalence figures exist. However, clinical experience suggests that approximately 0.1 0.5% of patients
in hospital-based diabetes practices may have monogenic
forms of severe IR.
III. Generic Clinical Features of Severe IR

A. Abnormal glucose homeostasis
Clinical awareness of IR is greatest among those caring for patients with established diabetes mellitus, where
it is recognized most commonly by a requirement for large
500
Semple et al.
Severe Insulin Resistance Syndromes
doses of exogenous insulin. However, hyperglycemia is

not usually the earliest clinical manifestation of severe IR.
It may be recognized much earlier by the presence of acanthosis nigricans and/or ovarian hyperandrogenism in
women. Furthermore, symptomatic hypoglycemia often
precedes hyperglycemia, sometimes by many years. Characteristically, hypoglycemia related to severe IR occurs
postprandially, with autonomic symptoms sometimes
progressing to neuroglycopenia and seizures if not abrogated
by oral carbohydrate. Such severe postprandial hypoglycemia may be seen in patients with insulin receptor defects (17),
insulin signal transduction defects, or primary lipodystrophies (18, 19). Its mechanism is unclear, but it most likely
relates to severe impairment of hepatic insulin clearance due
primarily to a insulin receptor defect or secondarily to the
consequences of hepatic steatosis (20).
Even in the context of severe loss of insulin receptor
function, hyperplasia of pancreatic -cells, with attendant
extreme hyperinsulinemia, may prevent hyperglycemia
for many years, indicating that the receptor on islets themselves is not a prerequisite for -cell expansion, as suggested by some murine studies (21). However, in most
cases pancreatic -cell hyperplasia does eventually fail to
compensate for severe IR, and hyperglycemia ensues.
Commonly, hyperglycemia diagnostic of diabetes is only
seen after an oral glucose challenge, contrasting with fasting hypoglycemia or normoglycemia, making fasting glucose alone an inadequate diagnostic test for diabetes in the
context of severe IR. Compounding this, glycosylated hemoglobin may be normal, or even low, at the time when
postload glucose levels are diagnostic of diabetes. Although these observations suggest that the various current
diagnostic criteria for diabetes may have different utilities
in predicting risk of diabetic complications in severe IR,
this has not yet been studied. The time taken to -cell
decompensation varies substantially, with diabetes developing in the neonatal period in the most severe cases and
in the fourth decade or beyond at the milder end of the
spectrum, especially in men.
B. Ovarian dysfunction
Severe IR most commonly presents to clinical attention

first as oligomenorrhea and severe hyperandrogenism in
young women after menarche, although the underlying
hyperinsulinemia is often not recognized. Ovarian ultrasonography usually reveals multiple peripheral cysts as
seen in idiopathic polycystic ovary syndrome. In severe
cases, cysts may become very large and vulnerable to hemorrhage or torsion, and surgical removal may be required,
sometimes in infancy (Fig. 2). Hyperandrogenism in IR
may be severe, with testosterone levels above 10 nmol/liter
sometimes seen, well in excess of thresholds commonly
Fig. 2. Ovarian appearances in severe IR. A, Ultrasound appearance

of an ovary in a 14-yr-old patient with severe IR due to a heterozygous
mutation in the insulin receptor. B, Perioperative appearance of large
ovarian and Fallopian tube cysts in a patient with digenic severe IR due
to heterozygous mutations in the PPARG and PPP1R3A genes (121). C
and D, Ovarian histology of the same patient, showing prominent
sclerosis of the superficial ovarian cortex associated with multiple
follicle cysts (C) and stromal hyperthecosis with nests of eosinophilic
luteinized cells (arrows) (D) embedded in hyalinized ovarian stroma.
[Histological images courtesy of Dr. Merche Jimenez-Linan.]
reported to discriminate virilizing tumors from nontumoral hyperandrogenism (22).

The ovarian hyperandrogenism of IR is driven by synergy between gonadotropin and insulin action on the
ovary (23, 24). Thus, it may be clinically apparent during
both infancy and postpubertal life, when the hypothalamic-pituitary-gonadal axis is fully active, and it may also
accelerate puberty (25). Severe ovarian hyperandrogenism
may occur postmenopausally, in which case ovarian histology characteristically reveals hyperthecosis, or hyperplasia of the androgen-secreting theca cells (26). However,
hyperandrogenism is not seen, despite extreme hyperinsulinemia, when insulin receptor function is lost for the
first time postmenopausally (12), suggesting that hyperinsulinemia around the time of the menopause may be
necessary to sustain androgen-secreting theca cells.
The main differential diagnosis of IR-related severe hyperandrogenism is congenital adrenal hyperplasia or an
androgen-secreting tumor, but in these cases acanthosis
nigricans is not usually prominent unless the patient is also
overweight or obese. Although congenital adrenal hyperplasia is easily diagnosed biochemically, discriminating autonomous androgen secretion and hence virilizing tumors may
be more challenging (27). A complicating consideration is
that ovarian tumors may arise in the context of sustained
severe hyperinsulinemia, most likely due to chronic activation of IGF-I receptor-mediated signaling (28).
C. Acanthosis nigricans
Another feature of nearly all known forms of severe IR

is acanthosis nigricans, a velvety thickening of the skin. It
is usually found in the axillae, nape of the neck, and groin,

but it can occur in any flexures and in the most extreme
cases may be periocular, perioral, perianal, or even occur
on planar surfaces (Fig. 3). It is commonly associated with
acrochordons (skin tags). Histologically, acanthosis nigricans is characterized by hyperkeratosis, sometimes with
hyperpigmentation, as well as mild papillomatosis, suggesting that both keratinocytes and dermal fibroblasts are
affected (29). The precise pathogenesis is unclear, but it
may also rarely be found in congenital syndromes without
IR (29) or as a paraneoplastic syndrome (30), and several
lines of evidence suggest that enhanced signaling through
mitogenic tyrosine kinase-type receptors including the
IGF-I receptor plays a central role (29, 31). In IR, acanthosis depends on hyperinsulinemia, and this is not seen in
the rare situation of pre receptor IR due to unusually
high levels of anti-insulin antibodies in those receiving
exogenous insulin therapy (32). Fading of acanthosis indicates a reduction in insulin levels either due to lessening
of IR or, conversely, worsening of -cell failure. Acanthosis nigricans may become excoriated and/or infected, and
in concert with IR-related hyperandrogenism may contribute to hydradenitis suppurativa (33).
501
whether due to a primary signaling defect or due to lipodystrophy. Some features of severe IR syndromes, in contrast, are seen in only some subtypes.
A. Dyslipidemia and hepatic steatosis
Hypertriglyceridemia and low high-density lipoprotein

cholesterol levels (hereafter designated metabolic dyslipidemia) are closely associated with prevalent forms of IR
(34 37) and are seen in more severe form also in patients
with severe monogenic IR. Indeed, in some cases, hypertriglyceridemia may be complicated by pancreatitis and
eruptive xanthomata, and hepatic steatosis may progress
to steatohepatitis, cirrhosis, and hepatocellular carcinoma
(38). The presence of significant dyslipidemia and hepatic
steatosis is a sensitive but nonspecific clinical indicator of
underlying lipodystrophy. Their absence in a patient with
severe IR is suggestive of a primary insulin receptoropathy
(39, 40). Recently published mouse data (41 43), supported by our own observations in patients with severe IR
(39), suggest that hepatic steatosis and dyslipidemia are a
consequence of selective postreceptor (or partial-) hepatic
IR (44).
B. Abnormal adipose development or topography
IV. Clinical Features Limited to Some Severe

IR Subtypes
All the above are seen in severe IR irrespective of underlying etiology, whether congenital or acquired, and
Lipodystrophy is a common cause of severe IR and

should be considered in all cases. The fact that fat mass in
lean women is close to double that in lean men, coupled
with the readily recognizable femorogluteal depot usually
present 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 of
a 15-yr-old boy with severe IR due to a heterozygous INSR mutation (C), on the foot of a patient with congenital generalized lipodystrophy and
severe IR due to homozygous AGPAT2 mutations (D), on the knuckles in a prepubertal patient with severe IR of unknown cause (E), and on the
neck of a prepubertal girl with RMS due to a homozygous INSR mutation (F). G, Histological appearances from a nuchal skin biopsy showing
characteristic papillomatosis (solid arrows), hyperkeratosis, and some acanthosis (open arrow). [Histological image courtesy of Dr. Ed Rytina.]
502
Semple et al.
more readily detected in women than men. Lean athletic

men can be very difficult to distinguish from lipodystrophic men, particularly those with partial lipodystrophy.
C. Growth disorders
Severe IR per se may be associated with a range of

growth disorders, including linear growth impairment
(40, 45), prepubertal linear growth acceleration (46), or
pseudoacromegalic soft tissue overgrowth in adulthood (4750). Although the precise molecular basis of this
close association between severe IR and growth abnormalities has yet to be determined, it may well relate to
perturbation of the cross talk between the endocrine axis
controlling growth and insulin action, or perhaps to abnormal paracrine action of IGF-I or IGF-II (45). Both
IGF-I, the major hormone driving linear growth, and IGFII, which is an important determinant of growth in utero,
but which remains present at high levels in serum in postnatal life in humans but not rodents, exert mitogenic effects through the IGF-I receptor and also have significant
ability to stimulate the insulin receptor. Insulin, conversely, is able to stimulate the IGF-I receptor at concentrations seen in extreme hyperinsulinemia (51, 52). Added
to this direct cross talk, insulin or IR has been shown in a
variety of contexts to influence action of IGF through alterations in expression of the ligands themselves, of their
binding proteins, or of their receptors (53). These observations have yet to be synthesized into a coherent model
accounting for growth abnormalities in severe IR; however, improving understanding of these phenomena will
not only be of relevance to these rare conditions, but may
also give mechanistic insights into the link between common obesity/IR and both the prevalence and prognosis of
a variety of different cancers (52, 54, 55).
V. Sexual Dimorphism in Severe IR

A prominent feature of severe IR is the earlier presentation
and more severe metabolic derangement seen in affected
women (56). A major contributor to this is hyperinsulinemia-driven ovarian dysfunction, with hyperandrogenism
and oligomenorrhea serving as clinical red flags that lead
to early presentation (57). Men, in contrast, exhibit only
acanthosis nigricans, and sometimes symptomatic postprandial hypoglycemia. Even if noticed, these are much
less likely to lead to medical consultation. However,
women also have much more severe hyperinsulinemia and
dyslipidemia than men. In lipodystrophy, this is almost
certainly explained at least in part by the larger amount of
white adipose tissue as a proportion of total body mass in
healthy women.
VI. Biochemical Subphenotyping of Severe IR

