REVIEW
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Clinical implications of a molecular genetic
classification of monogenic β-cell diabetes
Rinki Murphy, Sian Ellard and Andrew T Hattersley*
S U M M A RY
Monogenic diabetes resulting from mutations that primarily reduce
β-cell function accounts for 1–2% of diabetes cases, although it is often
misdiagnosed as either type 1 or type 2 diabetes. Knowledge of the genetic
etiology of diabetes enables more-appropriate treatment, better prediction
of disease progression, screening of family members and genetic counseling.
We propose that the old clinical classifications of maturity-onset diabetes
of the young and neonatal diabetes are obsolete and that specific genetic
etiologies should be sought in four broad clinical situations because of their
specific treatment implications. Firstly, diabetes diagnosed before 6 months
of age frequently results from mutation of genes that encode Kir6.2 (ATP-
sensitive inward rectifier potassium channel) or sulfonylurea receptor 1
subunits of an ATP-sensitive potassium channel, and improved glycemic
control can be achieved by treatment with high-dose sulfonylureas rather
than insulin. Secondly, patients with stable, mild fasting hyperglycemia
detected particularly when they are young could have a glucokinase
mutation and might not require specific treatment. Thirdly, individuals
with familial, young-onset diabetes that does not fit with either type 1 or
type 2 diabetes might have mutations in the transcription factors HNF-1α
(hepatocyte nuclear factor 1-α) or HNF-4α, and can be treated with low-
dose sulfonylureas. Finally, extrapancreatic features, such as renal disease
(caused by mutations in HNF-1β) or deafness (caused by a mitochondrial
m.3243A>G mutation), usually require early treatment with insulin.
KEYWORDS genetics, glucokinase, maturity onset diabetes of the young,
neonatal diabetes, transcription factor
REVIEW CRITERIA
For this Review we selected papers and abstracts listed in PubMed that reported
on the clinical features, genetics, prevalence, pathophysiology and treatment
of β-cell monogenic diabetes. We concentrated on neonatal diabetes and those
types of diabetes previously classified as maturity-onset diabetes of the young.
CME
R Murphy was a Clinical Research Fellow, S Ellard is Professor of Human
Molecular Genetics, and AT Hattersley is Professor of Molecular Medicine at
the Peninsula Medical School, Exeter, UK.
Correspondence
*Peninsula Medical School, Barrack Road, Exeter, Devon EX2 5DW, UK
andrew.hattersley@pms.ac.uk
Received 29 October 2007 Accepted 14 December 2007 Published online 26 February 2008
www.nature.com/clinicalpractice
doi:10.1038/ncpendmet0778
200 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM
Continuing Medical Education online
Medscape, LLC is pleased to provide online continuing
medical education (CME) for this journal article,
allowing clinicians the opportunity to earn CME credit.
Medscape, LLC is accredited by the Accreditation
Council for Continuing Medical Education (ACCME) to
provide CME for physicians. Medscape, LLC designates
this educational activity for a maximum of 1.0 AMA PRA
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please go to http://www.medscape.com/cme/ncp
and complete the post-test.
Learning objectives
Upon completion of this activity, participants should be
able to:
1 List the 4 proposed clinical subtypes of monogenic
diabetes.
2 Describe the clinical features of glucokinase
hyperglycemia/diabetes.
3 Describe the criteria for testing to distinguish dia-
betes caused by hepatocyte nuclear factor-1alpha
(HNF-1alpha) mutations from type 1 and 2 diabetes.
4 Describe the clinical features of permanent and
transient neonatal diabetes.
Competing interests
The authors declared no competing interests. Désirée
Lie, the CME questions author, declared no relevant
financial relationships.
INTRODUCTION
Since 1992, numerous genetic subtypes of diabetes
have been described in which gene mutations
result in diabetes primarily through β-cell dysfunc-
tion. This knowledge means that patients who
were previously categorized clinically as having
maturity-onset diabetes of the young (MODY),
permanent neonatal diabetes mellitus (PNDM)
or transient neonatal diabetes mellitus (TNDM)
can now usually be classified by genetic subgroup.
Definition of the genetic subgroup can result in
appropriate treatment, genetic counseling and
prognostic information.
In this article we describe the challenge of
identifying the minority of patients who have
monogenic β-cell diabetes (1–2% of all diabetes
cases) amongst the vast majority who have type 1
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Table 1 Differentiation of β-cell monogenic diabetes from type 1 and type 2 diabetes.
Features Type 1 diabetes Young-onset GCK DM TF DM KATP PNDM 3243 MIDD
type 2 diabetes
Insulin dependence Yes No No No Yes Yes or no
Parent affected 2–4% Yes Yes Yes 15% Mother
Age of onset 6 months to Adolescence and Birth Teens to young <6 months Young adulthood
young adulthood young adulthood adulthood
Obesitya Population Increased Population Population Population Rare
frequency frequency frequency frequency frequency
Acanthosis No Yes No No No No
nigricans
Glycemia High Variable Mild High High Variable
β-Cell autoantibodies Yes No No No No No
C-peptide (nmol/l) <0.33 0.5–>1 0.1–0.7 0.1–0.7 <0.2 0.1–0.7
aThe population frequency is the frequency of obesity that occurs in the general population. Abbreviations: 3243 MIDD, maternally inherited diabetes and
deafness associated with mitochondrial m.3243A>G mutation; GCK DM, diabetes mellitus associated with mutations in glucokinase; KATP PNDM, permanent
neonatal diabetes associated with mutations in the ATP-sensitive potassium channel; TF DM, diabetes mellitus associated with mutations in transcription factors
(e.g. hepatocyte nuclear factor 1-α [HNF1-α], HNF4-α, or HNF-1β).

