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The New England Journal of Medicine

Review Article
Mechanisms of Disease
Volume 345:971-980

September 27, 2001

Number 13
Molecular Mechanisms and Clinical Pathophysiology of Maturity-Onset Diabetes
of the Young
Stefan S. Fajans, M.D., Graeme I. Bell, Ph.D., and Kenneth S. Polonsky, M.D.

Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous
group of disorders characterized by nonketotic diabetes mellitus, an
autosomal dominant mode of inheritance, an onset usually before the age of
25 years and frequently in childhood or adolescence, and a primary defect in
the function of the beta cells of the pancreas. MODY can result from
mutations in any one of at least six different genes ( Table 1
<http://content.nejm.org/cgi/content/full/345/13/#T1> ). One of these genes
encodes the glycolytic enzyme glucokinase (associated with MODY 2), 3
<http://content.nejm.org/cgi/content/full/345/13/#R3>  and the other five
encode transcription factors: hepatocyte nuclear factor (HNF) 4{alpha}
(associated with MODY 1), 4
<http://content.nejm.org/cgi/content/full/345/13/#R4>  HNF-1{alpha} (MODY
3), 5 <http://content.nejm.org/cgi/content/full/345/13/#R5>  insulin
promoter factor 1 (IPF-1 [MODY 4]), 6
<http://content.nejm.org/cgi/content/full/345/13/#R6>  HNF-1{beta} (MODY 5),
7 <http://content.nejm.org/cgi/content/full/345/13/#R7>  and neurogenic
differentiation factor 1 (NeuroD1), also known as beta-cell E-box
transactivator 2 (BETA2 [MODY 6]). 8
<http://content.nejm.org/cgi/content/full/345/13/#R8>  All these genes are
expressed in beta cells, and mutation of any of them leads to beta-cell
dysfunction and diabetes mellitus ( Figure 1
<http://content.nejm.org/cgi/content/full/345/13/#F1> ). These genes are
also expressed in other tissues, and abnormalities in liver and kidney
function may also be evident in some forms of MODY. Factors that affect
insulin sensitivity, such as infection, puberty, pregnancy, and (in rare
cases) obesity, may trigger the onset of diabetes and increase the severity
of hyperglycemia in patients with MODY, but otherwise, nongenetic factors
have no important role in the development of this disorder. Studies of MODY
have led to a better understanding of the genetic causes of beta-cell
dysfunction.


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Table 1. MODY-Related Genes and the Clinical Phenotypes Associated with
Mutations in the Genes.



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Figure 1. Model of a Pancreatic Beta Cell and the Proteins Implicated in
Maturity-Onset Diabetes of the Young (MODY).
Glucose is transported into the beta cell by a specific glucose-transporter
protein (GLUT-2) on the cell surface. The MODY-associated glycolytic enzyme
glucokinase (associated with MODY 2) catalyzes the transfer of phosphate
from ATP to glucose to form glucose-6-phosphate. By means of this reaction,
glucokinase functions as the glucose sensor of the beta cell. The generation
of ATP by glycolysis and the Krebs cycle leads to inhibition and closure of
the ATP-sensitive potassium channels (the target of sulfonylurea drugs),
depolarization of the plasma membrane, opening of the voltage-dependent
calcium channels, and influx of extracellular calcium and mobilization of
calcium from intracellular stores, leading to the fusion of
insulin-containing secretory granules with the plasma membrane and the
release of insulin into the circulation. A mutation in one of the alleles of
the gene encoding glucokinase leads to a reduction in beta-cell glucokinase
activity, resulting in decreased glucose phosphorylation in the beta cell
and glucose-stimulated insulin release at any blood glucose concentration.
The MODY-associated transcription factors — hepatocyte nuclear factor (HNF)
4{alpha} (associated with MODY 1), HNF-1{alpha} (MODY 3), insulin promoter
factor 1 (IPF-1 [MODY 4]), HNF-1{beta} (MODY 5), and neurogenic
differentiation factor 1 (NeuroD1), or beta-cell E-box transactivator 2
(BETA2 [MODY 6]) — function in the nucleus of the beta cell and regulate the
transcription of the insulin gene (either directly, as in the case of
HNF-1{alpha}, HNF-1{beta}, IPF-1, and NeuroD1 or BETA2, or indirectly,
through effects on the expression of other transcription factors, as in the
case of HNF-4{alpha}); they also regulate the transcription of genes
encoding enzymes involved in the transport and metabolism of glucose as well
as other proteins required for normal beta-cell function.

