The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Kathy M. Tran, M.D., Case Records Editorial Fellow
Emily K. McDonald, Tara Corpuz, Production Editors

Case 6-2020: A 34-Year-Old Woman

with Hyperglycemia
Miriam S. Udler, M.D., Ph.D., Camille E. Powe, M.D.,
and Christina A. Austin‑Tse, Ph.D.​​

Pr e sen tat ion of C a se

Dr. Max C. Petersen (Medicine): A 34-year-old woman was evaluated in the diabetes From the Departments of Medicine
clinic of this hospital for hyperglycemia. (M.S.U., C.E.P.) and Pathology (C.A.A.-T.),
Massachusetts General Hospital, and
Eleven years before this presentation, the blood glucose level was 126 mg per the Departments of Medicine (M.S.U.,
deciliter (7.0 mmol per liter) on routine laboratory evaluation, which was per- C.E.P.) and Pathology (C.A.A.-T.), Har-
formed as part of an annual well visit. The patient could not recall whether she vard Medical School — both in Boston.

had been fasting at the time the test had been performed. One year later, the fast- N Engl J Med 2020;382:745-53.
ing blood glucose level was 112 mg per deciliter (6.2 mmol per liter; reference DOI: 10.1056/NEJMcpc1913475
Copyright © 2020 Massachusetts Medical Society.
range, <100 mg per deciliter [<5.6 mmol per liter]).
Nine years before this presentation, a randomly obtained blood glucose level
was 217 mg per deciliter (12.0 mmol per liter), and the patient reported polyuria.
At that time, the glycated hemoglobin level was 5.8% (reference range, 4.3 to 5.6);
the hemoglobin level was normal. One year later, the glycated hemoglobin level
was 5.9%. The height was 165.1 cm, the weight 72.6 kg, and the body-mass index
(BMI; the weight in kilograms divided by the square of the height in meters) 26.6.
The patient received a diagnosis of prediabetes and was referred to a nutritionist.
She made changes to her diet and lost 4.5 kg of body weight over a 6-month pe-
riod; the glycated hemoglobin level was 5.5%.
Six years before this presentation, the patient became pregnant with her first
child. Her prepregnancy BMI was 24.5. At 26 weeks of gestation, the result of a
1-hour oral glucose challenge test (i.e., the blood glucose level obtained 1 hour
after the oral administration of a 50-g glucose load in the nonfasting state) was
186 mg per deciliter (10.3 mmol per liter; reference range, <140 mg per deciliter
[<7.8 mmol per liter]). She declined a 3-hour oral glucose tolerance test; a pre-
sumptive diagnosis of gestational diabetes was made. She was asked to follow a
meal plan for gestational diabetes and was treated with insulin during the preg-
nancy. Serial ultrasound examinations for fetal growth and monitoring were per-
formed. At 34 weeks of gestation, the fetal abdominal circumference was in the
76th percentile for gestational age. Polyhydramnios developed at 37 weeks of
gestation. The child was born at 39 weeks 3 days of gestation, weighed 3.9 kg at