or 2 diabetes. First, we discuss why we think
the term MODY might be outdated. Next,
we describe how to differentiate monogenic
diabetes from other types of diabetes. We then
outline the monogenic β-cell forms of diabetes
under the following four main phenotypic cate-
gories for clearer clinical identification: diabetes
diagnosed before 6 months of age (which is usually
associated with mutations in Kir6.2 or sulfonyl-
urea receptor 1 [SUR1], or with abnormalities in
chromosome 6q24); familial, mild fasting hyper-
glycemia (associated with glucokinase muta-
tion); familial, young-onset diabetes (associated
with HNF1 homeobox A gene [HNF1A; previ-
ously termed TCF1] or HNF4 homeobox A gene
[HNF4A]); and diabetes with extrapancreatic
features (associated with HNF1 homeobox B
gene [HNF1B; previously termed TCF2] or
mitochondrial m.3243A>G mutation).
At least seven discrete genetic etiologies of
diabetes2–4 have been described, and these
account for much of the clinical heterogeneity
apparent among patients receiving a diagnosis
of MODY on the basis of this clinical definition.
The different genetic subtypes differ in age of
onset, pattern of hyperglycemia, response to
treatment and associated extrapancreatic mani-
festations, which suggests that it is inappropriate
to lump them all into a single category. The
‘maturity-onset’ part of MODY implies a resem-
blance to type 2 diabetes, but all the subtypes—
as well as differing from each other—are very
different from type 2 diabetes. Since the classifi-
cation of diabetes was revised in 1998 to reflect
etiology,5 we propose that the term MODY is
now obsolete and that the correct monogenic
names of the different forms of young-onset
diabetes should be used when possible.

WHY THE TERM MODY IS DEAD DIFFERENTIATION OF MONOGENIC FROM

The confusing term maturity-onset diabetes of
the young originates from the time when the
terms juvenile-onset and maturity-onset were
used to distinguish between type 1 (insulin-
dependent) and type 2 (noninsulin-dependent)
diabetes. MODY was used to describe a subgroup
of autosomal-dominantly inherited diabetes that
despite having a young age of onset (at least one
family member diagnosed before 25 years of
age) was noninsulin-dependent (as patients had
moderate but insufficient circulating C-peptide
levels 5 years after diagnosis).1
OTHER TYPES OF DIABETES
Differentiation from apparent
type 1 diabetes
Patients with a clinical diagnosis of type 1
diabetes who also have a two-generation or
three-generation family history of diabetes with
evidence of noninsulin dependence should be
suspected of having monogenic diabetes (Table 1).
Absence of autoantibodies against pancreatic
antigens and detection of measurable C-peptide
in the presence of hyperglycemia outside the
‘honeymoon period’ (the period of up to 5 years

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after diagnosis when there is some endogenous
insulin secretion) are atypical for type 1 diabetes
and increase the probability that the patient has
monogenic diabetes. We recommend genetic
testing for HNF1A mutations (the most common
transcription factor mutations that cause mono-
genic diabetes) in any young adult with apparent
type 1 diabetes and a diabetic parent, and who is
antibody-negative at diagnosis, especially if there
is preservation of C-peptide levels in both the
child and the parent.
Differentiation from apparent young-onset
type 2 diabetes
Monogenic forms of diabetes should be suspected
in cases of young-onset, apparent type 2 diabetes
when obesity and features of insulin resistance
are absent (Table 1). In patients with young-
onset diabetes, lack of obesity, absence of acan-
thosis nigricans or polycystic ovarian syndrome,
and elevated or normal HDL-cholesterol and
reduced or normal triglyceride levels6–8 are all
features that make presence of monogenic β-cell
forms of diabetes likely.
As mentioned above, when monogenic
diabetes is diagnosed it can be classified under
four phenotypic categories: diabetes diagnosed
before 6 months of age; familial, mild fasting
hyperglycemia; familial, young-onset diabetes
(Figure 1); or diabetes with extrapancreatic
features (Figure 2). We now detail when each of
these categories should be considered, and the
features of each.
DIABETES DIAGNOSED BEFORE
6 MONTHS OF AGE
Diabetes diagnosed before 6 months of age
is likely to be one of the monogenic forms of
neonatal diabetes and not autoimmune type 1
diabetes.9,10 The diabetes resolves in approxi-
mately half of all patients with neonatal diabetes,
and the majority of cases of TNDM (~70%) are
linked to abnormalities in the chromosome 6q24
region.11 In individuals with PNDM, mutations in
KCNJ11 (potassium inwardly rectifying channel,
subfamily J, member 11 gene) or ABCC8 (ATP-
binding cassette, subfamily C, member 8 gene)—
which encode the Kir6.2 and SUR1 subunits,
respectively, of the ATP-sensitive potassium
channel (KATP channel)—are found in half of the
patients.12–17 It is important to identify patients
with these mutations because—despite being
insulin dependent—oral sulfonylurea provides
the most effective therapy.18
202 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM
Mutations in KCNJ11 or ABCC8 can also
cause TNDM.16,19 At the time of diagnosis, it is
not known whether the diabetes in an infant will
be transient or permanent. We therefore recom-
mend testing for 6q24 abnormalities and KCNJ11
mutations first, and for ABCC8 mutations
if these tests are negative (Figure 1).
Neonatal diabetes due to mutations in the
ATP-sensitive potassium channel
Clinical features
The majority of patients with Kir6.2 neonatal
diabetes (i.e. neonatal diabetes caused by
Kir6.2 mutations) have isolated diabetes; most
have PNDM rather than TNDM, but 20% have
neurological features (Table 2). These features
occasionally constitute a severe syndrome of
developmental delay, epilepsy and neonatal
diabetes (DEND) or, more commonly, inter-
mediate DEND, which is characterized by
diabetes and less-severe developmental delay
without epilepsy.20 The diabetes typically
presents from birth to 26 weeks of age (mean
5 weeks), usually with marked hyperglycemia
and ketoacidosis.15 Low birth weight (mean
2,500 g) is common because of fetal insulin defi-
ciency in utero, because insulin is a major fetal
growth factor in the third trimester of preg-
nancy.21 SUR1 neonatal diabetes has a similar
phenotype, but TNDM is more common than
PNDM, and DEND syndrome is rare.
Pathophysiology
Four Kir6.2 and four SUR1 subunits make up the
pancreatic KATP channel; this channel regulates
insulin secretion by linking intracellular ATP
production to β-cell membrane potential and
insulin secretion. Activating KCNJ11 or ABCC8
mutations mostly reduce the response of the
channel to ATP, which prevents channel closure
and consequent insulin secretion. The specific
mutation determines the phenotype,15,22 and for
Kir6.2 mutations there is a striking correlation
with the functional severity of the muta-
tion (reviewed by Hattersley and Ashcroft20),
although there are a few exceptions.23,24
Therapy
The identification of KATP channel mutations in
patients with PNDM has had a dramatic impact
on their diabetes therapy. These patients have little
or no endogenous insulin secretion and C-peptide
is usually undetectable,12 so they were previously
assumed to require lifelong insulin treatment.
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Clinical subtypes of β-cell Diabetes with extrapancreatic