Growing evidence suggests that some syndromes of severe IR exhibit different patterns of IR among insulinresponsive tissues and pathways. Thus, the generalized IR
of insulin receptor (INSR) defects is associated with a normal lipid profile and relative lack of fatty liver (39, 40),
suggesting that some insulin signaling is needed to drive
hepatic fat synthesis and secretion. This is quite unlike the
situation in patients with lipodystrophy or with defects in
the insulin signal transducer AKT2, all of whom show
severe dyslipidemia and fatty liver (39).
The mechanisms linking hyperinsulinemia in prevalent
forms of IR and fatty liver/dyslipidemia are of particular
importance, given the enormous associated prevalence of
atherosclerosis, and are the subject of intense investigation. Full consideration of progress in the field is beyond
the scope of this article; however, recent cell-based studies
have strongly implicated activation of the mammalian target of rapamycin complex 1 (mTORC1), hitherto widely
perceived to be predominantly a mediator of insulins
actions on cell growth, in driving hepatic de novo lipogenesis in response to insulin (58 60). Such up-regulation of hepatic lipogenesis has been suggested to be a
significant contributor to fatty liver and atherogenic
dyslipidemia in humans (61, 62), whereas aberrant activation of mTORC1 is well documented in IR (63),
potentially explaining why lipogenesis appears to be increased in these states. However, many critical questions
remain to be answered, including whether enhanced de
novo lipogenesis in IR may truly be explained as a hepatocyte autonomous phenomenon related to resistance to
only some of insulins cellular effects, or whether it may
instead reflect parallel hyperactivation of mTORC1 by
increased delivery to hepatocytes of, for example,
branched chain amino acids, which have been reported to
be elevated in many forms of IR (59, 64, 65).
INSR defects may also be discriminated from other
forms of IR by unexpectedly high adiponectin (66 68),
SHBG (69), and IGF binding protein-1 (IGFBP1) (70) levels, providing further evidence that in prevalent forms of
IR (7173), in lipodystrophies (15, 67), and in nonreceptoropathy severe IR (70, 74), where the levels of these
proteins are usually reduced, hyperinsulinemia is able to
exert effects through intact elements of the cellular insulin
signal transduction network to suppress gene expression
in both adipose tissue and liver (62, 75). Parenthetically,
because adiponectin is nearly exclusively expressed in adipose tissue and because circulating SHBG and IGFBP1 are
products of hepatic expression, determination of these
markers in states of IR may also allow assessment to be
made of the insulinization of distinct insulin target tissues
in future, enhancing clinical ability to discern any organselective forms of severe IR.
This concept of IR subphenotypes has been exploited
diagnostically by using it to subclassify IR and target genetic screening, greatly enhancing efficiency of molecular
diagnosis of INSR defects (68, 70). Thus, in the context of
severe IR, we have found that adiponectin levels above 7
mg/liter have a 97% positive predictive value for insulin
receptoropathy (70), although the precise cutoff is assayspecific. SHBG and IGFBP1 levels have lesser, although
still significant, utility.
VII. Monogenic IR Classification/Nomenclature

The nomenclature in the field of severe IR dates from the
1970s. Then, in seminal publications, Kahn and colleagues (9, 16) designated severe IR in nonobese patients
as type A or type B, the latter discriminated by the
presence of anti-insulin receptor antibodies. In a series of
independent publications around the same time, the term
HAIR-AN came to be used commonly (76). However,
HAIR-AN (hyperandrogenism, insulin resistance, and
acanthosis nigricans) is an entirely generic description of
severe IR in women. If it has any utility, it is where it is used
to discriminate women with severe IR who also have a
body mass index above 30 kg/m2, who are much less likely
to harbor pathogenic single gene defects than their nonobese counterparts. However, the imprecise and overlapping usage of these different diagnostic terms and increasing understanding of subgroups of severe IR suggest that
a reclassification of syndromes of severe IR may be timely.
Based on the above observations, such a classification is
suggested in Table 1.
503
The key subdivision in this proposed mechanism-based

classification is between those disorders in which there is
a primary defect in canonical insulin signal transduction
and those in which severe IR is a consequence of adipose
tissue abnormalities, or adipose failure. Primary IR is
then subdivided into generalized IR, in which there is a
defect at the level of the insulin receptor, and biochemically distinguishable partial IR, in which there is a signaling defect that is limited either to only some parts of the
postreceptor signal transduction pathway or to some tissues. Few examples of this group currently exist, but it is
to be anticipated that increased recognition of this group,
allied to modern sequencing technologies, will lead to further examples and refinement of this subgroup.
Adipose failure may also be subdivided into a group
with manifest lipodystrophy, in which there is a deficiency
in generating adipose tissue, leading to severe IR despite
low or normal adipose tissue mass, and a group in which
the dominant defect is unrestrained accumulation of adipose tissue, most commonly due to hyperphagia, such
that even a relatively normal capacity safely to accrue triglyceride in adipose tissue is overcome.
Severe IR is also seen in a group of complex disorders
(see Table 3), in association with other defects; however,
because the IR in these conditions is subjected to mechanistic study with the above framework in mind, we anticipate that they may be accommodated within one of the
two 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 defects
A. Generalizeda INSR mutations (40) or anti-INSR antibodies (12)
B. Partialb AKT2 (19), AS160 (91, 169), others to be defined
II. Secondary to adipose tissue abnormalitiesc
A. Severe obesity e.g., MC4R (170), POMC (171), LEP (126), LEPR (172),
SH2B1 (173)
B. Lipodystrophy (generalized or partial, Table 2)
Extreme hyperinsulinemia but normal lipid profile (39, 40),

preserved or elevated adiponectin, SHBG, and IGFBP1 (70)
Likely to depend upon precise signaling defect
Early onset severe, hyperphagic obesity
Tall stature (MC4R)
Hypogonadotropic hypogonadism (LEP)
Red hair and hypoadrenalism (POMC)
Disproportionate IR SH2B1 (173)
Congenitally absent adipose tissue, or regional deficiency of
adipose tissue
Usually severe dyslipidemia, fatty liver
Low adiponectin and leptin levels
An alternative term for this cluster of disorders is insulin receptoropathies.
Affecting only some intracellular arms of the insulin signaling pathway, or variable among tissues.
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 and
severe dyslipidemia despite grossly normal whole body adipose tissue mass.
504
Semple et al.
Fig. 4. Clinical spectrum of insulin receptoropathies.
more than 100 allelic variants have now been described.

These genetic insulin receptoropathies form a continuum
of clinical severity but are best divided into two groups
(Fig. 4). The first consists of rare and severe autosomal
recessive (AR) disorders presenting in the first decade of
life and usually classified, arbitrarily, as Donohue syndrome (DS; formerly leprechaunism) or Rabson Mendenhall syndrome (RMS), based on the original clinical
descriptions (80, 81). These syndromes have been well
described (40, 82). As well as fasting hypoglycemia, postprandial hyperglycemia, and extreme hyperinsulinemia,
their dominant features are markedly retarded linear
growth, impaired muscle and adipose tissue development,
and overgrowth or precocious development of sex hormone-dependent tissues such as genitalia and nipples, and
of other tissues including hair, skin, and viscera (Fig. 4).
When -cells decompensate, hyperglycemia may become
refractory to treatment. In DS, death usually occurs during
intercurrent infection in infancy, whereas in RMS, advanced microvascular complications or diabetic ketoacidosis are the commonest modes of death, usually in the
second or third decade (40).
Some aspects of the DS phenotype remain to be fully
explained. In particular, it remains to be determined definitively why affected infants are resistant to ketoacidosis
at least in the first year of life, even in those with no functional insulin receptor, although suggestions include continued action of extremely elevated insulin on persisting
hepatic IGF-I receptors in the immature liver or deficiency
of GH secretion or action (83).
More commonly, INSR defects present peripubertally
as oligomenorrhea and hyperandrogenism with acanthosis nigricans (40). At presentation, hyperglycemia has often yet to develop. In the prediabetic phase, males exhibit
only acanthosis nigricans and sometimes hypoglycemia,
and they often remain undiagnosed even after the development of symptomatic diabetes, which may not occur
until the fourth decade or beyond.
In some patients with DS or RMS, loss of INSR expression from one allele has been identified and has been
inferred to be due to a mutation in a regulatory sequence
such as the promoter (84). However, four patients with
severe IR and extremely low expression of both alleles of
the INSR gene have also been described harboring either
a heterozygous deletion or mutation of the HMGA1 gene,
but no mutations in the INSR gene (85). HMGA1 is an
architectural transcription factor that binds to key sites in
the promoter of the INSR gene to facilitate its transcription. Based on the single report to date, these patients
appeared to share many characteristics of patients with
INSR defects, consistent with the notion that a key function for HMGA1 is the stimulation of INSR expression.
IX. Downstream Insulin Signaling Defects

Rapid progress in elucidating the key components of the
insulin signaling pathway in the early 1990s raised hope
that defects may be found in the genes encoding these
signaling elements in patients with severe IR but without
INSR mutations. However, few such sequence variants
have been reported in severe IR, and in most cases the
resulting signaling defects in vitro have been subtle at best
(86 90).
One exception was a single family in which three members carried a nonfunctional, heterozygous mutation in
AKT2, encoding a critical serine/threonine kinase downstream from the INSR in the signal transduction pathway
(19). Clinical features seen in affected family members
included acanthosis nigricans, ovarian hyperandrogenism, diabetes mellitus presaged by several years of
postprandial hypoglycemia, metabolic dyslipidemia, and
fatty liver (19). The female proband also exhibited partial
lipodystrophy, highlighting the role of insulin in adipogenesis and the need for awareness that primary defects in
the insulin signaling cascade may impair adipose tissue
generation in vivo. However, although a generalized deficiency in adipose tissue development is seen in severe
insulin receptoropathies, the metabolic characteristics of
this differ dramatically from the fat failure phenotype of
primary generalized lipodystrophy, and they may more
appropriately be regarded as states of nonlipidated rather
than absent adipose tissue.
More recently, a heterozygous nonsense mutation in
AS160, a small GTPase-activating protein that forms a key
link between insulin signaling and glucose uptake by the
GLUT4 transporter, has been described in a family in
whom affected members had acanthosis nigricans and disproportionate hyperinsulinemia after a glucose challenge
(91). Surprisingly, no other mutations have been found to
date in other, more distal signaling components involved

in GLUT4 transporter translocation to the cell membrane
in response to insulin.
X. Disorders of Adipose Tissue Development/