Clinical Presentation
The most common clinical presentation of MODY is mild, asymptomatic
hyperglycemia in nonobese children, adolescents, and young adults who have a
prominent family history of diabetes, often in successive generations (a
pattern consistent with an autosomal dominant mode of inheritance). Some
patients have mild fasting hyperglycemia for many years, whereas others have
varying degrees of glucose intolerance for several years before the onset of
persistent fasting hyperglycemia. 9
<http://content.nejm.org/cgi/content/full/345/13/#R9> , 10
<http://content.nejm.org/cgi/content/full/345/13/#R10> , 11
<http://content.nejm.org/cgi/content/full/345/13/#R11> , 12
<http://content.nejm.org/cgi/content/full/345/13/#R12>  Since mild
hyperglycemia may not cause the classic symptoms of diabetes, the diagnosis
may not be made until adulthood. However, according to prospective testing,
it appears that in most patients the onset is in childhood or adolescence.
In some patients, there may be rapid progression to overt asymptomatic or
symptomatic hyperglycemia, necessitating therapy with an oral hypoglycemic
drug or insulin. 9 <http://content.nejm.org/cgi/content/full/345/13/#R9> ,
10 <http://content.nejm.org/cgi/content/full/345/13/#R10> , 11
<http://content.nejm.org/cgi/content/full/345/13/#R11> , 12
<http://content.nejm.org/cgi/content/full/345/13/#R12> , 13
<http://content.nejm.org/cgi/content/full/345/13/#R13>  The presence of
persistently normal plasma glucose concentrations in persons with mutations
in any of the known MODY-related genes is unusual, and in the majority of
them diabetes eventually develops (with the exception of many patients with
glucokinase mutations, as discussed below). According to current estimates,
MODY may account for 1 to 5 percent of all cases of diabetes in the United
States and other industrialized countries. 3
<http://content.nejm.org/cgi/content/full/345/13/#R3> , 14
<http://content.nejm.org/cgi/content/full/345/13/#R14>
Several clinical characteristics distinguish patients with MODY from those
with type 2 diabetes, including a prominent family history of diabetes in
three or more generations, a young age at presentation, and the absence of
obesity ( Table 2 <http://content.nejm.org/cgi/content/full/345/13/#T2> ).
In recent years, type 2 diabetes has been recognized with increasing
frequency in adolescents who are obese, as are most older patients with type
2 diabetes.


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Table 2. Distinguishing Clinical Characteristics of MODY and Type 2
Diabetes.

Function of the Gene Products Implicated in MODY
Glucokinase
Glucokinase is expressed at its highest concentrations in pancreatic beta
cells and in the liver. It catalyzes the transfer of phosphate from ATP to
glucose, generating glucose-6-phosphate ( Figure 1
<http://content.nejm.org/cgi/content/full/345/13/#F1> ). This reaction is
the first, rate-limiting step in glucose metabolism. Glucokinase functions
as the glucose sensor in beta cells by controlling the rate of entry of
glucose into the glycolytic pathway (glucose phosphorylation) and by
controlling the rate of its subsequent metabolism. 16
<http://content.nejm.org/cgi/content/full/345/13/#R16>  The glucokinase that
is expressed in the liver plays a key part in the ability of that organ to
store glucose as glycogen, particularly in the postprandial state.
Heterozygous mutations in the gene encoding glucokinase lead to a partial
deficiency of this enzyme and are associated with MODY 2; homozygous
mutations result in a complete deficiency of this enzyme and lead to
permanent neonatal diabetes mellitus. 17
<http://content.nejm.org/cgi/content/full/345/13/#R17>
HNF-1{alpha}, HNF-1{beta}, and HNF-4{alpha}
The liver-enriched transcription factors HNF-1{alpha}, HNF-1{beta}, and
HNF-4{alpha} were first discovered in studies designed to identify the
proteins responsible for the tissue-specific regulation of gene expression
in the liver. 18 <http://content.nejm.org/cgi/content/full/345/13/#R18>
They are also found in other tissues and organs, including the pancreatic
islets, the kidneys, and genital tissues. HNF-1{alpha} and HNF-1{beta} are
members of a family of transcription factors. 18
<http://content.nejm.org/cgi/content/full/345/13/#R18>  HNF-4{alpha} is an
orphan nuclear receptor. 19
<http://content.nejm.org/cgi/content/full/345/13/#R19>  HNF-1{alpha},
HNF-1{beta}, and HNF-4{alpha} constitute part of a network of transcription
factors that function together to control gene expression during embryonic
development and during adulthood in tissues in which they are coexpressed.