monogenic diabetes features (see Figure 2)

Diabetes diagnosed Familial, mild fasting Familial, young-onset

before 6 months of age hyperglycemia (>5.5 mmol/l)a diabetes

Transient Permanent Onset at birth Onset in adolescence or

Stable hyperglycemia young childhood
OGTT: low increment Progressive hyperglycemia
(<4.5 mmol/l) between 0 h and OGTT: large increment
2 h glucose (>4.5 mmol/l) between 0 h and
Test for Test for Complications rare 2 h glucose
chromosome KCNJ11 and, Complications frequent
6q24 if negative,
abnormalities ABCC8
and, if negative,
for KCNJ11 and
ABCC8

If negative, Test for heterozygous Test for HNF1A and

consider INS or GCK mutations if negative HNF4A
GCK mutations
or rare causes in
presence of
other features
(Table 2)

Transient Oral No treatment Oral sulfonylurea (low dose)

insulin sulfonylurea
(high dose)

Observe for Use May require insulin in pregnancy

relapse of glibenclamide depending on fetal growth
diabetes in if neurological
teenage years features
present

Figure 1 Clinical subtypes and management of monogenic β-cell diabetes that does not have
extrapancreatic features. See Figure 2 for diabetes that has extrapancreatic features. To convert plasma
glucose measurements to mg/dl, multiply by 18.02. Abbreviations: ABCC8, ATP-binding cassette,
subfamily C, member 8 gene; GCK, glucokinase gene; HNF, hepatocyte nuclear factor; HNF1A, HNF1
homeobox A gene; HNF4A, HNF4 homeobox A gene; INS, insulin gene; KCNJ11, potassium inwardly
rectifying channel, subfamily J, member 11 gene; OGTT, oral glucose tolerance test.

Sulfonylureas do, however, bind to the SUR1
subunits of the KATP channel and close the channel
in an ATP-independent manner. Approximately
90% of patients with Kir6.2 neonatal diabetes can
transfer from insulin to sulfonylurea tablets and
achieve improved glycemic control,18,23 and a
similar pattern is emerging for patients with SUR1
neonatal diabetes.16,22
Most patients with KATP channel mutations
are treated with glibenclamide. The doses used are
considerably higher than those used for the
treatment of type 2 diabetes,13,18 and these high
doses (typically 0.4–0.8 mg/kg/day) may cause
transitory diarrhea.25 Glibenclamide binds
nonspecifically to SUR subunits found in KATP
channels in nerve, muscle and brain, in addi-
tion to β cells, and hence enables some improve-
ment of associated neurological symptoms as
well as the diabetes. Although many patients
with mild developmental delay and diabetes
(intermediate DEND) treated with sulfonylurea
therapy have been able to discontinue insulin,
and have shown improved motor function,
concentration and speech,26 others with the

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Diabetes with
extrapancreatic features

Renal cysts Deafness Optic atrophy Megaloblastic anemia

Exocrine pancreatic deficiency Short stature Diabetes insipidus Deafness
Genitourinary abnormalities Pigmentary retinopathy Deafness Cardiac abnormalities
Renal tract abnormalities Neurological abnormalities
Neurological abnormalities

Test for RCAD syndrome: Test for MIDD: mitochondrial Test for Wolfram syndrome: Test for TRMA syndrome:
HNF1B m.3243A>G mutation WFS1 SLC19A2

Early insulin Oral sulfonylurea initially, Insulin Thiamine and/or sulfonylurea

but rapid insulin requirement and/or early insulin

Figure 2 Clinical subtypes and management of monogenic β-cell diabetes that has extrapancreatic features. See Figure 1 for diabetes
without extrapancreatic features. Abbreviations: HNF1B, HNF1 homeobox B gene; MIDD, maternally inherited diabetes and deafness;
RCAD, renal cysts and diabetes; SLC19A2, solute carrier family 19, member 2 gene; TRMA, thiamine-responsive megaloblastic
anemia; WFS1, Wolfram syndrome 1 gene.

