Session 2: Type 2 Diabetes and MODY

Horm Res 2002;57(suppl 1):2933

Maturity-Onset Diabetes of the Young

(MODY): Genetic and Clinical
Characteristics
Gilberto Velho a Jean-Jacques Robert b
a INSERM

U-342, Hpital Saint-Vincent-de-Paul, and b Unit de Diabtologie de lEnfant, Hpital Necker

Enfants Malades, Paris, France

Key Words
Diabetes mellitus W MODY W Glucokinase W Transcription
factors W Insulin secretion W Genetics W Heterogeneity

Abstract
Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of familial
diabetes mellitus characterized by early onset, autosomal dominant inheritance and primary defects of insulin
secretion. Mutations in six genes cause most of the
MODY cases. These genes encode the enzyme glucokinase and the transcription factors hepatocyte nuclear
factor 4, hepatocyte nuclear factor 1, insulin promoter
factor-1, hepatocyte nuclear factor 1 and neuroD1. Additional MODY genes remain to be identified. The study
of families with MODY has shown that the different
MODY subtypes present different metabolic and clinical
profiles.
Copyright 2002 S. Karger AG, Basel

Definition and Diagnosis of MODY

The term MODY, standing for maturity-onset diabetes of the young, describes a group of affections characterized by familial hyperglycaemia with autosomal domi-

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nant inheritance [1, 2]. This form of hereditary transmission implies that half the subjects of both sexes will be
affected in each generation of a MODY family. Hyperglycaemia in MODY subjects usually develops at childhood,
adolescence or young adulthood, and is associated with
primary insulin secretion defects. These characteristics
distinguish MODY from other forms of type 2 (or noninsulin-dependent) diabetes (T2DM). The inheritance of
T2DM is rarely dominant, and it may develop at paediatric age only in particular circumstances such as the presence of obesity or the administration of drugs such as steroids or -adrenergic agonists. However, it is noteworthy
that MODY can also be revealed during treatment with
such drugs. It is important in hyperglycaemic children,
adolescents and young adults to exclude type 1 (or insulindependent) diabetes (T1DM), which requires immediate
insulin treatment. MODY differs from the T1DM in several ways. A family history of diabetes is always present in
MODY, the hyperglycaemia is usually mild, without tendency to ketosis, the insulin secretion in response to oral
(OGTT) or intravenous (IVGTT) glucose administration
is only moderately decreased, and autoimmunity is absent. A molecular diagnosis of most cases of MODY is
now possible by screening the known MODY genes (see
below) [1].

Dr Gilberto Velho
INSERM U-342, Hpital Saint-Vincent-de-Paul
82 Avenue Denfert Rochereau
F75014 Paris (France)
Tel. +33 1 40 48 82 48, Fax +33 1 40 48 83 52, E-Mail gvelho@infobiogen.fr

Clinical Features of MODY

MODY might not have any clinical expression during

childhood [3]. Often, it results only in a moderate rise in
fasting glycaemia (6.07.0 mM ). The glucose tolerance
assessed by OGTT may be normal or only moderately
impaired (7.811.1 mM at 2 h), and seldom shows diabetic glycaemic levels (611.1 mM at 2 h). The diagnosis of
hyperglycaemia in the majority of the children is fortuitous, most often during the course of a routine check-up
(school) or prospective testing because of a strong family
history of diabetes. In adults, MODY can remain clinically quiet for a long time or even indefinitely. The circumstances of diagnosis are similar to those in children: routine check-up (military service, work, pregnancy) or testing of members of suspected or known MODY families.
However, in other cases the hyperglycaemia will worsen
with age and evolve to clinical diabetes [4]. It might then
be practically impossible to distinguish on clinical
grounds MODY from other forms of T2DM, if not for the
evocative family context. Glycosuria due to a primitive
renal defect, and without direct relationship to the severity of the hyperglycaemia, can be observed in certain forms
of MODY [5].