In pancreatic beta cells, these transcription factors regulate the
expression of the insulin gene as well as the expression of genes encoding
proteins involved in glucose transport and metabolism 20
<http://content.nejm.org/cgi/content/full/345/13/#R20>  and mitochondrial
metabolism 21 <http://content.nejm.org/cgi/content/full/345/13/#R21>  — all
of which are linked to insulin secretion. In the liver, these proteins
regulate lipoprotein biosynthesis. 22
<http://content.nejm.org/cgi/content/full/345/13/#R22>  The expression of
HNF-1{alpha} is regulated at least in part by HNF-4{alpha}. 21
<http://content.nejm.org/cgi/content/full/345/13/#R21>
IPF-1
IPF-1 is a transcription factor that was originally isolated as a regulator
of the transcription of the insulin and somatostatin genes. 23
<http://content.nejm.org/cgi/content/full/345/13/#R23>  It also plays a
central part in the development of the pancreas and in the regulation of the
expression of a variety of genes in the pancreatic islets, including (in
addition to the insulin gene) the genes encoding glucokinase, islet amyloid
polypeptide, and glucose transporter 2. 23
<http://content.nejm.org/cgi/content/full/345/13/#R23>  IPF-1 also appears
to mediate glucose-induced stimulation of insulin-gene transcription. 24
<http://content.nejm.org/cgi/content/full/345/13/#R24>
NeuroD1 (BETA2)
The transcription factor NeuroD1, or BETA2, was isolated on the basis of its
ability to activate the transcription of the insulin gene. It is required
for the normal development of the pancreatic islets. 25
<http://content.nejm.org/cgi/content/full/345/13/#R25>
Clinical Features of Subtypes of MODY
MODY 2
Glucokinase-related MODY (MODY 2) is a common form of this disorder,
especially in children with mild hyperglycemia and in women with gestational
diabetes and a family history of diabetes. It has been described in persons
of all racial and ethnic groups. 26
<http://content.nejm.org/cgi/content/full/345/13/#R26>  More than 130
MODY-associated mutations have been found in the glucokinase gene.
Heterozygous mutations in glucokinase are associated with a mild form of
nonprogressive hyperglycemia that is usually asymptomatic at diagnosis and
is treated with diet alone. 27
<http://content.nejm.org/cgi/content/full/345/13/#R27>  The mild fasting
hyperglycemia (blood glucose concentration, 110 to 145 mg per deciliter [6.1
to 8.0 mmol per liter]) and impaired glucose tolerance in most affected
carriers may be recognized by biochemical testing at a young age, possibly
as early as birth. 3 <http://content.nejm.org/cgi/content/full/345/13/#R3> ,
28 <http://content.nejm.org/cgi/content/full/345/13/#R28>  About 50 percent
of the women who are carriers may have gestational diabetes. 3
<http://content.nejm.org/cgi/content/full/345/13/#R3> , 29
<http://content.nejm.org/cgi/content/full/345/13/#R29>  Less than 50 percent
of the carriers have overt diabetes; of those who do, many are obese or
elderly. Two percent of carriers require insulin therapy. 30
<http://content.nejm.org/cgi/content/full/345/13/#R30>  Diabetes-associated
complications are rare in this form of MODY.
The hyperglycemia in persons with glucokinase-related MODY appears to result
from a reduction in the sensitivity of beta cells to glucose 31
<http://content.nejm.org/cgi/content/full/345/13/#R31>  as well as a defect
in postprandial glycogen synthesis in the liver. 32
<http://content.nejm.org/cgi/content/full/345/13/#R32>  Heterozygous
mutations in the gene encoding glucokinase are associated with MODY and
gestational diabetes. They are also associated with a reduction in birth
weight of 500 g or more, possibly because of their effect on fetal insulin
secretion. 33 <http://content.nejm.org/cgi/content/full/345/13/#R33>  As
noted above, homozygous mutations cause a complete deficiency of glucokinase
and are associated with permanent neonatal diabetes mellitus, which is
characterized by low birth weight and severe diabetes, necessitating insulin
treatment within the first few days of life. 17
<http://content.nejm.org/cgi/content/full/345/13/#R17>
In patients with glucokinase-related MODY, the decrease in glucokinase
activity in the pancreatic beta cells leads to a decrease in glucose
phosphorylation in the beta cells, a reduction in the sensitivity of beta
cells to glucose, and a shift to the right in the dose–response relation
between the plasma glucose concentration and insulin secretion ( Figure 2
<http://content.nejm.org/cgi/content/full/345/13/#F2>  and Figure 3
<http://content.nejm.org/cgi/content/full/345/13/#F3> ). These effects occur
across a broad range of glucose concentrations. There is an increase in the
threshold concentration of glucose necessary to stimulate insulin secretion,
from a normal basal concentration of about 90 mg per deciliter (5.0 mmol per
liter) to approximately 108 to 126 mg per deciliter (6.0 to 7.0 mmol per
liter). As a result of this upward shift in the plasma glucose threshold for
stimulation of insulin secretion, patients with glucokinase mutations have
mildly increased basal and postprandial plasma glucose concentrations
 Figure 4 <http://content.nejm.org/cgi/content/full/345/13/#F4> ). 31
<http://content.nejm.org/cgi/content/full/345/13/#R31>  Surprisingly, in
view of the key part played by glucokinase in the sensitivity of beta cells
to glucose and in insulin secretion, the hyperglycemia in these patients is
usually mild and does not increase substantially over the course of many
years. 3 <http://content.nejm.org/cgi/content/full/345/13/#R3> , 27
<http://content.nejm.org/cgi/content/full/345/13/#R27>  It appears that in
patients with glucokinase mutations, physiologic adaptation within the
pancreatic beta cells limits the severity of hyperglycemia.