full DEND syndrome have not responded to
sulfonylurea therapy. Since a sulfonylurea drug
would be used in a situation where it does not
have a license, we recommend liaison with
centers that have experience in transferring
patients from insulin to sulfonylureas to help
guide this process.
Genetic counseling
Families with two or more generations affected
are rare (~15% of cases), and most children with
KATP channel mutations are born to parents who
do not have diabetes. The majority of sporadic
cases result from de novo heterozygous muta-
tions, but around 40% of patients with PNDM
as a result of ABCC8 mutations show recessive
inheritance.17 For parents of children with reces-
sively inherited ABCC8 mutations the risk of
neonatal diabetes for each future child is 25%,
but the affected child is at very low risk of having
affected offspring. Affected individuals with
a heterozygous KATP channel mutation have a
50% chance of passing the mutation to their chil-
dren. Unaffected parents of a child with a de novo
mutation, however, should be counseled that the
recurrence risk of a second child being affected
is not negligible because germline mosaicism (in
which mutations may be present in the gonads
but not detectable in blood) has been reported
in several families.27,28
Transient neonatal diabetes due
to disordered imprinting
Clinical features
TNDM is usually diagnosed in the first week of
life (range 1–81 days). Affected children are typi-
cally born with lower birth weight (mean 2,000 g)
than those with PNDM, but require less insulin
and doses can be tapered so that they are no
longer insulin-treated by a median of 12 weeks.29
The relapse rate is 50–60%, at an average age of
14 years; diabetes at this stage results predomi-
nantly from moderate β-cell dysfunction.
One-third of patients with TNDM have macro-
glossia, and occasionally an umbilical hernia
is present.
Pathophysiology
Gene imprinting occurs when only the paternal
or maternal allele of a gene is expressed. In 70%
of cases of TNDM11 there is an abnormality of
a region of chromosome 6q24 that results in the
overexpression of the paternally expressed genes
PLAGL1 (pleiomorphic adenoma gene-like 1;
also termed tumor repressor ZAC) and HYMAI
(hydatidiform mole associated and imprinted
gene).29 Three types of abnormality have been
described: paternal uniparental disomy, which
accounts for 50% of sporadic TNDM cases;
paternal duplication of 6q24, found in most
familial cases; and abnormal methylation of

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Table 2 Causes of neonatal diabetes mellitus.

Pancreatic Protein, chromosome Reported prevalence Inheritance Features in addition to neonatal diabetes
pathophysiology or gene affected and low birth weight
Reduced β-cell KATP channel 50% of PNDM and 25% Autosomal dominant Developmental delay and epilepsy
function of TNDM or recessive
Chromosome 6q24 70% of TNDM Variable Macroglossia and umbilical hernia
GCK (recessive 6 cases of PNDM77–79 Autosomal recessive Both parents have heterozygous GCK-
mutation) (6 families) associated hyperglycemia
SLC2A2 1 case of PNDM80 Autosomal dominant Hypergalactosemia, hepatic failure
(1 family)
GLIS3 6 cases of PNDM81,82 Autosomal recessive Congenital hypothyroidism, glaucoma, liver
(3 families) fibrosis and cystic kidney disease
Reduced PTF1A 5 cases of PNDM83 Autosomal recessive Pancreatic and cerebellar agenesis
pancreas mass (2 families)
PDX1 2 cases of PNDM56,84 Autosomal recessive Pancreatic agenesis
(2 families)
HNF1B 1 case of PNDM, 1 case Autosomal dominant Exocrine pancreas insufficiency and
of TNDM10,65 (2 families) renal cysts
Increased β-cell EIF2AK3 25 cases of PNDM85–87 Autosomal recessive Spondyloepiphyseal dysplasia, renal failure,
destruction (15 families) recurrent hepatitis and mental retardation
FOXP3 17 cases of PNDM88–92 X-linked Immune dysregulation, intractable diarrhea,
(13 families) eczematous skin rash and elevated IgE
INS 21 cases of PNDM31 Autosomal dominant None
(16 families)
Abbreviations: EIF2AK3, eukaryotic translation initiation factor 2-α kinase 3 gene; FOXP3, forkhead box P3 gene; GCK, glucokinase gene; GLIS3, GLIS family zinc
finger 3 gene; HNF1B, HNF1 homeobox B gene; INS, insulin gene; KATP channel, ATP-sensitive potassium channel; PDX1, pancreatic and duodenal homeobox 1
gene (previously termed IPF1); PNDM, permanent neonatal diabetes mellitus; PTF1A, pancreas specific transcription factor, 1a gene; SLC2A2, solute carrier
family 2, member 2 gene (previously termed GLUT2); TNDM, transient neonatal diabetes mellitus.