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 The n e w e ng l a n d j o u r na l
birth, and had hypoglycemia after birth, which
subsequently resolved. Six weeks post partum, the
patient’s fasting blood glucose level was 120 mg
per deciliter (6.7 mmol per liter), and the result of
a 2-hour oral glucose tolerance test (i.e., the blood
glucose level obtained 2 hours after the oral
administration of a 75-g glucose load in the fast-
ing state) was 131 mg per deciliter (7.3 mmol per
liter; reference range, <140 mg per deciliter).
Three months post partum, the glycated hemo-
globin level was 6.1%. Lifestyle modification for
diabetes prevention was recommended.
Four and a half years before this presentation,
the patient became pregnant with her second
child. Her prepregnancy BMI was 25.1. At 5 weeks
of gestation, she had an elevated blood glucose
level. Insulin therapy was started at 6 weeks of
gestation, and episodes of hypoglycemia occurred
during the pregnancy. Serial ultrasound exami-
nations for fetal growth and monitoring were
performed. At 28 weeks of gestation, the fetal
abdominal circumference was in the 35th percen-
tile for gestational age, and the amniotic fluid
level was normal. Labor was induced at 38 weeks
of gestation; the child weighed 2.6 kg at birth.
Neonatal blood glucose levels were reported as
stable after birth. Six weeks post partum, the
patient’s fasting blood glucose level was 133 mg
per deciliter (7.4 mmol per liter), and the result
of a 2-hour oral glucose tolerance test was 236 mg
per deciliter (13.1 mmol per liter). The patient
received a diagnosis of type 2 diabetes mellitus;
lifestyle modification was recommended. Three
months post partum, the glycated hemoglobin
level was 5.9% and the BMI was 30.0. Over the
next 2 years, she followed a low-carbohydrate
diet and regular exercise plan and self-moni-
tored the blood glucose level.
Two years before this presentation, the pa-
tient became pregnant with her third child.
Blood glucose levels were again elevated, and
insulin therapy was started early in gestation.
She had episodes of hypoglycemia that led to ad-
justment of her insulin regimen. The child was
born at 38 weeks 5 days of gestation, weighed
3.0 kg at birth, and had hypoglycemia that re-
solved 48 hours after birth. After the birth of her
third child, the patient started to receive metfor-
min, which had no effect on the glycated hemo-
globin level, despite adjustment of the therapy to
the maximal dose.
One year before this presentation, the patient
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of m e dic i n e
became pregnant with her fourth child. Insulin
therapy was again started early in gestation. The
patient reported that episodes of hypoglycemia
occurred. Polyhydramnios developed. The child
was born at 38 weeks 6 days of gestation and
weighed 3.5 kg. The patient sought care at the
diabetes clinic of this hospital for clarification
of her diagnosis.
The patient reported following a low-carbohy-
drate diet and exercising 5 days per week. There
was no fatigue, change in appetite, change in
vision, chest pain, shortness of breath, polydipsia,
or polyuria. There was no history of anemia,
pancreatitis, hirsutism, proximal muscle weak-
ness, easy bruising, headache, sweating, tachy-
cardia, gallstones, or diarrhea. Her menstrual
periods were normal. She had not noticed any
changes in her facial features or the size of her
hands or feet.
The patient had a history of acne and low-back
pain. Her only medication was metformin. She
had no known medication allergies. She lived
with her husband and four children in a subur-
ban community in New England and worked as
an administrator. She did not smoke tobacco or
use illicit drugs, and she rarely drank alcohol.
She identified as non-Hispanic white. Both of her
grandmothers had type 2 diabetes mellitus. Her
father had hypertension, was overweight, and had
received a diagnosis of type 2 diabetes at 50 years
of age. Her mother was not overweight and had
received a diagnosis of type 2 diabetes at 48 years
of age. The patient had two sisters, neither of
whom had a history of diabetes or gestational
diabetes. There was no family history of hemo-
chromatosis.
On examination, the patient appeared well.
The blood pressure was 126/76 mm Hg, and the
heart rate 76 beats per minute. The BMI was
25.4. The physical examination was normal. The
glycated hemoglobin level was 6.2%.
A diagnostic test was performed.
Differ en t i a l Di agnosis
Dr. Miriam S. Udler: I am aware of the diagnosis in
this case and participated in the care of this
patient. This healthy 34-year-old woman, who had
a BMI just above the upper limit of the normal
range, presented with a history of hyperglycemia
of varying degrees since 24 years of age. When
she was not pregnant, she was treated with life-
 Case Records of the Massachuset ts Gener al Hospital
style measures as well as metformin therapy for
a short period, and she maintained a well-con-
trolled blood glucose level. In thinking about
this case, it is helpful to characterize the extent
of the hyperglycemia and then to consider its
possible causes.
Characterizing Hyperglycemia
This patient’s hyperglycemia reached a threshold
that was diagnostic of diabetes1 on two occa-
sions: when she was 25 years of age, she had a
randomly obtained blood glucose level of 217 mg
per deciliter with polyuria (with diabetes defined
as a level of ≥200 mg per deciliter [≥11.1 mmol per
liter] with symptoms), and when she was 30 years
of age, she had on the same encounter a fasting
blood glucose level of 133 mg per deciliter (with
diabetes defined as a level of ≥126 mg per deci-
liter) and a result on a 2-hour oral glucose toler-
ance test of 236 mg per deciliter (with diabetes
defined as a level of ≥200 mg per deciliter). On
both of these occasions, her glycated hemoglo-
bin level was in the prediabetes range (defined
as 5.7 to 6.4%). In establishing the diagnosis of
diabetes, the various blood glucose studies and
glycated hemoglobin testing may provide discor-
dant information because the tests have differ-
ent sensitivities for this diagnosis, with glycated
hemoglobin testing being the least sensitive.2
Also, there are situations in which the glycated
hemoglobin level can be inaccurate; for example,
the patient may have recently received a blood
transfusion or may have a condition that alters
the life span of red cells, such as anemia, hemo-
globinopathy, or pregnancy.3 These conditions
were not present in this patient at the time that
the glycated hemoglobin measurements were ob-
tained. In addition, since the glycated hemoglo-
bin level reflects the average glucose level typi-
cally over a 3-month period, discordance with
timed blood glucose measurements can occur if
there has been a recent change in glycemic con-
trol. This patient had long-standing mild hyper-
glycemia but met criteria for diabetes on the
basis of the blood glucose levels noted.
Diabetes
Type 1 and Type 2 Diabetes
Now that we have characterized the patient’s
hyperglycemia as meeting criteria for diabetes, it
is important to consider the possible types. More
