Genetically Defined Forms of Diabetes in Children
Simeon I. Taylor and
Elif Arioglu
Diabetes Branch, National Institute of Diabetes and Digestive and
Kidney Disease, National Institutes of Health, Bethesda, Maryland
20892
Address correspondence and requests for reprints to: Simeon I. Taylor, M.D., Ph.D., National Institutes of Health, Building 10, Room 9S-213, 10 Center Drive, Bethesda, Maryland 20892. E-mail:
Simeon_Taylor{at}nih.gov
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Introduction
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ALTHOUGH type 1 diabetes has its highest
incidence in the pediatric age range, there are also other forms of
diabetes that affect children. From a clinical point of view, it is
important to recognize these other forms of diabetes because of the
important implications with respect to both prognosis and therapy. In
addition, these relatively uncommon forms of diabetes provide an
instructive model for the pathophysiological mechanisms that cause
diabetes. Some syndromes are caused by insulin deficiency
[e.g. maturity-onset type diabetes of the young (MODY)].
Unlike patients with type 1 diabetes who exhibit near total absence of
insulin due to autoimmune destruction of the ß cell, MODY is
characterized by a milder form of insulin deficiency caused by
mutations in genes required for normal ß cell function (1, 2, 3, 4, 5, 6).
However, not all cases of diabetes are caused by insulin deficiency.
Indeed, some patients develop diabetes even though their ß cells
secrete sufficient insulin to achieve significant hyperinsulinemia
(e.g. lipoatrophic diabetes and syndromes due to mutations
in the insulin receptor gene) (7, 8, 9, 10).
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Insulin Deficiency
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MODY: clinical features
MODY was originally defined by three diagnostic criteria (1): 1)
onset at less than 25 yr of age; 2) autosomal dominant inheritance; and
3) noninsulin-dependent physiology. However, recent progress has led to
the identification of at least five genes that are responsible for
causing MODY (2, 3, 4, 5, 6). Thus, based on the locus of the mutation causing
disease, the heterogeneous group of MODY patients can be subdivided
into relatively homogeneous groups of patients with subtypes of MODY
(see below). Assignment to a specific subtype of MODY has important
prognostic implications. For example, MODY2 is characterized by mild
hyperglycemia that has onset early in childhood and is nonprogessive
(11). Indeed, only half the patients have sufficient hyperglycemia to
meet the criteria for diagnosis of diabetes. As predicted by the mild
degree of hyperglycemia, MODY2 does not carry a high risk of developing
chronic complications of diabetes. In contrast, the degree of
hyperglycemia and the risk of diabetic complications is much greater in
MODY1, MODY3, and MODY5 (1). MODY4 seems to be intermediate in severity
(5). Different authorities have published various estimates of the
prevalence of the subtypes of MODY, but MODY2 and MODY3 are the most
common, together accounting for up to 80% of cases.
Like MODY, the syndrome due to mutations in the insulin gene has early
onset and is transmitted with autosomal dominant inheritance (12).
Although heterozygosity for a mutation in the insulin gene does not
necessarily cause diabetes, it seems to be a genetic risk factor that
predisposes to the development of insulin deficiency and diabetes in
some patients. However, unlike MODY, patients with mutations in the
insulin gene have elevated levels of circulating immunoreactive insulin
because of the accumulation of abnormal molecules with markedly reduced
biological activity.
Diabetes due to mutations in mitochondrial DNA is transmitted with
matrilineal inheritance and incomplete penetrance. In pedigrees where
the mutation is transmitted to daughters (who can transmit the mutation
to their own children), the pattern can resemble autosomal inheritance.
Furthermore, because this syndrome may lead to early-onset diabetes, it
may occasionally be confused with MODY. However, unlike MODY, diabetes
due to mutations in mitochondrial DNA is often associated with other
clinical features, such as deafness (13, 14, 15). Wolframs syndrome is
another genetic form of diabetes mellitus with onset in childhood, but
this syndrome has multiple features that distinguish it from MODY:
autosomal recessive inheritance and association with optic atrophy,
diabetes insipidus, and deafness. The gene for Wolframs has been
mapped to chromosome 4p and has recently been cloned (16).
MODY: molecular genetics
Glucokinase catalyzes the first step in intracellular glucose
metabolism (i.e. phosphorylation of glucose) (17, 18).