the maternal copy of chromosome 6, found Other subtypes of neonatal diabetes

in sporadic cases.29 Most of the remainder of
patients with TNDM have KATP channel muta-
tions,11,19 but there is virtually no overlap with
the mutations observed in PNDM cases.
Therapy
Treatment during the neonatal phase is with
insulin; however, on relapse treatment may
include dietary modification, oral hypoglycemic
agents and/or insulin.30
Genetic counseling
Genetic counseling of TNDM cases depends
on the genetic etiology. Cases with uniparental
disomy of chromosome 6 are sporadic and,
therefore, have low recurrence risk in siblings
and offspring. In cases of familial paternal
duplications of the 6q24 region, males have a
50% chance of transmitting TNDM to their
children. If females pass on this duplica-
tion, their children will not be affected but
the sons may pass on the risk of TNDM to
their children.
Heterozygous mutations in the insulin gene (INS)
have been identified and could account for 15–
20% of cases of PNDM.31 Patients with PNDM
and an INS mutation have permanent diabetes
without extrapancreatic features except a low
birth weight, which is a feature of all subtypes
of neonatal diabetes. The other known genetic
causes of neonatal diabetes are rare (Table 2).
Clinical features, such as pancreatic aplasia or
extrapancreatic features, and knowledge of
consanguinity can be very helpful when deciding
whether to test for other genetic subtypes.
FAMILIAL, MILD FASTING HYPERGLYCEMIA
Patients who have mild fasting hyperglycemia
(5.5–8.0 mmol/l; to convert to mg/dl, multiply
by 18.02) that shows little deterioration with age
might have heterozygous glucokinase gene (GCK)
mutations that do not require any specific treat-
ment. Although the mild hyperglycemia can be
present from birth, patients are asymptomatic
and most remain undiagnosed until later in life.
The age at testing will determine the clinical

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classification given to patients; individuals can
be diagnosed as having incidental hyperglycemia
or even type 1 diabetes (if detected during child-
hood), gestational diabetes (if detected during
pregnancy) or well-controlled type 2 diabetes (if
detected in adulthood). A diagnosis of incidental
hyperglycemia in a young child might trigger
intensive monitoring for incipient type 1 diabetes
and in some cases unnecessary treatment with
insulin.32 Making a genetic diagnosis of gluco-
kinase hyperglycemia is, therefore, worthwhile.33
Fasting hyperglycemia in a child is strongly sugges-
tive of a GCK mutation and apparently unaffected
parents should be tested for asymptomatic fasting
hyperglycemia (Figure 1).
Prevalence
No large-scale population studies to assess
the prevalence of GCK mutations have been
performed. Approximately 2% of pregnant women
are diagnosed as having gestational diabetes,
and of these approximately 2–5% have a GCK
mutation,34 which would suggest a population
prevalence of 0.04–0.10%.
Pathophysiology
The glucokinase enzyme catalyzes the rate-
limiting step of glucose phosphorylation and,
therefore, enables the β cell and hepatocyte to
respond appropriately to the degree of glycemia.35
The kinetics of the glucokinase enzyme mean that
heterozygous mutations cause an increased fasting
glucose set point but that glucose metabolism is
regulated to this new level. As a result, most indivi-
duals with heterozygous GCK mutations have
fasting plasma glucose levels between 5.5 and
8.0 mmol/l. Patients with mutated GCK produce
adequate insulin responses, and most have a
small increment in plasma glucose (<3 mmol/l in
70% of patients) 2 h after an oral glucose load.36
This feature also explains why hemoglobin A1c
levels rarely exceed 7.5% and why microvascular
complications are rare.37 Approximately half of
all patients with a GCK mutation are diagnosed
as diabetic based on an oral glucose tolerance
test (OGTT), with the majority being diagnosed
according to fasting values rather than 2 h values.
Most of those without diabetes have impaired
fasting glucose levels.36,38
Management
Hypoglycemic medication is not appropriate
for most patients with heterozygous glucokinase
diabetes, as they have mild hyperglycemia;
206 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM
furthermore, because of the preserved regula-
tion of glycemia, such medication has minimal
effect. In 28 patients we observed identical hemo-
globin A1c values (6.3%) before and after treatment
with insulin or other medication was discontinued
(O Gill-Carey et al., unpublished data).
Pregnancy is the one exception in which hypo-
glycemic medication might be appropriate, but
insulin is required only in cases in which there is
excess fetal growth.39 The fetus has a 50% chance
of inheriting the GCK mutation from its mother,
and the presence of the GCK mutation in the
fetus influences its sensing of maternal glycemia.
If the fetus does not inherit the GCK mutation
it will respond to maternal hyperglycemia by
excess insulin production and, therefore, excess
growth; however, if the fetus does inherit the
GCK mutation it will produce normal amounts
of insulin and grow normally.40,41 If increased
fetal growth is detected it will be hard to lower
the mother’s glucose level (which is regulated
at the raised level); thus, greater-than-replacement
doses of insulin will be required.39 Early delivery
is often the most helpful intervention.
Even though microvascular complications
are rare in glucokinase diabetes, it is prudent
to maintain regular retinopathy screening in
patients over 40 years of age. The inheritance
of a GCK mutation does not protect against
the concurrent development of type 2 diabetes,
which occurs at a similar prevalence in those with
GCK mutations as in the general population.
Genetic counseling
Each child of a parent with glucokinase diabetes
has a 50% chance of inheriting the GCK muta-
tion. Predictive genetic testing of children is not
advocated since measurement of fasting blood
glucose provides a simple diagnostic test—GCK
mutation carriers have mild hyperglycemia from
birth. Molecular genetic analysis can then be used
as a confirmatory test. In the rare circumstance
in which both parents have glucokinase diabetes
(more likely in consanguineous couples), each
child has a 25% chance of having PNDM caused
by inheriting two GCK mutations.
FAMILIAL, YOUNG-ONSET DIABETES
Those patients in whom diabetes is diagnosed
before age 25 years and does not fit the phenotypes
of either type 1 or type 2 diabetes, and who also
have a strong family history of diabetes, need to be
evaluated for mutations in transcription factors,
most commonly hepatocyte nuclear factor 1-α
MURPHY ET AL. APRIL 2008 VOL 4 NO 4