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Figure 2. Effect of Mutations in the Gene Encoding Glucokinase on the
Threshold for Glucose-Stimulated Insulin Release.
The results of mathematical modeling to predict the effects of two mutations
in the gene encoding glucokinase (substitution of alanine for valine at
position 203 [V203A] and substitution of lysine for glutamic acid at
position 70 [E70K]) on the capacity of the beta cell for glucose
phosphorylation at various plasma glucose concentrations are shown. The
responses in subjects with two wild-type alleles (WT/WT) and in subjects
with one wild-type allele and one mutant allele (E70K/WT or V203A/WT) are
shown. The enzymatic properties of the recombinant wild-type and mutant
forms of glucokinase were determined, and the V203A form was found to have
low activity and the E70K form to have intermediate activity relative to the
wild-type protein. Mathematical modeling suggests that the threshold for
glucose-stimulated insulin release is achieved when the
glucose-phosphorylation capacity is about 25 percent of maximum. This occurs
at a plasma glucose concentration of about 5.0 mmol per liter in subjects
with two wild-type glucokinase alleles and at higher concentrations (6.0 and
7.0 mmol per liter) in subjects with one wild-type and one mutant allele,
respectively. The glucose concentrations required for peak postprandial
glucose-stimulated insulin release in subjects with two wild-type alleles
and the higher required concentrations in subjects with a mutant allele are
also indicated. To convert the values for glucose to milligrams per
deciliter, divide by 0.05551. Adapted from Bell et al. 26
<http://content.nejm.org/cgi/content/full/345/13/#R26>



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Figure 3. Relation between Average Plasma Glucose Concentrations and
Insulin-Secretion Rates during Graded Glucose Infusions in Prediabetic
Subjects with Mutations in the Genes for HNF-4{alpha}, Glucokinase, and
HNF-1{alpha} and in Normal Subjects.
There is a linear relation between the insulin-secretion rate and plasma
glucose concentration in the normal subjects. The subjects with mutations in
the gene for HNF-4{alpha} or HNF-1{alpha} have a normal response at low
glucose concentrations, but the response cannot be sustained as the glucose
concentration continues to rise. The subjects with mutations in the
glucokinase gene have a reduced response at all glucose concentrations; the
greatest reduction occurs at plasma glucose concentrations below 7 mmol per
liter. To convert the values for glucose to milligrams per deciliter, divide
by 0.05551. The bars represent the standard errors.



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Figure 4. Mean Hourly Plasma Glucose Concentrations during a
Weight-Maintenance Diet in Subjects with Type 2 Diabetes or
Glucokinase-Related Maturity-Onset Diabetes of the Young (MODY) and in
Normal Subjects.
Time 0 corresponds to 6 a.m., when sampling began. To convert the values for
glucose to milligrams per deciliter, divide by 0.05551. The bars represent
the standard errors. Adapted from Polonsky. 34
<http://content.nejm.org/cgi/content/full/345/13/#R34>

This hypothesis was explored in a study of subjects with different types of
glucokinase mutations and normal subjects. 35
<http://content.nejm.org/cgi/content/full/345/13/#R35>  In two subjects who
had glucokinase mutations associated with only a small decrease in enzymatic
activity, the decrease in insulin secretion was directly proportional to the
decrease in the glucokinase-mediated flux of glucose. However, in four
subjects with glucokinase mutations that resulted in severe decreases in
enzymatic activity, the amount of insulin secreted was less than that in
normal subjects, but the difference was smaller than predicted, suggesting
the presence of compensatory mechanisms within the pancreatic beta cells
that resulted in a relative increase in the insulin-secretion response.