The Genetics of MODY

MODY is one of the few forms of diabetes whose primary genetic defects have been identified. Early clinical
studies had showed that families with MODY could
present with different phenotypes characterized by hyperglycaemia of variable severity, which suggested that the
disorder was genetically heterogeneous [6]. Indeed, it is
now recognized that MODY is not a single entity but
presents genetic, as well as metabolic and clinical, heterogeneity (table 1). Mutations in six genes cause most of the
MODY cases. These genes encode the enzyme glucokinase (MODY2/GCK) [7] and the transcription factors
hepatocyte nuclear factor 4 (HNF-4/MODY1) [8], hepatocyte nuclear factor 1 (HNF-1/MODY3) [8], insulin
promoter factor 1 (IPF-1/MODY4) [9], hepatocyte nuclear factor 1 (HNF-1/MODY5) [10] and neuroD1
[11]. Except for a mutational hot-spot in HNF-1 that
seems to account for 2025% of MODY3 mutations in
several Caucasian populations [12], there is practically a
different mutation for each MODY family.
MODY has a worldwide distribution, but its prevalence is still unknown. Although commonly thought to be
a relatively rare form of diabetes, its frequency might

30

Horm Res 2002;57(suppl 1):2933

have been underestimated, as the hyperglycaemia can

remain undiagnosed until adulthood. It has been estimated that 25% of patients with type 2 diabetes may in
fact have MODY [13]. Furthermore, it has been shown
that as many as 10% of subjects originally classified as
having type 1 diabetes but not carrying high-risk HLA
haplotypes might indeed have MODY [14]. The relative
prevalence of the different subtypes of MODY has been
shown to vary greatly in studies of MODY families from
different populations [1]. MODY2 represents 863% of
cases and MODY3 2164% of cases. The other MODY
subtypes are rare disorders, having been described in only
a few families, while an additional unknown MODY
locus or loci (MODY-X) represent 1645% of the cases of
MODY. These contrasting results may be due to differences in the genetic background of these populations, or
else may reflect, at least partly, ascertainment bias in the
recruitment of families.

Metabolic Consequences of the Genetic

Defects

The identification of the MODY genes provided a

major boost for the understanding of the molecular basis
of hyperglycaemia in the different subtypes of the disease.
Glucokinase phosphorylates glucose to glucose-6-phosphate in pancreatic -cells and hepatocytes, and plays a
key role in the regulation and integration of glucose
metabolism in these tissues. In pancreatic -cells, glucose
metabolism and insulin secretion are strongly dependent
on the enzymatic activity of glucokinase. Expression studies have shown that the enzymatic activities of the glucokinase mutants detected in MODY2 families were impaired [15], resulting in decreased glycolytic flux in pancreatic -cells. This defect translates in vivo as a glucosesensing defect leading to an increase in the blood glucose
threshold that triggers insulin secretion [16], and a right
shift in the dose- response curve relating insulin secretion
to glucose levels [17]. Comparison of insulin secretion
rates at different glucose levels demonstrated that glucokinase-deficient MODY2 subjects present an average 60%
reduction in insulin secretion for a given glucose level
[17]. Interestingly, insulin levels in MODY2 subjects are
usually normal throughout the day, at the expense of the
hyperglycaemia [17]. The release of insulin in response to
other secretagogues such as arginine is usually well preserved [18], which suggests that this secretory defect is
indeed related to a relative glucose blindness of -cells. In
addition to the altered -cell function, abnormalities in