(HNF-1α; encoded by HNF1A). An important
reason for making this genetic diagnosis is that,
in many cases, treatment with low-dose oral
sulfonylurea is highly effective (Figure 1).
Heterozygous mutations in the transcription
factor genes HNF1A, HNF4A, or HNF1B (effects
of mutations in this gene are detailed in the
later section on diabetes with extrapancreatic
features), and more rarely in PDX1 (pancre-
atic and duodenal homeobox 1 gene; previ-
ously termed IPF1) or NEUROD1 (neurogenic
differentiation 1 gene), result in similar diabetes
phenotypes. Patients with these mutations differ
from those with glucokinase diabetes by having
normal glucose levels at birth and progressive
deterioration in glucose tolerance. As a conse-
quence of their increasing hyperglycemia they
are at high risk of diabetic complications. In the
early stages of diabetes, fasting glucose remains
relatively normal initially, but increases greatly
following meals or a glucose load.36
HNF1A mutation carriers
Clinical features
Patients with HNF1A mutations typically present
in their teens or early adult life with symptomatic
diabetes and have progressive β-cell failure that
results in increasing hyperglycemia throughout
life. HNF1A mutation carriers often have fasting
plasma glucose levels that remain normal initially,
despite diabetes being indicated by elevated
2 h plasma glucose concentrations during
OGTT,36 with a large increment value (typically
>4.5 mmol/l). This test result occurs because
initially the insulin secretion rate in HNF1A
mutation carriers is appropriate to their insulin
sensitivity at glucose values below 8 mmol/l.42
The frequency of microvascular complications
in patients with HNF1A diabetes is similar to
that in patients with type 1 and type 2 diabetes,
and is related to poor glycemic control.43 Although
the frequency of hypertension in patients with
HNF1A diabetes is similar to that in patients
with type 1 diabetes, the frequency of coronary
heart disease seems to be greater in patients with
HNF1A diabetes.43 Raised HDL-cholesterol levels
are observed in patients with HNF1A diabetes,
in contrast to the reduced levels seen in patients
with type 2 diabetes and the normal levels seen
in patients with type 1 diabetes.7 The elevated
HDL-cholesterol level does not, however, seem
to be cardioprotective.
Glycosuria is a key feature of HNF1A mutation
carriers before they develop diabetes.44 A
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positive urine test for glycosuria after a large
unrefined carbohydrate meal could, therefore,
suggest the need for a formal OGTT and genetic
testing in young children from families with an
HNF1A mutation.
Prevalence
Mutations in the HNF1A gene are the commonest
monogenic form of transcription factor diabetes,
with 193 different mutations reported; the most
common mutation is the insertion of a C nucleotide
(Pro291fsinsC) in a polyC-tract mutation hotspot.45
We estimate that patients with mutations in HNF1A
account for approximately 1–2% of patients with
diabetes, although most cases are not diagnosed.
This prevalence level would result in a population
frequency of approximately 0.02–0.04%.
Pathophysiology
Patients with HNF1A mutations have a progres-
sive β-cell defect. HNF-1α is one of several tran-
scription factors within a complex regulatory
network that includes HNF-4α, PDX1 and HNF-
1β. This network is crucial for pancreatic β-cell
development and functioning.
Penetrance
HNF1A mutations have a high penetrance, with
63% of carriers developing diabetes by 25 years of
age, 79% by 35 years and 96% by 55 years.46 The
age at diagnosis is determined in part by the loca-
tion of the mutation: patients with mutations in the
terminal exons (8–10) diagnosed on average 8 years
later than those with mutations in exons 1–6.47
Intrauterine exposure to maternal diabetes
reduces the age of onset of this type of diabetes in
the offspring by approximately 12 years.48
Management
The importance of diagnosing patients who have
HNF1A diabetes is that this type of diabetes is
very sensitive to sulfonylurea therapy.49 The
therapy is highly effective because the β-cell
defects that result from reduced transcription
factor function are in glucose metabolism and
are, therefore, bypassed by sulfonylureas, which
act on the KATP channel to stimulate insulin
release.49 We recommend sulfonylurea therapy
initially in very low doses (e.g. 20–40 mg glicla-
zide daily) as the first-line pharmacological treat-
ment in HNF1A diabetes, and that patients on
other oral agents or insulin should have a trial of
sulfonylureas. Currently, insulin remains the most
common treatment during pregnancy for this
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patient group, but further studies are required
to validate the safety and efficacy of sulfonylureas
such as glibenclamide (also known as glyburide)
that have least permeability through the placenta
and have been used in gestational diabetes.50
Genetic counseling
A parent with HNF1A diabetes has a 50% chance
of passing on the mutation to each child. Predictive
genetic testing in unaffected family members may
be helpful but should be preceded by counseling to
enable relatives to make an informed decision. The
main advantages of knowing this genetic informa-
tion include reduction in uncertainty over the risk
of diabetes and increased efficiency in monitoring
for early signs of diabetes.51
HNF4A mutation carriers
Clinical features
The diabetes of HNF4A mutation carriers presents
in a very similar way to that of HNF1A mutation
carriers. Unlike HNF1A mutation carriers, however,
these carriers have reduced levels of lipoprotein A1,
lipoprotein A2 and HDL cholesterol, whereas
LDL-cholesterol levels tend to be increased; thus,
the lipid patterns of HNF4A mutation carriers
resemble those commonly seen in patients with
type 2 diabetes.8 Increased birth weight (by
~800 g) and macrosomia are common features of
HNF4A mutation carriers, and transient neonatal
hypoglycemia may precede the diabetes.52
Prevalence
The prevalence of HNF4A diabetes is 20–30%
in patients thought to have transcription factor
diabetes who do not have a mutation in HNF1A.8
Pathophysiology
Similar to patients with HNF1A diabetes, patients
with HNF4A mutations have a progressive β-cell
dysfunction. The mechanism that underlies the
biphasic pattern of hyperinsulinism in utero
followed by diabetes in later life is unknown.52
Penetrance
Generally, HNF4A has a high penetrance, with the
majority of carriers developing diabetes by
the age of 25 years; however, in some families the
age of diagnosis is older.52
Management
Long-term treatment with low-dose sulfonyl-
ureas seems effective for HNF4A diabetes.8 The
clinical significance of reduced HDL-cholesterol
208 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM
and increased LDL-cholesterol levels in these
patients remains to be determined; at present
the cholesterol levels of patients with HNF4A
mutations should be managed in light of other
cardiovascular risk factors, as for other patients
with diabetes. Genetic counseling is similar to
that for individuals with HNF1A mutations.
Other etiologies
Mutations in the transcription factor genes PDX1
and NEUROD1 are extremely rare,53–56 but from
the limited data it seems that the diabetes pheno-
type, penetrance and pathophysiology resemble
those in patients with mutations in the tran-
scription factor HNF-1α. Two different mutations
in the transcription factor gene PAX4 (paired
box 4 gene) have been identified in Thai fami-
lies with MODY.57 Two families with diabetes
and exocrine pancreatic dysfunction have been
found who have mutations in the gene encoding
the enzyme carboxyl ester lipase (CEL).3
In at least 11% of families with autosomal-
dominant β-cell disease a genetic diagnosis cannot
be made, presumably because of the presence of
as-yet-undetermined gene mutations.4
DIABETES WITH EXTRAPANCREATIC
FEATURES
Very rare diabetes-related disorders (Figure 2), such
as Wolfram syndrome and thiamine-responsive
megaloblastic anemia, are fairly easy to recog-
nize because of the presence of comorbidities;
Wolfram syndrome (also known as DIDMOAD
because of the occurrence of diabetes insipidus,
diabetes mellitus, optic atrophy and deaf-
ness) is also characterized by progressive neuro-
degeneration. Patients with thiamine-responsive
megaloblastic anemia in addition to hemato-
logical manifestations might also have deafness,
cardiac abnormalities and neurological abnormal-
ities. Two diabetes subtypes with extrapancreatic
features that are frequently underdiagnosed at
present, however, are the renal cysts and diabetes
syndrome resulting from mutations or dele-
tions of the transcription factor gene HNF1B,
and maternally inherited diabetes and deafness
(MIDD) resulting from the mitochondrial point
mutation m.3243A>G.
Renal cysts and diabetes syndrome
Clinical features
The predominant phenotype of patients with
HNF1B mutations is developmental renal
disease, which is characterized by renal cysts
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A B Pigmentary
retinopathy
Deafness