Whereas hexokinases are capable of phosphorylating all hexoses,
glucokinase is specific for glucose. In addition, whereas hexokinases
have such low Km that they are saturated at physiological
concentrations of glucose, glucokinase has a Km of
10
mM so that the flux through the enzyme is sensitive to
changes in the glucose concentration within the the physiological
range. Furthermore, glucokinase is specifically expressed in
hepatocytes and pancreatic ß cells, where it plays a crucial role in
glucose metabolism. Abundant evidence has demonstrated that glucokinase
is a necessary component in the ß cell glucose-sensor. Indeed, the
fact that inactivating mutations in the glucokinase gene lead to
impaired insulin secretion and diabetes (MODY2) provides one of the
most convincing pieces of evidence proving the role of glucokinase in
regulating insulin secretion (3). This conclusion is further reinforced
by the observation that an activating mutation in glucokinase led to
hyperinsulinism and hypoglycemia (19). Consistent with the dominant
inheritance in this syndrome, patients with MODY2 have inherited one
mutant allele of the glucokinase gene. Furthermore, studies in an
animal model have demonstrated that selective knock-out of glucokinase
expression in the ß cell can cause diabetes, suggesting that impaired
insulin secretion is the major mechanism whereby these mutations cause
diabetes (20, 21). Nevertheless, there is some evidence that the defect
in hepatic glucokinase may also contribute to the pathophysiology of
the disease.
The remaining four subtypes of MODY are caused by mutations in the
genes encoding transcription factors that regulate the expression of
genes in the ß cell (22): hepatocyte nuclear factor-4
(HNF-4
)
in MODY1 (2), HNF-1
in MODY 3 (4), insulin promoter factor-1 (IPF-1)
in MODY4 (5), and HNF-1ß in MODY5 (6). IPF-1 contributes to the
regulation of the insulin gene as well as additional genes that are
important for ß cell function. Indeed, homozygosity for inactivating
mutations of IPF-1 leads to pancreatic agenesis (23). [In contrast,
heterozygosity for a mutation in IPF-1 causes MODY (5).] As suggested
by their names, the family of HNF also plays a role in regulation of
genes expressed in the liver. Although it is likely that mutations in
HNF-1
, -1ß and -4
cause diabetes because they impair insulin
secretion, it is possible that metabolic defects within the hepatocyte
also contribute to disease pathogenesis.
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Insulin Resistance
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Clinical features
Two clinical features are commonly observed in patients with
extreme insulin resistance, regardless of the pathogenetic mechanism
causing the disease: acanthosis nigricans and hyperandrogenism (7, 8, 9, 24). Acanthosis nigricans is a hyperkeratotic, hyperpigmented skin
lesion located primarily in skin folds such as the axillae and
antecubital fossae (Fig. 1
).
Hyperandrogenism results from hypersecretion of androgens by the
ovaries (7, 24). Clinically, the elevated levels of testosterone are
manifested as a syndrome of polycystic ovaries, oligomenorrhea,
hirsutism, and, sometimes, virilization. Several lines of evidence
suggest that both acanthosis nigricans and hyperandrogenism are caused
by hyperinsulinemiapresumably exerting "toxic" effects on the
skin and ovaries. For example, when patients with type B insulin
resistance enter remission because of a decrease in the titer of
autoantibodies directed against the insulin receptor, this results in
amelioriation (even disappearance) of acanthosis nigricans and
hyperandrogenism. Similarly, in insulin-resistant patients with
polycystic ovarian syndrome, administration of drugs such as metformin
and thiazolidinediones leads to a decrease in plasma insulin levels and
a concomitant amelioriation in hyperandrogenism (25, 26). Although the
mechanism whereby hyperinsulinemia elicits these toxic effects has not
been elucidated, it is likely not to be mediated by conventional
insulin receptors inasmuch as these are functionally impaired as the
result of inactivating mutations.
In addition to the clinical signs that the various syndromes share in
common, distinct syndromes are characterized by the presence or absence
of specific features. For example, there are at least three clinical
syndromes caused by mutations in the insulin receptor gene. Type A
insulin resistance is defined by the triad of insulin resistance,
acanthosis nigricans, and hyperandrogenism in the absence of obesity or
lipoatrophy (27). Patients with leprechaunism have multiple
abnormalities, including intrauterine growth retardation, fasting
hypoglycemia, and death within the first 12 yr of life (Fig. 2
) (28, 29, 30). Interestingly, patients with
leprechaunism are reported to exhibit striking degrees of ß cell
hyperplasia. Thus, near-total absence of insulin receptors does not
impair the ability of human ß cells to become hyperplastic, a
reaction that can be rationalized as an attempt to compensate for
severe insulin resistance. The Rabson-Mendenhall syndrome is associated
with short stature, protruberant abdomen, and abnormalities of teeth
and nails (Fig. 3
); pineal hyperplasia
was a characteristic in the original description of this syndrome (31).