Velho/Robert

liver glucose metabolism contribute to the pathogenesis of

hyperglycaemia in patients with MODY2. Decreased net
accumulation of hepatic glycogen and increased hepatic
gluconeogenesis following meals were observed in glucokinase-deficient subjects [19].
The other subtypes of MODY are also characterized by
primary insulin secretion defects, but the pathophysiological mechanisms leading to these defects are still unclear.
It is noteworthy that no primary defect of insulin action
was observed in MODY subjects. The MODY genes other
than the glucokinase gene code for transcription factors
which play a key role in the development of the fetal pancreas, in the differentiation and the proliferation of the
insulin-secreting cells and in the expression of genes
involved in the control of glucose metabolism and the
production of insulin. Thus, studies in -cells from HNF1 (MODY3) knockout mice showed that a defect in
adenosine triphosphate (ATP) production in response to
glucose related to failure to generate the reduced form of
nicotinamide-adenine dinucleotide (NADH) from glycolytic substrates [20]. Although the precise nature of the
defect remains elusive, these studies suggested that a
reduction in the expression of one or more of the enzymes
of the glycolytic pathway proximal to the enolase step
accounts for the defects observed in glucose-stimulated
signal transduction and insulin secretion observed in
these animals. In this regard, the transcription factor
HNF-1 function as a heterodimer with the structurally
related HNF-1 to bind to DNA and, thus, MODY5 and
MODY3 may have common pathophysiological mechanisms in -cells.
HNF-4 is a member of the steroid/thyroid hormone
receptor superfamily, and it was demonstrated that longchain fatty acids directly modulate its transcriptional
activity by binding to the ligand-binding domain of the
HNF-4 gene [21]. Here again, the molecular mechanisms by which a reduction of HNF-4 activity results in
-cell defects and diabetes (MODY1) are not clearly
determined. Studies in embryonic stem cells demonstrated that loss of function of HNF-4 leads to impaired
expression of genes involved in glucose transport (GLUT2) and glycolysis (aldolase B, glyceraldehyde-3-phosphate
dehydrogenase) as well as the gene encoding liver pyruvate kinase [22]. HNF-4 is an upstream regulator of
HNF-1a/MODY3 expression. Decrease of HNF-1 expression as a result of an HNF-4 mutation might thus
contribute to the MODY1 phenotype.
IPF-1 (also known as IDX-1, STF-1 or PDX-1) is critically required for the embryonic development of the pancreatic islets, as well as for the transcriptional regulation

of insulin, glucose transporter-2 (GLUT2) and glucokinase genes in -cells. IPF-1 is normally expressed in all
cells of the pancreatic bud, and its absence in mice arrests
development at the bud stage, leading to pancreatic agenesis [23]. The transcription factor neuroD1 is involved in
the regulation of endocrine pancreas development. In
mice homozygous for a targeted disruption of neuroD1,
pancreatic islet morphogenesis is abnormal and expression of the insulin gene is decreased [24].

MODY: Genetic and Clinical

Characteristics

Horm Res 2002;57(suppl 1):2933

Clinical Heterogeneity of MODY

One of the most interesting consequences of the identification of the different MODY genes is the possibility of
characterizing the clinical expression of the various subtypes. The study of MODY families showed significant
differences between subjects with MODY2 and those
with MODY3 or MODY1 (table 1).
Hyperglycaemia associated with glucokinase mutations is often mild, with fewer than 50% of subjects presenting overt diabetes [3]. However, it develops during
the early years of life (youngest age of diagnosis: 12
months) and its penetrance in the affected families is very
rapidly complete in that the individuals who carry the
mutation are nearly always affected before puberty. The
progression of the hyperglycaemia is slow and in some
patients the glucose intolerance may remain unchanged
over several decades. There is a lower prevalence of diabetes microvascular complications (retinopathy and proteinuria) in MODY2 than in other subtypes of MODY
and late-onset type 2 diabetes [3, 4]. Moreover, the wellestablished association of type 2 diabetes or impaired glucose tolerance with a cluster of risk factors for macrovascular disease, including hypertension, obesity and dyslipidaemia, is very rare in MODY2 subjects, which is consistent with the low frequency of coronary heart disease in
these individuals. Interestingly, inheritance of a glucokinase mutation not only results in hyperglycaemia after
birth, but also reduced fetal growth and decreased birth
weight [25, 26]. This effect might be due to a reduction in
fetal insulin secretion [27]. Despite the reduced birth
weight, no differences in height, weight or body mass
index (BMI) are observed in pre-adolescent, adolescent
and adult MODY2 subjects as compared with their unaffected sibs [26]. Complete glucokinase deficiency has
recently been described in two children homozygous for
glucokinase mutations. These children presented marked
fetal growth retardation (birth weight less than the 3rd
percentile) and severe persistent neonatal diabetes [28].