Cardiomyopathy
Abnormal Focal
LFTs segmental
glomerulosclerosis
Diabetes
Developmental
Pancreatic Diabetes
kidney disease
atrophy
Constipation
Urogenital
abnormalities Myopathy

Gout

Figure 3 Phenotypes seen in diabetes with extra-pancreatic features. (A) Renal cysts and diabetes
syndrome caused by mutation in HNF1 homeobox B gene (HNF1B). (B) Maternally inherited diabetes and
deafness caused by mitochondrial m.3243A>G mutation. Kidney manifestations of HNF1B mutations
include hypoplastic glomerulocystic kidney disease, cystic renal dysplasia, solitary functioning kidney,
horseshoe kidney and oligomeganephronia. Urogenital manifestations of HNF1B mutations include
bicornuate uterus, bilateral agenesis of vas deferens, large epididymal cysts and asthenospermia.
Abbreviation: LFTs, liver function tests.

(the most common phenotype), renal dysplasia,
renal-tract malformations and/or familial hypo-
plastic glomerulocystic kidney disease.10 Female
genital-tract malformations, gout and hyper-
uricemia can also occur (Figure 3A).58,59 Birth
weight is reduced by around 800 g as a result
of reduced insulin secretion in utero.60 Half of
all HNF1B mutation carriers have early-onset
diabetes that presents in a similar fashion to
HNF1A diabetes, but HNF1B mutation carriers
are more insulin resistant.61 Common vari-
ants in the HNF1B gene are associated with an
increased risk for prostate cancer but protect
against type 2 diabetes.62
Prevalence
HNF1B mutations are less frequent than HNF1A
or HNF4A mutations in patients with diabetes,
but they are common in patients with develop-
mental renal disease.63 A family history of renal
disease (or diabetes) is not essential to prompt a
screen for this disorder, as spontaneous muta-
tions and deletions of this gene are common
(one-third to two-thirds of cases).63,64
Pathophysiology
HNF-1β is a transcription factor that is expressed
in early embryonic development of the kidney,
pancreas, liver and genital tract, which explains the
multiple organ involvement seen (Figure 3A).
Penetrance
There is wide variation in phenotypes even
within a single pedigree, such that different
combinations and severities of organ involve-
ment are manifest among affected individuals
who have identical mutations.58,59,63,65
Management
The coexisting pancreatic atrophy and associ-
ated insulin resistance means that the diabetes of
HNF1B carriers is not sensitive to sulfonylurea
medication, and early insulin therapy is required.
Maternally inherited diabetes and deafness
Clinical features
Maternally inherited diabetes associated with
young-onset, bilateral sensorineural deafness should
prompt genetic testing for the most common mito-
chondrial point mutation—m.3243A>G. This
mutation results in dysfunction of mitochondria
(organelles whose main purpose is to generate
energy by producing ATP); as a result, the manifes-
tations in patients with MIDD are within the organs
that are most metabolically active (Figure 3B).
At the most severe end of the spectrum, the