The nature of this compensatory or adaptive mechanism has been examined in
mice with glucokinase-related MODY (mice with only one glucokinase-gene
allele). 36 <http://content.nejm.org/cgi/content/full/345/13/#R36>  Islets
from these mice and from control mice were incubated at various glucose
concentrations, and the findings suggested that mild hyperglycemia leads to
increased expression of the single wild-type glucokinase-gene allele, thus
limiting the severity of the defect in glucose-stimulated insulin secretion.
Since the hepatic glucokinase promoter is regulated predominantly by insulin
and not by glucose, the compensatory mechanism is probably operative only in
beta cells.
MODY 1 and MODY 3
Not unexpectedly, the pathophysiologic mechanisms of MODY due to mutations
in the HNF-4{alpha} gene (MODY 1) and MODY due to mutations in the
HNF-1{alpha} gene (MODY 3) are very similar, since HNF-4{alpha} regulates
the expression of HNF-1{alpha}. Like persons with glucokinase mutations,
those with mutations in the HNF-4{alpha} gene or the HNF-1{alpha} gene may
present with a mild form of diabetes. Despite similarly mild elevations in
fasting plasma glucose concentrations, however, they have significantly
higher plasma glucose concentrations two hours after glucose administration
than do persons with glucokinase mutations. 27
<http://content.nejm.org/cgi/content/full/345/13/#R27>  The hyperglycemia in
patients with HNF-1{alpha}–related or HNF-4{alpha}–related MODY tends to
increase over time, resulting in the need for treatment with oral
hypoglycemic drugs or insulin in a substantial proportion of these patients
(30 to 40 percent require insulin). 9
<http://content.nejm.org/cgi/content/full/345/13/#R9> , 10
<http://content.nejm.org/cgi/content/full/345/13/#R10> , 11
<http://content.nejm.org/cgi/content/full/345/13/#R11> , 12
<http://content.nejm.org/cgi/content/full/345/13/#R12> , 13
<http://content.nejm.org/cgi/content/full/345/13/#R13>  These forms of MODY
are associated with a progressive decrease in insulin secretion. For
example, prospective studies in a large family with HNF-4{alpha}–related
MODY revealed that glucose-induced insulin secretion decreased at a rate of
1 to 4 percent per year. 12
<http://content.nejm.org/cgi/content/full/345/13/#R12>  This progression
suggests that the beta cells are not able to compensate for the deficiency
of HNF-4{alpha}.
In most populations, mutations in the HNF-1{alpha} gene (resulting in MODY
3) are the most common cause of MODY. To date, more than 120 mutations in
this gene have been identified in persons of all racial and ethnic
backgrounds — for example, European, Chinese, Japanese, African, and
American Indian 37 <http://content.nejm.org/cgi/content/full/345/13/#R37>
(and unpublished data). Mutations in the HNF-1{alpha} gene appear to be the
most common cause of MODY among adults seen in diabetes clinics. In
contrast, mutations in the HNF-4{alpha} gene (resulting in MODY 1) are
relatively uncommon; to date, only 13 families worldwide have been
identified as having this form of MODY.