Function (Lipodystrophies)
Far more success has been had in identifying primary defects in adipose tissue that lead to severe IR as a secondary
consequence. This probably reflects the fact that lipodystrophy, in contrast to many other forms of severe IR, is
relatively easily recognized clinically, facilitating identification of extended families with multiple affected members for genetic studies (9296). The possibility of lipodystrophy should be carefully considered in all severely
insulin-resistant patients with dyslipidemia and/or nonalcoholic fatty liver disease.
Lipodystrophy is a heterogeneous disorder characterized by pathological adipose tissue deficiency. The lack of
fat may be partial or generalized and inherited or acquired
in origin. The molecular pathogenesis and clinical features
of lipodystrophy have recently been reviewed (15, 97
505
101), are not covered in detail here, but are summarized in

Table 2. Within the past 2 yr, three novel subtypes of
congenital lipodystrophy were identified by a candidate
gene approach. Biallelic nonsense mutations in CAV1
(102) and PTRF (103106) were identified in patients
with generalized lipodystrophy and in CIDEC in a patient
with partial lipodystrophy (107). Caveolins are essential
for the formation of caveolae, which are abundant in adipocytes and appear to play a role in fatty acid uptake,
insulin receptor signaling (108), and lipid droplet formation (109). PTRF (polymerase 1 and transcript release factor) stabilizes caveolins 13 and is required for the formation of caveolae (110, 111). CAV3 mutations are
known to cause muscular dystrophy (112), which probably explains why PTRF mutations were also associated
with a muscular dystrophy phenotype.
One female patient with partial lipodystrophy (affecting limb, femorogluteal, and sc abdominal fat), white adipocytes with multiloculated lipid droplets, and insulinresistant diabetes was found to be homozygous for a
premature truncation mutation in the lipid droplet protein, CIDEC (cell death-inducing DNA fragmentation fac-
TABLE 2. Classification and clinical features of lipodystrophies

Inheritance
CGL
AGPAT2a
BSCL2a
CAV1a
PTRFa
Familial partial lipodystrophy
LMNAa
PPARGa
ZMPSTE24a
AKT2a
CIDECa
Acquired generalized
lipodystrophy
Associated with other
autoimmune diseases;
commonly also
associated with low C4
complement levels
Acquired partial lipodystrophy
HIV-associated
lipodystrophy
C3 nephritic factor
associated
AR
AR
AR (single case)
AR
AD
AD
AR
AD (single family)
AR (single case)
N/A
N/A
N/A
Major clinical features
Ref.
Common features: severe IR, T2DM, severe dyslipidemia,

fatty liver, pseudoacromegaly, PCOS
Adiponectin levels are particularly low in this form of
CGL, whereas they are slightly higher (although still
lower than the reference range) in BSCL2-associated
CGL
See note above
Short stature
Muscular dystrophy, modest metabolic disturbance (?)
Common features: IR, T2DM, dyslipidemia, fatty liver,
PCOS
Preserved/excess facial and neck fat
Preserved abdominal fat, hypertension (?)
Mandibuloacral dysplasia
15
Preserved facial and neck fat, multiloculated lipid

droplets
Common features: severe IR, T2DM, severe dyslipidemia,
fatty liver, pseudoacromegaly, PCOS
May be associated with juvenile dermatomyositis, SLE,
autoimmune hemolytic anemia, autoimmune
hepatitis. The low C4 complement subgroup is
particularly associated with autoimmune hepatitis and
autoimmune hemolytic anemia.
Not typically associated with severe IR but is
associated with IR, dyslipidemia, fatty liver
Cephalocaudal pattern of fat loss, low C3 complement
levels, MPGN, not usually insulin resistant, although
may become so if overweight
67, 174
174
102
103106
15, 175
18, 176, 177179
19
107
14, 15
11, 13, 14
14
180
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.
506
Semple et al.
tor A-like effector family-C) (107). Cidec knockdown cells

manifest multiloculated lipid droplets with increased mitochondria (113), and in mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets (114, 115).
However, in contrast to the human phenotype associated
with a homozygous loss of function mutation in CIDEC,
Cidec null mice are protected against diet-induced obesity
and IR (114 116). BSCL2, an enigmatic gene of unknown
function in which homozygous mutations were the first
identified cause of congenital lipodystrophy (95), has also
recently been implicated in lipid droplet biogenesis (117
119) and adipocyte differentiation (120).
XI. Digenic IR
In 2002 (121), we described a family in which five severely
insulin-resistant subjects and no unaffected relatives
were doubly heterozygous for frameshift/premature stop
mutations in two unlinked genes, namely PPARG, a key
regulator of adipocyte biology, and PPP1R3A, a musclespecific protein involved in regulating glycogen turnover
(122125). This report was of particular interest because
the observation that genetic defects in molecules primarily
involved in either lipid or carbohydrate metabolism can
combine to result in an extreme phenotype of IR provides
a model for the type of metabolic interaction that may
underlie common forms of IR/type 2 diabetes.
XII. Complex Syndromes

Several genetic syndromes feature severe IR as part of a
wider constellation of abnormality (Table 3). In many of
these, the IR is related to severe obesity. However, this

group may roughly be divided into those conditions in
which IR does not seem to be disproportionate to the degree of excess adiposity, such as genetically severe hyperphagia due to congenital leptin deficiency (126), and
those in which IR appears unusually severe, suggesting a
role for the defective genes concerned in systemic insulin
sensitivity as well as in hypothalamic appetite control.
However, in most cases this issue has not been rigorously
studied. One well-established example is Alstrom syndrome, which is due to genetic defects in the large centrosomal ALMS1 protein, where predominantly centripetal
adiposity is associated with severely disproportionate IR
and dyslipidemia (127).
Although the molecular pathogenesis of severe IR in
Alstrom syndrome is not clear, it is notable that defects in
the pericentrosomal protein pericentrin, causing osteodysplastic primordial dwarfism of Majewski type 2, are also
associated with highly penetrant severe IR (128), which
may also be true in many cases of Bardet Biedl syndrome
(129), caused by defects in a variety of proteins involved
in basal body/centrosomal function (130). Collectively,
these observations hint at an important role for the centrosome or basal body, or the cellular functions they subserve, in maintaining metabolic homeostasis.
Another notable group of disorders that feature disproportionate and often severe IR are associated with
DNA repair defects and/or progeria, including Werner
syndrome (131, 132), Bloom syndrome (133), and mandibuloacral dysplasia (97, 134). In further DNA repair
defects such as ataxia telangiectasia, severe IR has been
reported in several molecularly defined cases (135, 136).
However, the precise mechanism of severe IR in these settings has yet to be established.
TABLE 3. Selected complex genetic disorders associated with severe IR

Syndrome
Gene(s)
Alstrm
MOPDII
ALMS1
PCNT
Bardet Biedl
BBS1, BBS2, ARL6, BBS4, BBS5,

MKKS, BBS7, BBS8, BBS9,
BBS10, BBS11, BBS12,
MKS1, CEP290
RECQ2
RECQL2
LMNA
LMNA
Bloom
Werner
Mandibuloacral
dysplasia
Myotonic
dystrophy
ZMPSTE24
DMPK
Adipose tissue
phenotype
IR disproportionate
to adiposity?
Cellular component or
function affected
Centripetal obesity
Centripetal fat
distribution
Obesity
Yes (127)
Yes (128)
Centrosome/ basal body

Centrosome/basal body
Unclear (129)
Centrosome/basal body (130)
Lipodystrophy
Lipodystrophy
Yes (133)
Yes (131132)
DNA repair
DNA repair
Lipodystrophy
Yes (97, 134)
Involved in formation of nuclear

lamina
None
Yes (181)
Transcriptional/splicing regulation
on chromosome 19, including
the INSR (182)
MOPDII, Osteodysplastic primordial dwarfism of Majewski type II.
XIII. Therapy
The rarity and underdiagnosis of severe IR means that
almost all therapeutic decisions are based on rational targeting of underlying defects and anecdotal evidence rather
than randomized controlled trials. Therapy aims to reduce
hyperglycemia, to ameliorate dyslipidemia, and to lessen
the sometimes debilitating reproductive and cosmetic consequences of hyperinsulinemia. This is achieved first
through mitigation of the underlying signaling defect,
through minimizing secretory demands on the pancreatic
-cells, and through optimal delivery of exogenous insulin
when required. In the context of adipose tissue absence or
dysfunction, offloading adipose tissue by reducing lipid
delivery to it is also critical, and, finally, countering hyperandrogenism, ovulatory dysfunction, and acanthosis
nigricans by measures targeted at the relevant end organs
is also often of value. The treatment of such secondary
manifestations of the IR state has been reviewed elsewhere
(137, 138).
A. Dietary and lifestyle modification
In severe IR, whether or not a single gene defect is identified, weight gain inevitably exacerbates metabolic derangement and either worsens hyperglycemia in patients
with overt diabetes or increases -cell stress, so restricting
energy intake and maximizing aerobic exercise are essential elements of management. This is particularly important in lipodystrophy where the apparent leanness of patients frequently results in a failure of caregivers to place
sufficient emphasis on dietary modification. Indeed, failure to restrict energy intake in patients with lipodystrophy
makes it almost impossible to obtain good glycemic and
lipidemic control.
B. Insulin sensitization and replacement
Insulin-sensitizing agents also play a key role in management. Metformin is often effective, and in some cases
thiazolidinediones also exert markedly beneficial effects,
but no comparative studies exist to guide the choice of
therapy in different subgroups of severe IR. When -cell
decompensation occurs in severe IR to produce diabetes,
this is only relative to the very high insulin requirements,
and plasma insulin levels remain extremely elevated. This
means that insulin secretagogues such as sulfonylureas often produce little benefit. When insulin is required, this
may need to be used in concentrated form to achieve metabolic control (139), and limited evidence suggests that
delivery by sc infusion may be efficacious (140). Use of
recombinant human IGF-I has been reported mostly in the
setting of severe insulin receptoropathies and appears to
improve glycemia and perhaps survival in some infantile
cases (141151). It may exert activity by acting as an in-
507
sulin mimetic, as a trophic factor for pancreatic -cells, or