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Table 1. Subtypes of MODY

MODY1

MODY2

MODY3

MODY4

MODY5

MODY6

MODYX

Genetic locus

20q

7p

12q

13q

17cen-q21.3

Unknown

Gene

HNF-4

Glucokinase

HNF-1

IPF-1

HNF-1

NeuroD1

Unknown/
heterogeneous?

Distribution
(% of MODY families)

Rare

863%a

2164%a

Rare

Unknown

Rare

1645%

Age at diagnosis

Postpubertal Childhood

Postpubertal

Early
adulthood

Postpubertal

Early
adulthood

Heterogeneous

Primary defect

Pancreas/
liver

Pancreas/
liver

Pancreas/
kidney/other?

Pancreas/
other?

Pancreas/
kidney/other?

Pancreas/
other?

Pancreas/
heterogeneous?

Associated features

Reduced
birth weight

Reduced tubular
reabsorption of glucose
Decreased glucose
threshold for glycosuria

Glomerulocystic
kidney disease
Genital malformations

Severity of diabetes

Severe

Mild

Severe

Mild?

Mild?

Unknown

Mild/
heterogeneous?

Complications of diabetes

Frequent

Rare

Frequent

Rare?

Rare?

Unknown

Unknown

Different distributions in different populations; HNF = hepatocyte nuclear factor; IPF = insulin promoter factor.

In contrast to the usually mild hyperglycaemia due to

glucokinase deficiency, MODY1 and MODY3 are severe
forms of diabetes, often evolving to insulin requirement
[4, 29]. Hyperglycaemia starts later than in MODY2,
usually around or after the puberty. Microvascular complications of diabetes are observed as frequently in these
subjects as in subjects with type 2 diabetes with late onset
[4]. HNF-1 is also expressed in the kidney, and a defect
in the renal resorption of glucose, characterized by a
decreased glucose threshold for glycosuria and reduced
tubular reabsorption of glucose, is found in MODY3 subjects [5]. Studies in HNF-1 knockout mice showed that
this defect is due to reduced expression in the proximal
tubules of the low- affinity/high-capacity sodium-glucose
cotransporter (SGLT2), which is under the control of
HNF-1 [5]
Mutations in HNF-1 were recently described in a few
families with early-onset familial diabetes consistent with
MODY [10]. In these pedigrees, diabetes was associated
with genital malformations and glomerulocystic kidney
disease that may be diagnosed before the impairment of
glucose tolerance. The other MODY subtypes seem to be
much rarer and very little is known about their clinical
characteristics.
In short, the clinical phenotype of MODY1 and
MODY3 resembles, in its natural history, that of type 2
diabetes, with subjects rapidly progressing from impaired

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Horm Res 2002;57(suppl 1):2933

glucose tolerance to overt diabetes, and with deterioration

of insulin secretion. In contrast, MODY2 is milder and
progresses slowly. However, an aggravation of the hyperglycaemia is always possible in the case of pregnancy, obesity or simply because of aging, and a regular medical follow-up is always recommended.

Treatment of MODY

The treatment of MODY depends essentially on the

cause and the severity of hyperglycaemia. For instance, in
about two thirds of the MODY2 cases no hypoglycaemic
medication is required, and diet therapy satisfactorily
controls blood glucose levels. The patients must be instructed not to gain excessive weight and to have regular
physical activity. However, even in these milder cases, a
pregnancy must always be regarded as at risk: treatment
by insulin is often necessary. In the more severe forms,
whatever the genetic origin, the indications for oral hypoglycaemic agents and for insulin do not differ from those
of type 2 diabetes with late age of onset. The monitoring
of glycaemic control and of diabetes complications must
be as rigorous as in any other form of diabetes.

Velho/Robert

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