Patients with HNF-1{alpha}–related or HNF-4{alpha}–related MODY may have the
full spectrum of complications of diabetes. Microvascular complications,
particularly those involving the retinas and kidneys, are as common in these
patients as in patients with type 1 or type 2 diabetes (matched according to
the duration of diabetes and the degree of glycemic control) and are thus
probably determined by the degree of glycemic control ( Table 1
<http://content.nejm.org/cgi/content/full/345/13/#T1> ). 10
<http://content.nejm.org/cgi/content/full/345/13/#R10> , 30
<http://content.nejm.org/cgi/content/full/345/13/#R30> , 38
<http://content.nejm.org/cgi/content/full/345/13/#R38> , 39
<http://content.nejm.org/cgi/content/full/345/13/#R39>
Studies performed in prediabetic carriers of HNF-4{alpha} and HNF-1{alpha}
mutations showed that these two groups had similar defects in the pattern of
glucose-induced insulin secretion, without impairment of insulin
sensitivity. Thus, impaired beta-cell function, rather than a defect in
insulin activity, appears to be the primary cause of diabetes in persons
with these two forms of MODY. 40
<http://content.nejm.org/cgi/content/full/345/13/#R40> , 41
<http://content.nejm.org/cgi/content/full/345/13/#R41> , 42
<http://content.nejm.org/cgi/content/full/345/13/#R42> , 43
<http://content.nejm.org/cgi/content/full/345/13/#R43>  After an overnight
fast, insulin secretion is normal. However, as plasma glucose concentrations
increase to approximately 125 to 145 mg per deciliter (7.0 to 8.0 mmol per
liter), insulin secretion does not continue to increase, as it would in
nondiabetic persons, but rather begins to level off ( Figure 3
<http://content.nejm.org/cgi/content/full/345/13/#F3> ). 41
<http://content.nejm.org/cgi/content/full/345/13/#R41> , 42
<http://content.nejm.org/cgi/content/full/345/13/#R42>  It is possible to
distinguish persons with an HNF-1{alpha} mutation from those with an
HNF-4{alpha} mutation according to the ability of glucose to prime the
insulin-secretion response to a subsequent glucose stimulus. In the
prediabetic state, the normal priming effect of mild hyperglycemia on
insulin secretion is retained in persons with HNF-1{alpha} mutations (as it
is in those with glucokinase mutations or no mutations), but it is lost in
those with HNF-4{alpha} mutations.
Both prediabetic and diabetic persons with mutations in the HNF-4{alpha}
gene secrete decreased amounts of insulin in response to glucose and in
response to arginine and also have an impairment of glucagon secretion in
response to arginine. 44
<http://content.nejm.org/cgi/content/full/345/13/#R44>  Impairment of
glucagon secretion in response to arginine has also been reported in a
patient with diabetes due to a mutation in the HNF-1{alpha} gene (MODY 3).
45 <http://content.nejm.org/cgi/content/full/345/13/#R45>  Furthermore, a
defect in the hypoglycemia-induced secretion of pancreatic polypeptide has
been found in prediabetic and diabetic persons who have mutations in the
gene for HNF-4{alpha}. 46
<http://content.nejm.org/cgi/content/full/345/13/#R46>  These findings
suggest that a deficiency of HNF-4{alpha} activity resulting from mutations
in this gene may affect the function of the beta, alpha, and pancreatic
polypeptide cells of the pancreatic islets.
To examine the molecular basis of the defect in insulin secretion resulting
from decreased activity of HNF-1{alpha}, we have studied mice that lack this
gene. These animals have marked hyperglycemia and defects in glucose-induced
insulin secretion as a result of defective beta-cell glycolytic signaling.
47 <http://content.nejm.org/cgi/content/full/345/13/#R47> , 48
<http://content.nejm.org/cgi/content/full/345/13/#R48>  The consequences of
HNF-4{alpha} deficiency have also been studied in embryonic stem cells, 20
<http://content.nejm.org/cgi/content/full/345/13/#R20>  and the results show
that HNF-4{alpha} regulates the expression of proteins involved in glucose
transport and glycolysis, which are required for a normal, glucose-dependent
insulin secretory response. In the INS-1 cell line, defective
HNF-4{alpha}–dependent insulin secretion is linked to impaired mitochondrial
metabolism. 21 <http://content.nejm.org/cgi/content/full/345/13/#R21>
In addition to their effects on beta-cell function, deficiencies of
HNF-1{alpha} and HNF-4{alpha} affect kidney and liver function,
respectively. Patients with HNF-1{alpha} mutations have decreased renal
reabsorption of glucose (i.e., a low renal threshold for glucose) and
glycosuria. 49 <http://content.nejm.org/cgi/content/full/345/13/#R49> , 50
<http://content.nejm.org/cgi/content/full/345/13/#R50>  A deficiency of
HNF-4{alpha} affects triglyceride and apolipoprotein biosynthesis and is
associated with a 50 percent reduction in serum triglyceride concentrations
and a 25 percent reduction in serum concentrations of apolipoproteins AII
and CIII and Lp(a) lipoprotein. 51
<http://content.nejm.org/cgi/content/full/345/13/#R51> , 52
<http://content.nejm.org/cgi/content/full/345/13/#R52>
MODY 4
Mutations in the gene that encodes IPF-1 are a rare cause of MODY; in fact,
the current understanding of this form of MODY (MODY 4) is based on studies
of a single family. The proband was an infant with permanent neonatal
diabetes and pancreatic exocrine insufficiency resulting from congenital
agenesis of the pancreas. 53
<http://content.nejm.org/cgi/content/full/345/13/#R53>  Molecular genetic
studies revealed that this infant was homozygous for a frame-shift mutation
in the gene for IPF-1 and that both parents were heterozygous for this
mutation. 6 <http://content.nejm.org/cgi/content/full/345/13/#R6>  Studies
of the extended family revealed a high prevalence of a mild form of diabetes
that had an autosomal dominant pattern of inheritance and was associated
with the heterozygous mutation in IPF-1. The expression of diabetes in this
pedigree may occur at later ages than in families with other types of MODY.