by enhancing insulin sensitivity through postreceptor
cross 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 adipose

storage capacity is particularly difficult in lipodystrophy
because either absolute or relative leptin deficiency, in generalized and partial lipodystrophy, respectively, leads to
hyperphagia (152). Recombinant leptin therapy substantially reduces food intake in this setting and dramatically
improves dyslipidemia, hepatic steatosis, and glycemic
control (153157). The response to leptin and dose titration is largely based on clinical criteria because many patients develop antibodies that interfere with leptin assays
(158) but do not, on the whole, appear to reduce its longterm efficacy (159). Leptin has been used in all prevalent
forms of generalized and familial partial lipodystrophy,
with particularly dramatic results in the former (157). Initial reports also suggest that it may be useful in at least
some cases of HIV-associated partial lipodystrophy (160),
whereas a single study has also reported benefits in RMS
(161). In principle, increasing oxidative catabolism of excess calories may achieve the same benefits as limiting
intake, as illustrated by the dramatically beneficial effect
of suppressive doses of T4 in a patient with an INSR defect
who also had a papillary thyroid carcinoma (162), but this
strategy has yet to be developed safely for more widespread application.
Given the importance of restricting energy intake, particularly in patients with lipodystrophy, other weight loss
therapies used in obese diabetic patients, including glucagon-like peptide-1 agonists and appetite suppressants,
have the potential to produce clinical benefits (163), and
scattered reports have even suggested that bariatric surgery can be helpful in severe cases (164).
A complementary strategy to reducing the energy input
into adipose tissue is to increase its storage capacity by
using insulin-sensitizing thiazolidinedione peroxisome
proliferator-activated receptor agonists. These were an
obvious choice, particularly in lipodystrophy where it was
hoped that they might restore fat mass. However, thiazolidinediones are not helpful in generalized lipodystrophy
and exacerbate hepatic steatosis in animal models (165),
and reports of their use in partial lipodystrophy conflict
(166 168). Our own experience is similar to that of Simha
et al. (167), who noted that fat tended to accumulate in
residual adipose depots, with modest metabolic benefits.
508
Semple et al.
XIV. Summary
Genetic syndromes of severe IR, with or without lipodystrophy, are underrecognized conditions that exact an immense toll of early morbidity and mortality for those affected. Considerable progress over the past 20 yr in
identifying the molecular basis of these disorders now
presents the opportunity for trials or therapy targeted at
specific subgroups of these patients. It is anticipated that
this will not only improve clinical outcomes for these rare
patients but will also give insights into the pathophysiology and therapy of more prevalent forms of IR.
8.
9.
10.
11.
Acknowledgments
Address all correspondence and requests for reprints to: Dr. R. K. Semple
or Dr. D. B. Savage, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrookes Hospital, Hills
Road, Cambridge CB2 0QQ, United Kingdom. E-mail: rks16@cam.
ac.uk or dbs23@medschl.cam.ac.uk.
This work was supported by research grants from the Wellcome
Trust (Intermediate Clinical Fellowship 080952/Z/06/Z, to R.K.S.; Programme Grant 078986/Z/06/Z, to S.O.), GlaxoSmithKline (to D.B.S.),
the UK National Institute for Health Research Cambridge Biomedical
Research Centre, and the UK Medical Research Council Centre for Obesity and Related Metabolic Disease.
Disclosure Summary: R.K.S., D.B.S., E.K.C., and P.G. have nothing
to disclose. S.O. acts as a consultant in drug discovery for GlaxoSmithKline, Pfizer, and OSI Pharmaceuticals, Inc.
12.
13.
14.
15.
References
1. Resnick HE, Jones K, Ruotolo G, Jain AK, Henderson J, Lu
W, Howard BV 2003 Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease in nondiabetic American Indians: the Strong Heart Study. Diabetes Care 26:861 867
2. Hanson RL, Imperatore G, Bennett PH, Knowler WC 2002
Components of the metabolic syndrome and incidence
of type 2 diabetes. Diabetes 51:3120 3127
3. Dunaif A, Segal KR, Futterweit W, Dobrjansky A 1989
Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38:1165
1174
4. Reaven GM 1988 Banting lecture 1988. Role of insulin
resistance in human disease. Diabetes 37:15951607
5. Souren NY, Paulussen AD, Loos RJ, Gielen M, Beunen G,
Fagard R, Derom C, Vlietinck R, Zeegers MP 2007 Anthropometry, carbohydrate and lipid metabolism in the
East Flanders Prospective Twin Survey: heritabilities. Diabetologia 50:21072116
6. Freeman MS, Mansfield MW, Barrett JH, Grant PJ 2002
Heritability of features of the insulin resistance syndrome
in a community-based study of healthy families. Diabet
Med 19:994 999
7. Mills GW, Avery PJ, McCarthy MI, Hattersley AT, Levy
JC, Hitman GA, Sampson M, Walker M 2004 Heritability
16.
17.
18.
19.
20.
estimates for -cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to type 2 diabetes. Diabetologia 47:732738
Falchi M, Wilson SG, Paximadas D, Swaminathan R, Spector TD 2008 Quantitative linkage analysis for pancreatic
B-cell function and insulin resistance in a large twin cohort.
Diabetes 57:1120 1124
Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin
MM, Roth J 1976 The syndromes of insulin resistance and
acanthosis nigricans. Insulin-receptor disorders in man.
N Engl J Med 294:739 745
Sissons JG, West RJ, Fallows J, Williams DG, Boucher BJ,
Amos N, Peters DK 1976 The complement abnormalities
of lipodystrophy. N Engl J Med 294:461 465
Savage DB, Semple RK, Clatworthy MR, Lyons PA, Morgan BP, Cochran EK, Gorden P, Raymond-Barker P, Murgatroyd PR, Adams C, Scobie I, Mufti GJ, Alexander GJ,
Thiru S, Murano I, Cinti S, Chaudhry AN, Smith KG,
ORahilly S 2009 Complement abnormalities in acquired
lipodystrophy revisited. J Clin Endocrinol Metab 94:
10 16
Arioglu E, Andewelt A, Diabo C, Bell M, Taylor SI, Gorden
P 2002 Clinical course of the syndrome of autoantibodies
to the insulin receptor (type B insulin resistance): a 28-year
perspective. Medicine (Baltimore) 81:87100
Misra A, Garg A 2003 Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore)
82:129 146
Misra A, Peethambaram A, Garg A 2004 Clinical features
and metabolic and autoimmune derangements in acquired
partial lipodystrophy: report of 35 cases and review of the
literature. Medicine (Baltimore) 83:18 34
Garg A 2004 Acquired and inherited lipodystrophies.
N Engl J Med 350:1220 1234
Flier JS, Kahn CR, Roth J 1979 Receptors, antireceptor
antibodies and mechanisms of insulin resistance. N Engl
J Med 300:413 419
Hjlund K, Hansen T, Lajer M, Henriksen JE, Levin K,
Lindholm J, Pedersen O, Beck-Nielsen H 2004 A novel
syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes 53:15921598
Agostini M, Schoenmakers E, Mitchell C, Szatmari I, Savage D, Smith A, Rajanayagam O, Semple R, Luan J, Bath
L, Zalin A, Labib M, Kumar S, Simpson H, Blom D, Marais
D, Schwabe J, Barroso I, Trembath R, Wareham N, Nagy
L, Gurnell M, ORahilly S, Chatterjee K 2006 Non-DNA
binding, dominant-negative, human PPAR mutations
cause lipodystrophic insulin resistance. Cell Metab 4:303
311
George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S,
Wilson JC, Soos MA, Murgatroyd PR, Williams RM,
Acerini CL, Dunger DB, Barford D, Umpleby AM, Wareham NJ, Davies HA, Schafer AJ, Stoffel M, ORahilly S,
Barroso I 2004 A family with severe insulin resistance and
diabetes due to a mutation in AKT2. Science 304:1325
1328
Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S,
Yki-Jarvinen H 2008 Increased liver fat, impaired insulin
clearance, and hepatic and adipose tissue insulin resistance
in type 2 diabetes. Gastroenterology 135:122130
21. Okada T, Liew CW, Hu J, Hinault C, Michael MD,

Krtzfeldt J, Yin C, Holzenberger M, Stoffel M, Kulkarni
RN 2007 Insulin receptors in -cells are critical for islet
compensatory growth response to insulin resistance. Proc
Natl Acad Sci USA 104:8977 8982
22. Kaltsas GA, Isidori AM, Kola BP, Skelly RH, Chew SL,
Jenkins PJ, Monson JP, Grossman AB, Besser GM 2003
The value of the low-dose dexamethasone suppression test
in the differential diagnosis of hyperandrogenism in
women. J Clin Endocrinol Metab 88:2634 2643
23. Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC 1999
The insulin-related ovarian regulatory system in health and
disease. Endocr Rev 20:535582
24. Nestler JE, Jakubowicz DJ 1996 Decreases in ovarian cytochrome P450c17 activity and serum free testosterone
after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335:617 623
25. Musso C, Shawker T, Cochran E, Javor ED, Young J,
Gorden P 2005 Clinical evidence that hyperinsulinaemia
independent of gonadotropins stimulates ovarian growth.
Clin Endocrinol (Oxf) 63:7378
26. Dunaif A, Hoffman AR, Scully RE, Flier JS, Longcope C,
Levy LJ, Crowley Jr WF 1985 Clinical, biochemical, and
ovarian morphologic features in women with acanthosis
nigricans and masculinization. Obstet Gynecol 66:545
552
27. Kaltsas GA, Mukherjee JJ, Kola B, Isidori AM, Hanson JA,
Dacie JE, Reznek R, Monson JP, Grossman AB 2003 Is
ovarian and adrenal venous catheterization and sampling
helpful in the investigation of hyperandrogenic women?
Clin Endocrinol (Oxf) 59:34 43
28. Brisigotti M, Fabbretti G, Pesce F, Gatti R, Cohen A,
Parenti G, Callea F 1993 Congenital bilateral juvenile granulosa cell tumor of the ovary in leprechaunism: a case report. Pediatr Pathol 13:549 558
29. Torley D, Bellus GA, Munro CS 2002 Genes, growth factors and acanthosis nigricans. Br J Dermatol 147:1096
1101
30. Ellis DL, Kafka SP, Chow JC, Nanney LB, Inman WH,
McCadden ME, King Jr LE 1987 Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trelat, and
multiple acrochordons. A possible role for -transforming
growth factor in cutaneous paraneoplastic syndromes.
N Engl J Med 317:15821587
31. Hermanns-Le T, Scheen A, Pierard GE 2004 Acanthosis
nigricans associated with insulin resistance: pathophysiology and management. Am J Clin Dermatol 5:199 203
32. Greenfield JR, Tuthill A, Soos MA, Semple RK, Halsall DJ,
Chaudhry A, ORahilly S 2009 Severe insulin resistance
due to anti-insulin antibodies: response to plasma exchange and immunosuppressive therapy. Diabet Med 26:
79 82
33. Barth JH, Ng LL, Wojnarowska F, Dawber RP 1988 Acanthosis nigricans, insulin resistance and cutaneous virilism. Br J Dermatol 118:613 619
34. Utzschneider KM, Kahn SE 2006 Review: the role of insulin resistance in nonalcoholic fatty liver disease. J Clin
Endocrinol Metab 91:4753 4761
35. Bellentani S, Saccoccio G, Masutti F, Croce` LS, Brandi G,
Sasso F, Cristanini G, Tiribelli C 2000 Prevalence of and
risk factors for hepatic steatosis in northern Italy. Ann Intern Med 132:112117
509
36. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G,

