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 O’Rahilly
University of Cambridge Metabolic Research Laboratories (R.K.S., D.B.S., S.O.), Institute of Metabolic Science,
Addenbrooke’s 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.
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I. Introduction
I
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Endocrine Reviews, August 2011, 32(4):498 –514
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 (12–15).
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
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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
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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
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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
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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).
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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. C–F, 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.]
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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 (47–50). 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.
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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 insulin’s
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 insulin’s 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 (71–73), 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
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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.
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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 关INSR mutations (40) or anti-INSR antibodies (12)兴
B. Partialb 关AKT2 (19), AS160 (91, 169), others to be defined兴
II. Secondary to adipose tissue abnormalitiesc
A. Severe obesity 关e.g., MC4R (170), POMC (171), LEP (126), LEPR (172),
SH2B1 (173)兴
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 关SH2B1 (173)兴
Congenitally absent adipose tissue, or regional deficiency of
adipose tissue
Usually severe dyslipidemia, fatty liver
Low adiponectin and leptin levels
a
An alternative term for this cluster of disorders is “insulin receptoropathies.”
b
Affecting only some intracellular arms of the insulin signaling pathway, or variable among tissues.
c
In addition to frank obesity or lipodystrophy, there is a less well-defined group of disorders having clinical and biochemical evidence of “adipose tissue failure” and
severe dyslipidemia despite grossly normal whole body adipose tissue mass.
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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.
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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
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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 (92–96). 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 (103–106) 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 1–3 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
103–106
15, 175
18, 176, 177–179
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.
Severe Insulin Resistance Syndromes
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
(122–125). 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
Endocrine Reviews, August 2011, 32(4):498 –514
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 Alström 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
Alström 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)
Alström
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
MOPDII, Osteodysplastic primordial dwarfism of Majewski type II.
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 (131–132)
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)
Endocrine Reviews, August 2011, 32(4):498 –514
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 (141–151). It may exert activity by acting as an in-
edrv.endojournals.org
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 (153–157). 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.
Severe Insulin Resistance Syndromes
Endocrine Reviews, August 2011, 32(4):498 –514
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, Addenbrooke’s Hospital, Hills
Road, Cambridge CB2 0QQ, United Kingdom. E-mail: rks16@cam.
ac.uk or [email protected].
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.
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