Six diabetic family members who were heterozygous for the mutation (and
whose mean fasting plasma glucose concentration was 169 mg per deciliter
[9.4 mmol per liter]) had severe impairment of insulin secretion during a
hyperglycemic clamp study; no such impairment was seen in five family
members who did not have the mutation. 54
<http://content.nejm.org/cgi/content/full/345/13/#R54>
MODY 5
Mutations in the gene encoding HNF-1{beta} are the cause of an uncommon but
distinct form of MODY (MODY 5) that is characterized by both diabetes
mellitus and renal cysts (hypoplastic glomerulocystic kidney disease). 7
<http://content.nejm.org/cgi/content/full/345/13/#R7> , 55
<http://content.nejm.org/cgi/content/full/345/13/#R55> , 56
<http://content.nejm.org/cgi/content/full/345/13/#R56> , 57
<http://content.nejm.org/cgi/content/full/345/13/#R57> , 58
<http://content.nejm.org/cgi/content/full/345/13/#R58>  In addition, two of
four female carriers in one family had internal genital abnormalities
(vaginal aplasia and a rudimentary uterus), 56
<http://content.nejm.org/cgi/content/full/345/13/#R56>  and in another
family a female carrier had a bicornuate uterus. 57
<http://content.nejm.org/cgi/content/full/345/13/#R57>  Thus, heterozygous
mutations in the gene for HNF-1{beta} may be associated with a spectrum of
clinical features, which may be determined by the nature of the specific
mutation and its effect on HNF-1{beta} function.
MODY Associated with Mutations in Other Genes
The identification of mutations in the genes encoding glucokinase and
transcription factors HNF-4{alpha}, HNF-1{alpha}, HNF-1{beta}, and IPF-1
suggests that MODY is a disorder involving abnormal gene expression,
abnormal glucose metabolism, or both in the beta cells. This possibility has
led investigators to screen for mutations in other genes in these pathways,
especially those encoding transcription factors expressed in beta cells, in
families with MODY or autosomal dominant forms of type 2 diabetes.
Mutations in the gene encoding transcription factor NeuroD1 (BETA2) were
found in two families with autosomal dominant type 2 diabetes. 8
<http://content.nejm.org/cgi/content/full/345/13/#R8>  One of these families
met the criteria for MODY, including (in addition to an autosomal dominant
pattern of inheritance) an onset of diabetes before 25 years of age in three
carriers and a requirement for insulin treatment — a finding consistent with
the presence of beta-cell dysfunction — in five carriers. Thus, mutations in
NeuroD1 may be the cause of another subtype of MODY, designated MODY 6.
A nonsense mutation was found in the gene encoding beta-cell transcription
factor Islet-1 in a Japanese family. 59
<http://content.nejm.org/cgi/content/full/345/13/#R59>  This mutation led to
decreased activity of this transcription factor and thus may have been
pathogenic. However, additional genetic and clinical studies are required to
determine whether mutations in Islet-1 are the cause of another subtype of
MODY.
Families whose members have a clinical history compatible with a diagnosis
of MODY and who do not have mutations in any of the six known MODY-related
genes account for an estimated 15 to 20 percent of European persons who have
clinical MODY and as many as 80 percent of Japanese persons with clinical
MODY. 37 <http://content.nejm.org/cgi/content/full/345/13/#R37>  We believe
that, in time, additional MODY-related genes will be identified and that
they will explain the molecular basis of diabetes in these patients.
Mutations in MODY-Related Genes in Type 2 Diabetes
It does not appear that mutations in known MODY-related genes contribute to
the development of hyperglycemia in the majority of patients with type 2
diabetes, although mutations have been found in a few patients. 60
<http://content.nejm.org/cgi/content/full/345/13/#R60> , 61
<http://content.nejm.org/cgi/content/full/345/13/#R61> , 62
<http://content.nejm.org/cgi/content/full/345/13/#R62> , 63
<http://content.nejm.org/cgi/content/full/345/13/#R63>  One group in which a
mutation in a MODY-associated gene, the gene encoding HNF-1{alpha}, may be a
key genetic factor linked to type 2 diabetes is the Canadian Oji-Cree
Indians, who live in northwestern Ontario and Manitoba. 64
<http://content.nejm.org/cgi/content/full/345/13/#R64>  Thus, sequence
variation in MODY-related genes may contribute to the polygenic background
and to the development of type 2 diabetes ( Table 2
<http://content.nejm.org/cgi/content/full/345/13/#T2> ). The absence of an
association with type 2 diabetes in one population should not deter
investigators from studying these genes in other populations.