Meigs JB, Bonadonna RC, Muggeo M 2004 Populationbased incidence rates and risk factors for type 2 diabetes in
white individuals: the Bruneck study. Diabetes 53:1782
1789
37. Brown CD, Higgins M, Donato KA, Rohde FC, Garrison
R, Obarzanek E, Ernst ND, Horan M 2000 Body mass
index and the prevalence of hypertension and dyslipidemia. Obes Res 8:605 619
38. Starley BQ, Calcagno CJ, Harrison SA 2010 Nonalcoholic
fatty liver disease and hepatocellular carcinoma: a weighty
connection. Hepatology 51:1820 1832
39. Semple RK, Sleigh A, Murgatroyd PR, Adams CA, Bluck L,
Jackson S, Vottero A, Kanabar D, Charlton-Menys V, Durrington P, Soos MA, Carpenter TA, Lomas DJ, Cochran
EK, Gorden P, ORahilly S, Savage DB 2009 Postreceptor
insulin resistance contributes to human dyslipidemia and
hepatic steatosis. J Clin Invest 119:315322
40. Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA,
Taylor S, Gorden P 2004 Clinical course of genetic diseases
of the insulin receptor (type A and Rabson-Mendenhall
syndromes): a 30-year prospective. Medicine (Baltimore)
83:209 222
41. Shimomura I, Matsuda M, Hammer RE, Bashmakov Y,
Brown MS, Goldstein JL 2000 Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell
6:77 86
42. Biddinger SB, Hernandez-Ono A, Rask-Madsen C, Haas
JT, Aleman JO, Suzuki R, Scapa EF, Agarwal C, Carey
MC, Stephanopoulos G, Cohen DE, King GL, Ginsberg
HN, Kahn CR 2008 Hepatic insulin resistance is sufficient
to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab 7:125134
43. Brown MS, Goldstein JL 2008 Selective versus total insulin
resistance: a pathogenic paradox. Cell Metab 7:9596
44. Savage DB, Semple RK 2010 Recent insights into fatty
liver, metabolic dyslipidaemia and their links to insulin
resistance. Curr Opin Lipidol 21:329 336
45. Murphy R, Baptista J, Holly J, Umpleby AM, Ellard S,
Harries LW, Crolla J, Cundy T, Hattersley AT 2008 Severe
intrauterine growth retardation and atypical diabetes associated with a translocation breakpoint disrupting regulation of the insulin-like growth factor 2 gene. J Clin Endocrinol Metab 93:4373 4380
46. Srinivasan S, Waters MJ, Rowland JE, Baxter RC, Verge
CF 2003 Hyperinsulinism and overgrowth without obesity. Arch Dis Child 88:332334
47. Flier JS, Moller DE, Moses AC, ORahilly S, Chaiken RL,
Grigorescu F, Elahi D, Kahn BB, Weinreb JE, Eastman R
1993 Insulin-mediated pseudoacromegaly: clinical and
biochemical characterization of a syndrome of selective
insulin resistance. J Clin Endocrinol Metab 76:15331541
48. Kausch C, Bergemann C, Hamann A, Matthaei S 1999
Insulin-mediated pseudoacromegaly in a patient with severe insulin resistance: association of defective insulinstimulated glucose transport with impaired phosphatidylinositol 3-kinase activity in fibroblasts. Exp Clin
Endocrinol Diabetes 107:148 154
49. Dib K, Whitehead JP, Humphreys PJ, Soos MA, Baynes
KC, Kumar S, Harvey T, ORahilly S 1998 Impaired activation of phosphoinositide 3-kinase by insulin in fibro-
510
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
Semple et al.
blasts from patients with severe insulin resistance and pseudoacromegaly. A disorder characterized by selective
postreceptor insulin resistance. J Clin Invest 101:1111
1120
Kumar S, Durrington PN, ORahilly S, Laing I, Humphreys
PJ, Olukoga AO, Bhatnagar D, Mackness MI, Davis JR,
Boulton AJ 1996 Severe insulin resistance, diabetes mellitus, hypertriglyceridemia, and pseudoacromegaly. J Clin
Endocrinol Metab 81:34653468
Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine ID, Belfiore A, Vigneri R 1999 Insulin
receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells.
Mol Cell Biol 19:3278 3288
Pollak M 2008 Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915928
Rajaram S, Baylink DJ, Mohan S 1997 Insulin-like growth
factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev 18:801 831
Tsugane S, Inoue M 2010 Insulin resistance and cancer:
epidemiological evidence. Cancer Sci 101:10731079
Kang HW, Kim D, Kim HJ, Kim CH, Kim YS, Park MJ,
Kim JS, Cho SH, Sung MW, Jung HC, Lee HS, Song IS 2010
Visceral obesity and insulin resistance as risk factors for
colorectal adenoma: a cross-sectional, case-control study.
Am J Gastroenterol 105:178 187
Garg A 2000 Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy
(Dunnigan variety). J Clin Endocrinol Metab 85:1776
1782
Vantyghem MC, Vincent-Desplanques D, Defrance-Faivre
F, Capeau J, Fermon C, Valat AS, Lascols O, Hecart AC,
Pigny P, Delemer B, Vigouroux C, Wemeau JL 2008 Fertility and obstetrical complications in women with LMNArelated familial partial lipodystrophy. J Clin Endocrinol
Metab 93:22232229
Li S, Brown MS, Goldstein JL 2010 Bifurcation of insulin
signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci USA 107:34413446
Laplante M, Sabatini DM 2010 mTORC1 activates
SREBP-1c and uncouples lipogenesis from gluconeogenesis. Proc Natl Acad Sci USA 107:32813282
Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza
AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander
Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy
LO, Manning BD 2010 Activation of a metabolic gene
regulatory network downstream of mTOR complex 1.
Mol Cell 39:171183
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J,
Boldt MD, Parks EJ 2005 Sources of fatty acids stored in
liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115:13431351
Haas JT, Biddinger SB 2009 Dissecting the role of insulin
resistance in the metabolic syndrome. Curr Opin Lipidol
20:206 210
Dann SG, Selvaraj A, Thomas G 2007 mTOR Complex
1-S6K1 signaling: at the crossroads of obesity, diabetes and
cancer. Trends Mol Med 13:252259
Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD,
Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA,
Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy Jr WS,
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
Eisenson H, Musante G, Surwit RS, Millington DS, Butler

MD, Svetkey LP 2009 A branched-chain amino acid-related metabolic signature that differentiates obese and lean
humans and contributes to insulin resistance. Cell Metab
9:311326
Huffman KM, Shah SH, Stevens RD, Bain JR, Muehlbauer
M, Slentz CA, Tanner CJ, Kuchibhatla M, Houmard JA,
Newgard CB, Kraus WE 2009 Relationships between circulating metabolic intermediates and insulin action in
overweight to obese, inactive men and women. Diabetes
Care 32:1678 1683
Semple RK, Halberg NH, Burling K, Soos MA, Schraw T,
Luan J, Cochran EK, Dunger DB, Wareham NJ, Scherer
PE, Gorden P, ORahilly S 2007 Paradoxical elevation of
high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies. Diabetes
56:17121717
Antuna-Puente B, Boutet E, Vigouroux C, Lascols O,
Slama L, Caron-Debarle M, Khallouf E, Levy-Marchal C,
Capeau J, Bastard JP, Magre J 2010 Higher adiponectin
levels in patients with Berardinelli-Seip congenital lipodystrophy due to seipin as compared with 1-acylglycerol-3phosphate-o-acyltransferase-2 deficiency. J Clin Endocrinol Metab 95:14631468
Hattori Y, Hirama N, Suzuki K, Hattori S, Kasai K 2007
Elevated plasma adiponectin and leptin levels in sisters
with genetically defective insulin receptors. Diabetes Care
30:e109
Semple R, Savage DB, ORahilly S 2009 Sex hormonebinding globulin and risk of type 2 diabetes. N Engl J Med
361:2677; author reply 26772678
Semple RK, Cochran EK, Soos MA, Burling KA, Savage
DB, Gorden P, ORahilly S 2008 Plasma adiponectin as a
marker of insulin receptor dysfunction: clinical utility in
severe insulin resistance. Diabetes Care 31:977979
Maddux BA, Chan A, De Filippis EA, Mandarino LJ,
Goldfine ID 2006 IGF-binding protein-1 levels are related
to insulin-mediated glucose disposal and are a potential
serum marker of insulin resistance. Diabetes Care 29:
15351537
Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ 2004
Association of bioavailable, free, and total testosterone
with insulin resistance: influence of sex hormone-binding
globulin and body fat. Diabetes Care 27:861 868
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y,
Pratley RE, Tataranni PA 2001 Hypoadiponectinemia in
obesity and type 2 diabetes: close association with insulin
resistance and hyperinsulinemia. J Clin Endocrinol Metab
86:1930 1935
Semple RK, Soos MA, Luan J, Mitchell CS, Wilson JC,
Gurnell M, Cochran EK, Gorden P, Chatterjee VK, Wareham NJ, ORahilly S 2006 Elevated plasma adiponectin in
humans with genetically defective insulin receptors. J Clin
Endocrinol Metab 91:3219 3223
Cook JR, Semple RK 2010 Hypoadiponectinemia cause
or consequence of human insulin resistance? J Clin Endocrinol Metab 95:1544 1554
Barbieri RL, Ryan KJ 1983 Hyperandrogenism, insulin
resistance, and acanthosis nigricans syndrome: a common
endocrinopathy with distinct pathophysiologic features.
Am J Obstet Gynecol 147:90 101
Kadowaki T, Bevins CL, Cama A, Ojamaa K, Marcus-
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
Samuels B, Kadowaki H, Beitz L, McKeon C, Taylor SI