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m.3243A>G mutation can manifest in mito-
chondrial myopathy, encephalopathy, lactic acidosis
and stroke-like episodes syndrome.66
Diabetes in MIDD usually presents insidiously
in a similar way to type 2 diabetes, but approxi-
mately 20% of patients have an acute presenta-
tion that resembles that of type 1 diabetes, with
ketoacidosis occurring in 8%.67–69 The mean age
at diagnosis of diabetes is 37 years, and ranges
from 11 to 68 years.67
Prevalence
The prevalence of MIDD due to the m.3243A>G
mutation in Japanese patients with diabetes
is 1.5%, which seems to be higher than that in
Europeans and other ethnic groups (0.4%).70
Pathophysiology
The pathophysiology of diabetes in MIDD
is related to the mitochondrial dysfunction
in the highly metabolically active pancreatic
islets. This dysfunction causes abnormal β-cell
function, reduction in β-cell mass71,72 and
insulin deficiency.73,74
Penetrance
The penetrance of diabetes in offspring with
the m.3243A>G mutation is age dependent, but
is estimated to be more than 85% by the age
of 70 years.69,75
Management
The majority of patients with MIDD are initially
treated with dietary modification or oral hypo-
glycemic agents, but insulin is usually required
by 2 years after diagnosis.67–69 Metformin should
probably be avoided because of the theoretical
risk of exacerbating lactic acidosis, as metformin
is known to interfere with mitochondrial function
(although no cases have been reported to date).
Genetic counseling
Affected fathers should be reassured that they
will not transmit the disorder to their children.
An affected mother transmits the m.3243A>G
mutation to all her children, even though some
children may remain clinically unaffected.
CONCLUSIONS
With the advances in defining the monogenic
etiology of diabetes, which accounts for approxi-
mately 1–2% of all diabetes cases, we have learned
that these genetic subtypes of diabetes require
different treatments. Patients with Kir6.2 or SUR1
210 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM
PNDM require high-dose sulfonylurea therapy,
most cases of transcription factor diabetes require
low-dose sulfonylurea therapy, and glucokinase
diabetes requires no hypoglycemic treatment.
These therapies are different to those used to
treat type 1 or type 2 diabetes, so it is impor-
tant that we identify individuals with a probable
monogenic cause for their diabetes. Molecular
genetic testing for a mutation in the KCNJ11
or ABCC8 genes that encode the KATP channel
subunits should be considered in all patients
with diabetes diagnosed before 6 months of
age. Individuals with familial, young-onset
diabetes (diagnosed before 25 years of age)
that does not fit with type 1 or type 2 diabetes
should be screened for mutations in the tran-
scription factor gene HNF1A, and then for those
in HNF4A. Patients with familial, mild fasting
hyperglycemia that does not deteriorate with age
should be tested for GCK mutations. Diagnostic
molecular genetic testing is now available in
many countries.76 This testing can improve
the management of these monogenic forms of
diabetes, which are often underdiagnosed.
KEY POINTS
■ The old clinical classifications of maturity-
onset diabetes of the young (MODY) and
neonatal diabetes should now be replaced with
a molecular genetic diagnosis, as this offers a
more useful guide to clinical management
■ Monogenic β-cell diabetes is often
misdiagnosed as type 1 or type 2 diabetes and
a correct diagnosis can improve treatment
■ Diabetes diagnosed before 6 months of age will
be monogenic diabetes and the underlying gene
mutations can be identified in 75% of cases
■ Most neonatal patients with mutations in the
potassium-sensitive ATP channel subunits
Kir6.2 and sulfonylurea receptor 1 will be best
treated with high-dose sulfonylureas rather
than insulin injections, despite seeming
insulin dependent
■ Patients with glucokinase mutations have stable,
mild, regulated hyperglycemia throughout life
and do not need pharmacological treatment
except possibly during pregnancy
■ Patients with mutations in HNF1A have
hyperglycemia that deteriorates with age and
that can be severe; these patients, like patients
with mutations in HNF4A, are sensitive to the
hypoglycemic effects of sulfonylureas
MURPHY ET AL. APRIL 2008 VOL 4 NO 4

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75 Maassen JA (2002) Mitochondrial diabetes: 85 Delepine M et al. (2000) EIF2AK3, encoding translation Acknowledgments
pathophysiology, clinical presentation, and genetic initiation factor 2-α kinase 3, is mutated in patients with We thank all our colleagues
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Our research is supported
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344: 1588–1592 Diabetes 53: 1876–1883 Trust Clinical Research
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syndrome presenting with neonatal diabetes mellitus Foundation Trust (S Ellard).
89 Bennett CL et al. (2001) The immune dysregulation,
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84 Schwitzgebel VM et al. (2003) Agenesis of human competing interests.
of the immunodysregulation, polyendocrinopathy,
pancreas due to decreased half-life of insulin promoter enteropathy, X linked (IPEX) syndrome. J Med Genet
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