Despite the lack of evidence that mutations in MODY-related genes are
responsible for the development of type 2 diabetes in the majority of
patients with this disorder, the mechanisms by which these mutations lead to
hyperglycemia may be relevant to the pathophysiology of the beta-cell
defects in type 2 diabetes. Defects in the metabolism of glucose in
pancreatic beta cells may be the mechanism by which insulin secretion is
impaired in type 2 diabetes. Thus, lessons learned from studies of MODY may
improve our understanding of the insulin insufficiency associated with type
2 diabetes.
Genetic Screening for MODY
With the identification of genes responsible for MODY, it is possible to
identify members of pedigrees who have inherited the specific mutation
affecting their family, even before carbohydrate intolerance develops.
Indeed, in the past few years, some parents have requested that their
children undergo genetic screening for the mutation in their family. 65
<http://content.nejm.org/cgi/content/full/345/13/#R65>  If a child does not
carry the mutation, further clinical testing is unnecessary. If a child does
carry the mutation, periodic testing for slight abnormalities of
carbohydrate metabolism is recommended. These principles can be applied to
any family with MODY for which the mutation is known.
Genetic screening for and identification of a specific MODY-related mutation
in children may have important prognostic and therapeutic implications. If
carbohydrate intolerance or diabetes is due to a mutation in the gene
encoding glucokinase, limited therapy and follow-up are adequate, because of
the benign and nonprogressive course of diabetes in such cases. On the other
hand, persons who are genetically susceptible to diabetes due to mutations
in the genes for HNF-1{alpha} and HNF-4{alpha} should be monitored
frequently so that appropriate therapy can be instituted early in the course
of their hyperglycemia, because of the risk of progression to severe
hyperglycemia and insulin-requiring diabetes. Early treatment to achieve
normoglycemia should prevent vascular and neuropathic complications. Thus,
MODY is one type of diabetes that warrants genetic counseling, because of
the known mode of inheritance and high penetrance.
Genetic diagnosis may also be advised for patients who have been classified
as having type 1 diabetes and who have a strong family history of diabetes.
An appreciable fraction of these patients have been found to carry the
HNF-1{alpha} mutation. 66
<http://content.nejm.org/cgi/content/full/345/13/#R66> , 67
<http://content.nejm.org/cgi/content/full/345/13/#R67> , 68
<http://content.nejm.org/cgi/content/full/345/13/#R68>  The diagnosis of
HNF-1{alpha}–related MODY rather than type 1 diabetes has implications for
prognosis in these patients. Unfortunately, these approaches are currently
applicable only in a research setting; commercial tests for the
identification of MODY-related genes are not yet available.
Conclusions
A better understanding of the causes and pathophysiology of MODY is emerging
from genetic, molecular biologic, and physiological studies of this
disorder. We believe this knowledge will lead to new therapeutic approaches
and agents that will prevent, correct, or at least delay the decline in
pancreatic beta-cell function that characterizes not only MODY but also type
2 diabetes.
Supported by grants from the National Institutes of Health (DK-20572 and
DK-20595, to the Diabetes Research and Training Centers at the University of
Michigan and the University of Chicago, respectively; RR-00042 and RR-00055,
to the General Clinical Research Centers at the University of Michigan and
the University of Chicago, respectively; DK-31842; and DK-44840), by a gift
from the Blum–Kovler Foundation, and by funds from the Howard Hughes Medical
Institute.
We are indebted to Dr. Franz Matschinsky for valuable discussions about
glucokinase mutations.

Source Information
From the Department of Internal Medicine, Division of Endocrinology and
Metabolism, University of Michigan Health System, Ann Arbor (S.S.F.); the
Howard Hughes Medical Institute and Departments of Biochemistry and
Molecular Biology, Medicine, and Human Genetics, University of Chicago,
Chicago (G.I.B.); and the Departments of Medicine and Cell Biology and
Physiology, Washington University School of Medicine, St. Louis (K.S.P.).
Address reprint requests to Dr. Fajans at 3920 Taubman Ctr., Box 0354,
University Hospitals, Ann Arbor, MI 48109-0354, or at [log in to unmask]
<mailto:[log in to unmask]> .
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.