than 90% of adults with diabetes have type 2
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diabetes, which is due to progressive loss of in-
sulin secretion by beta cells that frequently oc-
curs in the context of insulin resistance. This
patient had received a diagnosis of type 2 diabe-
tes; however, some patients with diabetes may
be given a diagnosis of type 2 diabetes on the
basis of not having features of type 1 diabetes,
which is characterized by autoimmune destruc-
tion of the pancreatic beta cells that leads to
rapid development of insulin dependence, with
ketoacidosis often present at diagnosis.
Type 1 diabetes accounts for approximately
6% of all cases of diabetes in adults (≥18 years
of age) in the United States,4 and 80% of these
cases are diagnosed before the patient is 20 years
of age.5 Since this patient’s diabetes was essen-
tially nonprogressive over a period of at least
9 years, she most likely does not have type 1
diabetes. It is therefore not surprising that she
had received a diagnosis of type 2 diabetes, but
there are several other types of diabetes to con-
sider, particularly since some features of her
case do not fit with a typical case of type 2 dia-
betes, such as her age at diagnosis, the presence
of hyperglycemia despite a nearly normal BMI,
and the mild and nonprogressive nature of her
disease over the course of many years.
Less Common Types of Diabetes
Latent autoimmune diabetes in adults (LADA) is
a mild form of autoimmune diabetes that should
be considered in this patient. However, there is
controversy as to whether LADA truly represents
an entity that is distinct from type 1 diabetes.6
Both patients with type 1 diabetes and patients
with LADA commonly have elevated levels of dia-
betes-associated autoantibodies; however, LADA
has been defined by an older age at onset (typi-
cally >25 years) and slower progression to insu-
lin dependence (over a period of >6 months).7
This patient had not been tested for diabetes-
associated autoantibodies. I ordered these tests
to help evaluate for LADA, but this was not my
leading diagnosis because of her young age at
diagnosis and nonprogressive clinical course over
a period of at least 9 years.
If the patient’s diabetes had been confined
to pregnancy, we might consider gestational
diabetes, but she had hyperglycemia outside of
pregnancy. Several medications can cause hyper-
glycemia, including glucocorticoids, atypical anti-
psychotic agents, cancer immunotherapies, and
747
 The n e w e ng l a n d j o u r na l
some antiretroviral therapies and immunosup-
pressive agents used in transplantation.8 How-
ever, this patient was not receiving any of these
medications. Another cause of diabetes to con-
sider is destruction of the pancreas due to, for
example, cystic fibrosis, a tumor, or pancreatitis,
but none of these were present. Secondary endo-
crine disorders — including excess cortisol pro-
duction, excess growth hormone production, and
pheochromocytoma — were considered to be un-
likely in this patient on the basis of the history,
review of symptoms, and physical examination.
Monogenic Diabetes
A final category to consider is monogenic diabe-
tes, which is caused by alteration of a single gene.
Types of monogenic diabetes include maturity-
onset diabetes of the young (MODY), neonatal
diabetes, and syndromic forms of diabetes. Mono-
genic diabetes accounts for 1 to 6% of cases of
diabetes in children9 and approximately 0.4% of
cases in adults.10 Neonatal diabetes is diagnosed
typically within the first 6 months of life; syn-
dromic forms of monogenic diabetes have other
abnormal features, including particular organ
dysfunction. Neither condition is applicable to
this patient.
MODY
MODY is an autosomal dominant condition char-
acterized by primary pancreatic beta-cell dys-
function that causes mild diabetes that is diag-
nosed during adolescence or early adulthood. As
early as 1964, the nomenclature “maturity-onset
diabetes of the young” was used to describe
cases that resembled adult-onset type 2 diabetes
in terms of the slow progression to insulin use
(as compared with the rapid progression in type 1
diabetes) but occurred in relatively young pa-
tients.11 Several genes cause distinct forms of
MODY that have specific disease features that
inform treatment, and thus MODY is a clinically
important diagnosis. Most forms of MODY cause
isolated abnormal glucose levels (in contrast to
syndromic monogenic diabetes), a manifestation
that has contributed to its frequent misdiagnosis
as type 1 or type 2 diabetes.12
Genetic Basis of MODY
Although at least 13 genes have been associated
with MODY, 3 genes — GCK, which encodes
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of m e dic i n e
glucokinase, and HNF1A and HNF4A, which en-
code hepatocyte nuclear factors 1A and 4A, re-
spectively — account for most cases. MODY
associated with GCK (known as GCK-MODY) is
characterized by mild, nonprogressive hypergly-
cemia that is present since birth, whereas the
forms of MODY associated with HNF1A and
HNF4A (known as HNF1A-MODY and HNF4A-
MODY, respectively) are characterized by the
development of diabetes, typically in the early
teen years or young adulthood, that is initially
mild and then progresses such that affected
patients may receive insulin before diagnosis.
In patients with GCK-MODY, genetic variants
reduce the function of glucokinase, the enzyme
in pancreatic beta cells that functions as a glu-
cose sensor and controls the rate of entry of
glucose into the glycolytic pathway. As a result,
reduced sensitivity to glucose-induced insulin
secretion causes asymptomatic mild fasting hy-
perglycemia, with an upward shift in the normal
range of the fasting blood glucose level to 100 to
145 mg per deciliter (5.6 to 8.0 mmol per liter),
and also causes an upward shift in postprandial
blood glucose levels, but with tight regulation
maintained (Fig. 1).13 This mild hyperglycemia is
not thought to confer a predisposition to com-
plications of diabetes,14 is largely unaltered by
treatment,15 and does not necessitate treatment
outside of pregnancy.
In contrast to GCK-MODY, the disorders
HNF1A-MODY and HNF4A-MODY result in pro-
gressive hyperglycemia that eventually leads to
treatment.16 Initially, there may be a normal
fasting glucose level and large spikes in post-
prandial glucose levels (to >80 mg per deciliter
[>4.4 mmol per liter]).17 Patients can often be
treated with oral agents and discontinue insulin
therapy started before the diagnosis of MODY.18
Of note, patients with HNF1A-MODY or HNF4A-
MODY are typically sensitive to treatment with
sulfonylureas19 but may also respond to glucagon-
like peptide-1 receptor agonists.20
This patient had received a diagnosis of dia-
betes before 35 years of age, had a family his-
tory of diabetes involving multiple generations,
and was not obese. These features are suggestive
of MODY but do not represent absolute criteria
for the condition (Fig. 1).1 Negative testing for
diabetes-associated autoantibodies would fur-
ther increase the likelihood of MODY. There are
 Case Records of the Massachuset ts Gener al Hospital