1988 Two mutant alleles of the insulin receptor gene in a
patient with extreme insulin resistance. Science 240:787
790
Yoshimasa Y, Seino S, Whittaker J, Kakehi T, Kosaki A,
Kuzuya H, Imura H, Bell GI, Steiner DF 1988 Insulinresistant diabetes due to a point mutation that prevents
insulin proreceptor processing. Science 240:784 787
Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM,
Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M,
Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J 1985 Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature
313:756 761
Rabson SM, Mendenhall EN 1956 Familial hypertrophy of
pineal body, hyperplasia of adrenal cortex and diabetes
mellitus; report of 3 cases. Am J Clin Pathol 26:283290
Donohue WL, Uchida I 1954 Leprechaunism: a euphemism for a rare familial disorder. J Pediatr 45:505519
Semple RK, Savage DB, Halsall DJ, ORahilly S 2010 Syndromes of severe insulin resistance and/or lipodystrophy.
In: Weiss RE, Refetoff S, eds. Genetic diagnosis of endocrine disorders. Philadelphia: Elsevier
Ogilvy-Stuart AL, Soos MA, Hands SJ, Anthony MY,
Dunger DB, ORahilly S 2001 Hypoglycemia and resistance to ketoacidosis in a subject without functional insulin
receptors. J Clin Endocrinol Metab 86:3319 3326
Longo N, Langley SD, Griffin LD, Elsas 2nd LJ 1992 Reduced mRNA and a nonsense mutation in the insulin-receptor gene produce heritable severe insulin resistance.
Am J Hum Genet 50:998 1007
Foti D, Chiefari E, Fedele M, Iuliano R, Brunetti L, Paonessa F, Manfioletti G, Barbetti F, Brunetti A, Croce CM,
Fusco A, Brunetti A 2005 Lack of the architectural factor
HMGA1 causes insulin resistance and diabetes in humans
and mice. Nat Med 11:765773
Berger D, Barroso I, Soos M, Yeo G, Schafer AJ, ORahilly
S, Whitehead JP 2002 Genetic variants of insulin receptor
substrate-1 (IRS-1) in syndromes of severe insulin resistance. Functional analysis of Ala513Pro and Gly1158Glu
IRS-1. Diabet Med 19:804 809
Whitehead JP, Humphreys P, Krook A, Jackson R, Hayward A, Lewis H, Siddle K, ORahilly S 1998 Molecular
scanning of the insulin receptor substrate 1 gene in subjects
with severe insulin resistance: detection and functional
analysis of a naturally occurring mutation in a YMXM
motif. Diabetes 47:837 839
Bottomley WE, Soos MA, Adams C, Guran T, Howlett
TA, Mackie A, Miell J, Monson JP, Temple R, Tenenbaum-Rakover Y, Tymms J, Savage DB, Semple RK,
ORahilly S, Barroso I 2009 IRS2 variants and syndromes
of severe insulin resistance. Diabetologia 52:1208 1211
Tan K, Kimber WA, Luan J, Soos MA, Semple RK, Wareham NJ, ORahilly S, Barroso I 2007 Analysis of genetic
variation in Akt2/PKB- in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes. Diabetes 56:714 719
Baynes KC, Beeton CA, Panayotou G, Stein R, Soos M,
Hansen T, Simpson H, ORahilly S, Shepherd PR, Whitehead JP 2000 Natural variants of human p85 phosphoinositide 3-kinase in severe insulin resistance: a novel vari-
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
511
ant with impaired insulin-stimulated lipid kinase activity.

Diabetologia 43:321331
Dash S, Sano H, Rochford JJ, Semple RK, Yeo G, Hyden
CS, Soos MA, Clark J, Rodin A, Langenberg C, Druet C,
Fawcett KA, Tung YC, Wareham NJ, Barroso I, Lienhard
GE, ORahilly S, Savage DB 2009 A truncation mutation
in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia. Proc Natl Acad Sci USA 106:
9350 9355
Peters JM, Barnes R, Bennett L, Gitomer WM, Bowcock
AM, Garg A 1998 Localization of the gene for familial
partial lipodystrophy (Dunnigan variety) to chromosome
1q2122. Nat Genet 18:292295
Cao H, Hegele RA 2000 Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial
partial lipodystrophy. Hum Mol Genet 9:109 112
Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer
MF, Singh BM, Schmidt H, Brabant G, Kumar S, Durrington PN, Gregory S, ORahilly S, Trembath RC 2000
LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 24:153156
Magre J, Delepine M, Khallouf E, Gedde-Dahl Jr T, Van
Maldergem L, Sobel E, Papp J, Meier M, Megarbane A,
Bachy A, Verloes A, dAbronzo FH, Seemanova E, Assan
R, Baudic N, Bourut C, Czernichow P, Huet F, Grigorescu
F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret
H, Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M,
Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P,
Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson G, Panz
VR, Raal FJ, ORahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J 2001 Identification of the gene altered in
Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365370
Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI,
Bowcock AM, Barnes RI, Garg A 2002 AGPAT2 is mutated in congenital generalized lipodystrophy linked to
chromosome 9q34. Nat Genet 31:2123
Hegele RA, Joy TR, Al-Attar SA, Rutt BK 2007 Thematic
review series: adipocyte biology. Lipodystrophies: windows on adipose biology and metabolism. J Lipid Res 48:
14331444
Monajemi H, Stroes E, Hegele RA, Fliers E 2007 Inherited
lipodystrophies and the metabolic syndrome. Clin Endocrinol (Oxf) 67:479 484
Garg A, Agarwal AK 2009 Lipodystrophies: disorders of
adipose tissue biology. Biochim Biophys Acta 1791:507
513
Jeninga EH, Kalkhoven E 2010 Central players in inherited
lipodystrophies. Trends Endocrinol Metab 21:581588
Capeau J, Magre J, Caron-Debarle M, Lagathu C, Antoine
B, Bereziat V, Lascols O, Bastard JP, Vigouroux C 2010
Human lipodystrophies: genetic and acquired diseases of
adipose tissue. Endocr Dev 19:120
Kim CA, Delepine M, Boutet E, El Mourabit H, Le Lay S,
Meier M, Nemani M, Bridel E, Leite CC, Bertola DR,
Semple RK, ORahilly S, Dugail I, Capeau J, Lathrop M,
Magre J 2008 Association of a homozygous nonsense
caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab 93:1129 1134
Hayashi YK, Matsuda C, Ogawa M, Goto K, Tominaga K,
Mitsuhashi S, Park YE, Nonaka I, Hino-Fukuyo N, Hagi-
512
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
Semple et al.
noya K, Sugano H, Nishino I 2009 Human PTRF mutations cause secondary deficiency of caveolins resulting in
muscular dystrophy with generalized lipodystrophy. J Clin
Invest 119:26232633
Rajab A, Straub V, McCann LJ, Seelow D, Varon R, Barresi R, Schulze A, Lucke B, Lutzkendorf S, Karbasiyan M,
Bachmann S, Spuler S, Schuelke M 2010 Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling
(CGL4) due to PTRF-CAVIN mutations. PLoS Genet
6:e1000874
Shastry S, Delgado MR, Dirik E, Turkmen M, Agarwal
AK, Garg A 2010 Congenital generalized lipodystrophy,
type 4 (CGL4) associated with myopathy due to novel
PTRF mutations. Am J Med Genet A 152A:22452253
Dwianingsih EK, Takeshima Y, Itoh K, Yamauchi Y,
Awano H, Malueka RG, Nishida A, Ota M, Yagi M, Matsuo M 2010 A Japanese child with asymptomatic elevation
of serum creatine kinase shows PTRF-CAVIN mutation
matching with congenital generalized lipodystrophy type
4. Mol Genet Metab 101:233237
Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple
RK, Dash S, Hyden CS, Bottomley W, Vigouroux C,
Magre J, Raymond-Barker P, Murgatroyd PR, Chawla A,
Skepper JN, Chatterjee VK, Suliman S, Patch AM, Agarwal
AK, Garg A, Barroso I, Cinti S, Czech MP, Argente J,
ORahilly S, Savage DB 2009 Partial lipodystrophy and
insulin resistant diabetes in a patient with a homozygous
nonsense mutation in CIDEC. EMBO Mol Med 1:280
287
Cohen AW, Hnasko R, Schubert W, Lisanti MP 2004 Role
of caveolae and caveolins in health and disease. Physiol Rev
84:13411379
Blouin CM, Le Lay S, Eberl A, Kofeler HC, Guerrera IC,
Klein C, Le Liepvre X, Lasnier F, Bourron O, Gautier JF,
Ferre P, Hajduch E, Dugail I 2010 Lipid droplet analysis in
caveolin-deficient adipocytes: Alterations in surface phospholipid composition and maturation defects. J Lipid Res
51:945956
Liu L, Brown D, McKee M, Lebrasseur NK, Yang D, Albrecht KH, Ravid K, Pilch PF 2008 Deletion of Cavin/
PTRF causes global loss of caveolae, dyslipidemia, and
glucose intolerance. Cell Metab 8:310 317
de Haan W 2010 Lipodystrophy and muscular dystrophy
caused by PTRF mutations. Clin Genet 77:436 437
Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado
M, Masetti E, Mazzocco M, Egeo A, Donati MA, Volonte
D, Galbiati F, Cordone G, Bricarelli FD, Lisanti MP, Zara
F 1998 Mutations in the caveolin-3 gene cause autosomal
dominant limb-girdle muscular dystrophy. Nat Genet 18:
365368
Keller P, Petrie JT, De Rose P, Gerin I, Wright WS, Chiang
SH, Nielsen AR, Fischer CP, Pedersen BK, MacDougald
OA 2008 Fat-specific protein 27 regulates storage of triacylglycerol. J Biol Chem 283:1435514365
Toh SY, Gong J, Du G, Li JZ, Yang S, Ye J, Yao H, Zhang
Y, Xue B, Li Q, Yang H, Wen Z, Li P 2008 Up-regulation
of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of
fsp27 deficient mice. PLoS One 3:e2890
Nishino N, Tamori Y, Tateya S, Kawaguchi T, Shibakusa
T, Mizunoya W, Inoue K, Kitazawa R, Kitazawa S, Mat-
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
suki Y, Hiramatsu R, Masubuchi S, Omachi A, Kimura K,