In addition to genetic defects in insulin receptor function, there is
an autoimmune form of insulin resistance due to autoantibodies to
the insulin receptor (type B insulin resistance) (27). Although this
syndrome has been reported in the pediatric age range, most of the
patients have onset during adulthood.
Lipoatrophic diabetes, another clinical syndrome associated with
insulin resistance, is characterized by a paucity of subcutaneous fat,
hypertriglyceridemia, and hepatic steatosis. Although the mutations
causing genetic forms of lipoatrophic diabetes have not yet been
identified, current evidence suggests that insulin resistance is
secondary to the lipoatrophy and there may not be a primary genetic
defect in the insulin action pathway (32, 33). The genes causing two
forms of the lipoatrophy have been mapped: an autosomal recessive form
of congenital, generalized lipoatrophy (Seip-Berardinelli syndrome;
Figs. 3
and 4
) to chromosome 9q34 (34),
and an autosomal dominant form of partial (face-sparing) lipodystrophy
with onset during adolescence (Dunnigans syndrome; Figs. 4
and 5
) to chromosome 1q2122 (35). In
addition to the genetic forms of lipoatrophy, there are also syndromes
that are believed to have autoimmune pathogenesis inasmuch as they are
associated with well-defined autoimmune diseases, such as juvenile
dermatomyositis.

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Figure 4. Magnetic resonance imaging of the mid-thigh
region of patients with lipoatrophy. A, A normal 42-yr-old woman with a
body mass index of 24 kg/m2. The normal individual
demonstrates both sc adipose tissue (a circumferential band encircling
the thigh) and deep adipose tissue located between muscle bundles. B, A
37-yr-old woman with Dunnigans syndrome. This shows a marked
diminution in the sc fat, but relative preservation of deeper fat.
C, a 29-yr-old woman with Seip-Berardinelli syndrome.
This patient shows near total absence of both compartments of adipose
tissue, but the brightness of the muscle density is indicative of
increased triglyceride content in muscle tissue.
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Figure 5. Photograph of patient with face-sparing
lipoatrophy (Dunnigans syndrome). There is marked decrease in sc
adipose tissue in the legs. Please note that this patient has undergone
plastic surgery to achieve this normal facial appearance; before
surgery, she had a marked increase in the fat in her face and neck.
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Molecular genetics
Numerous (>70) mutations have been identified in the insulin
receptor gene in various insulin-resistant patients. The mutations can
be classified based on the mechanisms whereby they impair receptor
function (8, 9, 10). In some cases, the mutations decrease the number of
receptors expressed on the cell surface [e.g. by decreasing
the rate of receptor biosynthesis (class 1), accelerating the rate of
receptor degradation (class 5), or inhibiting the transport of
receptors to the plasma membrane (class 2)]. In addition, some
mutations impair the intrinsic function of the receptor
[e.g. by decreasing the affinity of insulin binding (class
3) or inactivating receptor tyrosine kinase activity (class 4)].
Leprechaunism and the Rabson-Mendenhall syndrome are both transmitted
with autosomal recessive patterns of inheritance; affected individuals
have inherited two inactivating mutations in the insulin receptor gene
(36, 37, 38). There are two forms of type A insulin resistance: a severe
form with autosomal recessive inheritance (39) and a milder form with
autosomal dominant inheritance, most commonly caused by dominant
negative mutations in the tyrosine kinase domain of the insulin
receptor (40, 41). Among patients who have inherited two mutant alleles
of the insulin receptor gene, it is not entirely clear why different
patients develop different clinical syndromes. At least two different
mechanisms have been proposed to correlate phenotype with genotype (8, 9, 42). First, the severity of the defect in receptor function seems to
correlate with the severity of the clinical syndrome, with the
most severe mutations causing leprechaunism and less
severe mutations causing type A insulin resistance. The
Rabson-Mendenhall syndrome is associated with defects that are
intermediate in severity. Second, differences in genetic background
(i.e. genotypes at other loci) may modulate the severity of
the clinical syndrome.
Class 1, decreased rate of receptor biosynthesis.Several genetic defects can interfere with receptor biosynthesis.