Saito M, Amo T, Ohta S, Yamaguchi T, Osumi T, Cheng
J, Fujimoto T, Nakao H, Nakao K, Aiba A, Okamura H,
Fushiki T, Kasuga M 2008 FSP27 contributes to efficient
energy storage in murine white adipocytes by promoting
the formation of unilocular lipid droplets. J Clin Invest
118:2808 2821
Puri V, Czech MP 2008 Lipid droplets: FSP27 knockout
enhances their sizzle. J Clin Invest 118:26932696
Szymanski KM, Binns D, Bartz R, Grishin NV, Li WP,
Agarwal AK, Garg A, Anderson RG, Goodman JM 2007
The lipodystrophy protein seipin is found at endoplasmic
reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci USA 104:20890
20895
Fei W, Shui G, Gaeta B, Du X, Kuerschner L, Li P, Brown
AJ, Wenk MR, Parton RG, Yang H 2008 Fld1p, a functional homologue of human seipin, regulates the size of
lipid droplets in yeast. J Cell Biol 180:473 482
Boutet E, El Mourabit H, Prot M, Nemani M, Khallouf E,
Colard O, Maurice M, Durand-Schneider AM, Chretien Y,
Gre`s S, Wolf C, Saulnier-Blache JS, Capeau J, Magre J
2009 Seipin deficiency alters fatty acid Delta9 desaturation
and lipid droplet formation in Berardinelli-Seip congenital
lipodystrophy. Biochimie 91:796 803
Payne VA, Grimsey N, Tuthill A, Virtue S, Gray SL, Dalla
Nora E, Semple RK, ORahilly S, Rochford JJ 2008 The
human lipodystrophy gene BSCL2/seipin may be essential
for normal adipocyte differentiation. Diabetes 57:2055
2060
Savage DB, Agostini M, Barroso I, Gurnell M, Luan J,
Meirhaeghe A, Harding AH, Ihrke G, Rajanayagam O,
Soos MA, George S, Berger D, Thomas EL, Bell JD,
Meeran K, Ross RJ, Vidal-Puig A, Wareham NJ, ORahilly
S, Chatterjee VK, Schafer AJ 2002 Digenic inheritance of
severe insulin resistance in a human pedigree. Nat Genet
31:379 384
Newgard CB, Brady MJ, ODoherty RM, Saltiel AR 2000
Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1. Diabetes
49:19671977
Lanner C, Suzuki Y, Bi C, Zhang H, Cooper LD, BowkerKinley MM, DePaoli-Roach AA 2001 Gene structure and
expression of the targeting subunit, RGL, of the musclespecific glycogen-associated type 1 protein phosphatase,
PP1G. Arch Biochem Biophys 388:135145
Suzuki Y, Lanner C, Kim JH, Vilardo PG, Zhang H, Yang
J, Cooper LD, Steele M, Kennedy A, Bock CB, Scrimgeour
A, Lawrence Jr JC, DePaoli-Roach AA 2001 Insulin control of glycogen metabolism in knockout mice lacking the
muscle-specific protein phosphatase PP1G/RGL. Mol Cell
Biol 21:26832694
Savage DB, Zhai L, Ravikumar B, Choi CS, Snaar JE,
McGuire AC, Wou SE, Medina-Gomez G, Kim S, Bock
CB, Segvich DM, Solanky B, Deelchand D, Vidal-Puig A,
Wareham NJ, Shulman GI, Karpe F, Taylor R, Pederson
BA, Roach PJ, ORahilly S, DePaoli-Roach AA 2008 A
prevalent variant in PPP1R3A impairs glycogen synthesis
and reduces muscle glycogen content in humans and mice.
PLoS Med 5:e27
Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau
H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN,
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB,
ORahilly S 1997 Congenital leptin deficiency is associated
with severe early-onset obesity in humans. Nature 387:
903908
Minton JA, Owen KR, Ricketts CJ, Crabtree N, Shaikh G,
Ehtisham S, Porter JR, Carey C, Hodge D, Paisey R,
Walker M, Barrett TG 2006 Syndromic obesity and diabetes: changes in body composition with age and mutation
analysis of ALMS1 in 12 United Kingdom kindreds with
Alstrom syndrome. J Clin Endocrinol Metab 91:3110
3116
Huang-Doran I, Bicknell LS, Finucane FM, Rocha N, Porter KM, Tung YC, Szekeres F, Krook A, Nolan JJ,
ODriscoll M, Bober M, ORahilly S, Jackson AP, Semple
RK 2011 Genetic defects in human pericentrin are associated with severe insulin resistance and diabetes mellitus.
Diabetes 60:925935
Green JS, Parfrey PS, Harnett JD, Farid NR, Cramer BC,
Johnson G, Heath O, McManamon PJ, OLeary E, PrysePhillips W 1989 The cardinal manifestations of BardetBiedl syndrome, a form of Laurence-Moon-Biedl syndrome. N Engl J Med 321:10021009
Zaghloul NA, Katsanis N 2009 Mechanistic insights into
Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest
119:428 437
Yamada K, Ikegami H, Yoneda H, Miki T, Ogihara T
1999 All patients with Werners syndrome are insulin resistant, but only those who also have impaired insulin secretion develop overt diabetes. Diabetes Care 22:2094
2095
Imura H, Nakao Y, Kuzuya H, Okamoto M, Okamoto M,
Yamada K 1985 Clinical, endocrine and metabolic aspects
of the Werner syndrome compared with those of normal
aging. Adv Exp Med Biol 190:171185
Diaz A, Vogiatzi MG, Sanz MM, German J 2006 Evaluation of short stature, carbohydrate metabolism and other
endocrinopathies in Blooms syndrome. Horm Res 66:
111117
Jacob KN, Garg A 2006 Laminopathies: multisystem dystrophy syndromes. Mol Genet Metab 87:289 302
Schalch DS, McFarlin DE, Barlow MH 1970 An unusual
form of diabetes mellitus in ataxia telangiectasia. N Engl
J Med 282:1396 1402
Blevins Jr LS, Gebhart SS 1996 Insulin-resistant diabetes
mellitus in a black woman with ataxia-telangiectasia.
South Med J 89:619 621
Koulouri O, Conway GS 2009 Management of hirsutism.
BMJ 338:b847
Higgins SP, Freemark M, Prose NS 2008 Acanthosis nigricans: a practical approach to evaluation and management. Dermatol Online J 14:2
Cochran E, Musso C, Gorden P 2005 The use of U-500 in
patients with extreme insulin resistance. Diabetes Care 28:
1240 1244
Lane WS 2006 Use of U-500 regular insulin by continuous
subcutaneous insulin infusion in patients with type 2 diabetes and severe insulin resistance. Endocr Pract 12:251
256
Takahashi Y, Kadowaki H, Momomura K, Fukushima Y,
Orban T, Okai T, Taketani Y, Akanuma Y, Yazaki Y,
Kadowaki T 1997 A homozygous kinase-defective muta-
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
513
tion in the insulin receptor gene in a patient with leprechaunism. Diabetologia 40:412 420
Nakae J, Kato M, Murashita M, Shinohara N, Tajima T,
Fujieda K 1998 Long-term effect of recombinant human
insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism. J Clin Endocrinol
Metab 83:542549
Longo N, Singh R, Griffin LD, Langley SD, Parks JS, Elsas
LJ 1994 Impaired growth in Rabson-Mendenhall syndrome: lack of effect of growth hormone and insulin-like
growth factor-I. J Clin Endocrinol Metab 79:799 805
Vestergaard H, Rossen M, Urhammer SA, Muller J, Pedersen O 1997 Short- and long-term metabolic effects of
recombinant human IGF-I treatment in patients with severe insulin resistance and diabetes mellitus. Eur J Endocrinol 136:475 482
Kuzuya H, Matsuura N, Sakamoto M, Makino H, Sakamoto Y, Kadowaki T, Suzuki Y, Kobayashi M, Akazawa
Y, Nomura M 1993 Trial of insulin-like growth factor I
therapy for patients with extreme insulin resistance syndromes. Diabetes 42:696 705
Zenobi PD, Glatz Y, Keller A, Graf S, Jaeggi-Groisman SE,
Riesen WF, Schoenle EJ, Froesch ER 1994 Beneficial metabolic effects of insulin-like growth factor I in patients with
severe insulin-resistant diabetes type A. Eur J Endocrinol
131:251257
Dozio N, Scavini M, Beretta A, Sartori S, Meschi F, Sarugeri E, Pozza G 1995 In vivo metabolic effects of insulinlike growth factor-I not mediated through the insulin receptor. J Clin Endocrinol Metab 80:13251328
Quin JD, Checkley A, Gallagher A, Jones J, MacCuish AC,
Miell JP 1994 Response of insulin-like growth factor
(IGF)-binding protein-1 (IGFBP-1) and IGFBP-3 to IGF-I
treatment in severe insulin resistance. J Endocrinol 141:
177182
George S, Johansen A, Soos MA, Mortensen H, Gammeltoft S, Saudek V, Siddle K, Hansen L, ORahilly S 2003
Deletion of V335 from the L2 domain of the insulin receptor results in a conformationally abnormal receptor
that is unable to bind insulin and causes Donohues syndrome in a human subject. Endocrinology 144:631 637
McDonald A, Williams RM, Regan FM, Semple RK,
Dunger DB 2007 IGF-I treatment of insulin resistance. Eur
J Endocrinol 157(Suppl 1):S51S56
Regan FM, Williams RM, McDonald A, Umpleby AM,
Acerini CL, ORahilly S, Hovorka R, Semple RK, Dunger
DB 2010 Treatment with recombinant human insulin-like
growth factor (rhIGF)-I/rhIGF binding protein-3 complex
improves metabolic control in subjects with severe insulin
resistance. J Clin Endocrinol Metab 95:21132122
Haque WA, Shimomura I, Matsuzawa Y, Garg A 2002
Serum adiponectin and leptin levels in patients with lipodystrophies. J Clin Endocrinol Metab 87:2395
Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A,
Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI,
Gorden P, Garg A 2002 Leptin-replacement therapy for
lipodystrophy. N Engl J Med 346:570 578
Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu
C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman
GI 2002 Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest
109:13451350
514
Semple et al.
155. Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM,
Premkumar A, Kleiner DE, Gorden P 2005 Leptin reverses
nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 41:753760
156. Beltrand J, Beregszaszi M, Chevenne D, Sebag G, De Kerdanet M, Huet F, Polak M, Tubiana-Rufi N, Lacombe D,
De Paoli AM, Levy-Marchal C 2007 Metabolic correction
induced by leptin replacement treatment in young children
with Berardinelli-Seip congenital lipoatrophy. Pediatrics
120:e291 e296
157. Chong AY, Lupsa BC, Cochran EK, Gorden P 2010 Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia 53:2735
158. Beltrand J, Lahlou N, Le Charpentier T, Sebag G, Leka S,
Polak M, Tubiana-Rufi N, Lacombe D, de Kerdanet M,
Huet F, Robert JJ, Chevenne D, Gressens P, Levy-Marchal
C 2010 Resistance to leptin-replacement therapy in Berardinelli-Seip congenital lipodystrophy: an immunological
origin. Eur J Endocrinol 162:10831091
159. Savage DB, ORahilly S 2010 Leptin therapy in lipodystrophy. Diabetologia 53:79
160. Mantzoros CS 2009 Whither recombinant human leptin
treatment for HIV-associated lipoatrophy and the metabolic syndrome? J Clin Endocrinol Metab 94:1089 1091
161. Cochran E, Young JR, Sebring N, DePaoli A, Oral EA,
Gorden P 2004 Efficacy of recombinant methionyl human
leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome. J Clin Endocrinol Metab 89:
1548 1554
162. Skarulis MC, Celi FS, Mueller E, Zemskova M, Malek R,
Hugendubler L, Cochran C, Solomon J, Chen C, Gorden
P 2010 Thyroid hormone induced brown adipose tissue
and amelioration of diabetes in a patient with extreme insulin resistance. J Clin Endocrinol Metab 95:256 262
163. Moreira RO, Zagury RL, Nascimento TS, Zagury L 2010
Multidrug therapy in a patient with Rabson-Mendenhall
syndrome. Diabetologia 53:2454 2455
164. Utzschneider KM, Trence DL 2006 Effectiveness of gastric
bypass surgery in a patient with familial partial lipodystrophy. Diabetes Care 29:1380 1382
165. Chao L, Marcus-Samuels B, Mason MM, Moitra J, Vinson
C, Arioglu E, Gavrilova O, Reitman ML 2000 Adipose
tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones. J Clin Invest 106:
12211228
166. Moreau F, Boullu-Sanchis S, Vigouroux C, Lucescu C, Lascols O, Sapin R, Ruimy D, Guerci B, Pinget M, Jeandidier
N 2007 Efficacy of pioglitazone in familial partial lipodystrophy of the Dunnigan type: a case report. Diabetes
Metab 33:385389
167. Simha V, Rao S, Garg A 2008 Prolonged thiazolidinedione
therapy does not reverse fat loss in patients with familial
partial lipodystrophy, Dunnigan variety. Diabetes Obes
Metab 10:12751276
168. Collet-Gaudillat C, Billon-Bancel A, Beressi JP 2009 Longterm improvement of metabolic control with pioglitazone
in a woman with diabetes mellitus related to Dunnigan
syndrome: a case report. Diabetes Metab 35:151154
169. Dash S, Langenberg C, Fawcett KA, Semple RK, Romeo S,
Sharp S, Sano H, Lienhard GE, Rochford JJ, Howlett T,
Massoud AF, Hindmarsh P, Howell SJ, Wilkinson RJ, Lys-
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
senko V, Groop L, Baroni MG, Barroso I, Wareham NJ,