In one patient with leprechaunism, there was a total deletion of the
insulin receptor gene (43). In several patients, there appear to be
regulatory mutations that decrease the level of insulin receptor
messenger RNA without altering the protein coding sequence of the gene
(37). Finally, various premature chain termination mutations can lead
to the synthesis of truncated receptors that are essentially inactive
(36, 37, 38).
Class 2, impaired transport of receptors to the plasma membrane.Some mutations appear to prevent folding of receptors into their
normal conformations. Various chaperone molecules within the
endoplasmic reticulum serve a "quality control" function, and
appear to target the receptors for intracellular degradation, resulting
in inefficient transport to the plasma membrane (39, 44, 45). Most
class 2 mutations have been identified in the N-terminal half of the
-subunit of the receptor (Fig. 6
), but
some mutations in the tyrosine kinase domain have also been reported to
promote intracellular degradation (46).

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Figure 6. Mapping of mutations in the insulin receptor
gene within the protein coding sequence of the complementary
DNA. This figure depicts the regions of the insulin receptor that are
the most common sites of missense mutations giving rise to the various
classes of defects in receptor function.
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Class 3, decreased affinity of insulin binding.The N-terminal
half of the
-subunit has been implicated in the ligand binding
domain of the insulin receptor and the homologous type 1 insulin-like
growth factor receptor. Thus, it is not surprising that most of the
mutations that inhibit insulin binding map to that domain of the
receptor (Fig. 6
) (8, 9, 10). In addition, at least two class 3 mutations
have been mapped near the C-terminal domain of the
-subunit.
Class 4, impaired receptor tyrosine kinase activity.Most
class 4 mutations are located in the tyrosine kinase domain in the
intracellular portion of the ß-subunit (Fig. 6
) (8, 9, 10). However,
mutations in the extracellular domain of the receptor have also been
reported to uncouple insulin binding from the ability to activate the
receptor tyrosine kinase (47). Unlike most other classes of mutation,
mutations in the kinase domain of the receptor exert a dominant
negative effect to cause insulin resistance (48, 49). The resulting
dominant inheritance pattern may be explained as follows: formation of
hybrid receptors (i.e. association of a mutant
ß-dimer to a mutant
ßmutant-dimer) leads to the
formation of a catalytically inactive
2ßßmutant-tetramer. Thus, in addition to
being inactive itself, the mutant receptor inhibit the activity of wild
type receptors.
Class 5, accelerated degradation of the receptor.This is the
least common class of mutations, with only two mutant alleles having
been reported to accelerate degradation of receptors after having been
inserted in the plasma membrane (50, 51). Both of these mutations are
located near the middle of the ß-subunit: Lys460Glu (36, 50) and
Asn462Ser (38, 51). In other words, although there seems not to be an
intrinsic defect in the ability of these mutant receptors to mediate
insulin action. Accelerated degradation of mutant receptors leads to a
marked decrease in the number of receptors expressed on the plasma
membrane. The impairment in the ability of the acid pH within endosomes
to dissociate insulin from the receptor is associated with accelerated
receptor degradation (36, 50, 52). Although the mechanism has not been
elucidated, this change in pH sensitivity is associated with
preferential sorting of internalized receptors away from the pathway
for recycling to the plasma membrane and toward the pathway for
lysosomal degradation.
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Conclusion
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In the past, the term "juvenile diabetes" was used to refer to
diabetes caused by autoimmune destruction of pancreatic ß cells (now
called type 1 diabetes). This term was discarded for a variety of
reasons; among them, the fact that there are multiple types of diabetes
with onset in childhood. As emphasized in this brief review, clinicians
had previously described numerous forms of early-onset diabetes, some
of which seemed to follow simple Mendelian forms of inheritance. As a
result of the incredible progress in molecular genetics in recent
years, the genes responsible for
10 forms of diabetes have been
identified. These developments provide a paradigm for future progress
toward the goal of using molecular medicine to diagnose specific forms
of diabetes in the hope that this will lead to develop therapeutic
approaches that are tailored to specific molecular defects. In some
cases, this may turn out to be gene replacement therapy, but it is also
likely that the efficacies of specific drugs will be shown to correlate
with the patients genotype. Finally, molecular diagnosis holds the
promise of diagnosing diabetes early in life, before the onset of overt
diabetes. This will facilitate early interventions designed to prevent
diabetes. This avenue of research has the potential to lead to
significant advances that will benefit patients suffering from the
disease.
Received September 20, 1999.
Accepted October 3, 1999.
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