ORahilly S, Savage DB 2010 Analysis of TBC1D4 in patients with severe insulin resistance. Diabetologia 53:
1239 1242
Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T,
ORahilly S 2003 Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med
348:10851095
Krude H, Biebermann H, Luck W, Horn R, Brabant G,
Gruters A 1998 Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155157
Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM,
Basdevant A, Bougne`res P, Lebouc Y, Froguel P, GuyGrand B 1998 A mutation in the human leptin receptor
gene causes obesity and pituitary dysfunction. Nature 392:
398 401
Bochukova EG, Huang N, Keogh J, Henning E, Purmann
C, Blaszczyk K, Saeed S, Hamilton-Shield J, Clayton-Smith
J, ORahilly S, Hurles ME, Farooqi IS 2010 Large, rare
chromosomal deletions associated with severe early-onset
obesity. Nature 463:666 670
Van Maldergem L, Magre J, Khallouf TE, Gedde-Dahl T
Jr, Delepine M, Trygstad O, Seemanova E, Stephenson T,
Albott CS, Bonnici F, Panz VR, Medina JL, Bogalho P,
Huet F, Savasta S, Verloes A, Robert JJ, Loret H, De Kerdanet M, Tubiana-Rufi N, Megarbane A, Maassen J, Polak
M, Lacombe D, Kahn CR, Silveira EL, DAbronzo FH,
Grigorescu F, Lathrop M, Capeau J, ORahilly S 2002
Genotype-phenotype relationships in Berardinelli-Seip
congenital lipodystrophy. J Med Genet 39:722733
Jackson SN, Howlett TA, McNally PG, ORahilly S, Trembath RC 1997 Dunnigan-Kobberling syndrome: an autosomal dominant form of partial lipodystrophy. QJM 90:
2736
Semple RK, Chatterjee VK, ORahilly S 2006 PPAR and
human metabolic disease. J Clin Invest 116:581589
Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M,
Gurnell M, Williams RL, Umpleby AM, Thomas EL, Bell
JD, Dixon AK, Dunne F, Boiani R, Cinti S, Vidal-Puig A,
Karpe F, Chatterjee VK, ORahilly S 2003 Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-. Diabetes 52:910 917
Agarwal AK, Garg A 2002 A novel heterozygous mutation
in peroxisome proliferator-activated receptor- gene in a
patient with familial partial lipodystrophy. J Clin Endocrinol Metab 87:408 411
Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T
2002 PPARG F388L, a transactivation-deficient mutant,
in familial partial lipodystrophy. Diabetes 51:3586 3590
Grinspoon SK 2005 Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency
virus. Am J Med 118(Suppl 2):23S28S
Moxley RT, Corbett AJ, Minaker KL, Rowe JW 1984
Whole body insulin resistance in myotonic dystrophy. Ann
Neurol 15:157162
Savkur RS, Philips AV, Cooper TA 2001 Aberrant regulation of insulin receptor alternative splicing is associated
with insulin resistance in myotonic dystrophy. Nat Genet
29:40 47

Sindromes de Insulino Resistencia

Transféré par

Informations du document

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Sindromes de Insulino Resistencia

Transféré par

Droits d'auteur :

Formats disponibles

R E V I E W

Genetic Syndromes of Severe Insulin Resistance

ISSN Print 0021-972X ISSN Online 1945-7197

* R.K.S. and D.B.S. contributed equally to this work.

Endocrine Reviews, August 2011, 32(4):498 514

Endocrine Reviews, August 2011, 32(4):498 514

mutations, and several of these have been identified in

II. Definition and Prevalence of Severe IR

Fig. 1. Diagnosis of possible monogenic severe IR. A, Suggested

glycemia and absolute insulin deficiency, diagnosis in the

III. Generic Clinical Features of Severe IR

Severe Insulin Resistance Syndromes

doses of exogenous insulin. However, hyperglycemia is

Severe IR most commonly presents to clinical attention

Endocrine Reviews, August 2011, 32(4):498 514

Fig. 2. Ovarian appearances in severe IR. A, Ultrasound appearance

reported to discriminate virilizing tumors from nontumoral hyperandrogenism (22).

Another feature of nearly all known forms of severe IR

Endocrine Reviews, August 2011, 32(4):498 514

is usually found in the axillae, nape of the neck, and groin,

Hypertriglyceridemia and low high-density lipoprotein

IV. Clinical Features Limited to Some Severe

Lipodystrophy is a common cause of severe IR and

Severe Insulin Resistance Syndromes

more readily detected in women than men. Lean athletic

Severe IR per se may be associated with a range of

V. Sexual Dimorphism in Severe IR

Endocrine Reviews, August 2011, 32(4):498 514

VI. Biochemical Subphenotyping of Severe IR

Endocrine Reviews, August 2011, 32(4):498 514

VII. Monogenic IR Classification/Nomenclature

The key subdivision in this proposed mechanism-based

VIII. The INSR Spectrum

TABLE 1. Proposed new classification for syndromes of severe IR

B. Lipodystrophy (generalized or partial, Table 2)

Extreme hyperinsulinemia but normal lipid profile (39, 40),

An alternative term for this cluster of disorders is insulin receptoropathies.

Severe Insulin Resistance Syndromes

Fig. 4. Clinical spectrum of insulin receptoropathies.

more than 100 allelic variants have now been described.

Endocrine Reviews, August 2011, 32(4):498 514

IX. Downstream Insulin Signaling Defects

Endocrine Reviews, August 2011, 32(4):498 514

date in other, more distal signaling components involved

X. Disorders of Adipose Tissue Development/

101), are not covered in detail here, but are summarized in

TABLE 2. Classification and clinical features of lipodystrophies

Major clinical features

Common features: severe IR, T2DM, severe dyslipidemia,

Preserved facial and neck fat, multiloculated lipid

Severe Insulin Resistance Syndromes

tor A-like effector family-C) (107). Cidec knockdown cells

XII. Complex Syndromes

Endocrine Reviews, August 2011, 32(4):498 514

these, the IR is related to severe obesity. However, this

TABLE 3. Selected complex genetic disorders associated with severe IR

BBS1, BBS2, ARL6, BBS4, BBS5,

Centrosome/ basal body

Centrosome/basal body (130)

Yes (97, 134)

Involved in formation of nuclear

MOPDII, Osteodysplastic primordial dwarfism of Majewski type II.

Endocrine Reviews, August 2011, 32(4):498 514

sulin mimetic, as a trophic factor for pancreatic -cells, or