Autosomal dominant pattern Glucose

transporter Glucose

NUCLEUS
Glucose

Glucokinase
GCK p.Ser263Pro

Glucose-6-phosphate
PANCREAS

Krebs
Glycolysis
cycle
Beta cell

ATP

Insulin MITOCHONDRION
ATP
secretion
Calcium ion
ATP-sensitive
Voltage-dependent potassium-ion
calcium-ion channel channel
Reduced glucokinase
function
Potassium ion
Depolarization

20
300
Blood Glucose (mmol/liter)

15 Type 2 diabetes
Blood Glucose (mg/dl)

216

10

GCK-MODY
126
5 90
Normal

Breakfast Lunch Dinner

0
0 4 8 12 16 20 24
Hours

Figure 1. Features of GCK-MODY in This Patient.

Key features suggesting maturity-onset diabetes of the young (MODY) in this patient were an age of less than 35 years
at the diagnosis of diabetes, a strong family history of diabetes with an autosomal dominant pattern of inheritance,
and hyperglycemia despite a close-to-normal body-mass index. None of these features is an absolute criterion. MODY
is caused by single gene–mediated disruption of pancreatic beta-cell function. In MODY associated with the GCK
gene (known as GCK-MODY), disrupted glucokinase function causes a mild upward shift in glucose levels through-
out the day and does not necessitate treatment.13 In the pedigree, circles represent female family members, squares
male family members, blue family members affected by diabetes, and green unaffected family members. The arrow
indicates the patient.

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 The n e w e ng l a n d j o u r na l
methods to calculate a patient’s risk of having
MODY associated with GCK, HNF1A, or HNF4A.21,22
Using an online calculator (www​.­diabetesgenes​
.­org/​­mody​-­probability​-­calculator), we estimate that
the probability of this patient having MODY is at
least 75.5%. Genetic testing would be needed to
confirm this diagnosis, and in patients at an
increased risk for MODY, multigene panel test-
ing has been shown to be cost-effective.23,24
Dr . Mir i a m S . Udl er’s Di agnosis
Maturity-onset diabetes of the young, most likely
due to a GCK variant.
Di agnos t ic Te s t ing
Dr. Christina A. Austin-Tse: A diagnostic sequencing
test of five genes associated with MODY was
performed. One clinically significant variant was
identified in the GCK gene (NM_000162.3): a
c.787T→C transition resulting in the p.Ser263Pro
missense change. Review of the literature and
variant databases revealed that this variant had
been previously identified in at least three pa-
tients with early-onset diabetes and had segre-
gated with disease in at least three affected
members of two families (GeneDx: personal
communication).25,26 Furthermore, the variant was
rare in large population databases (occurring
in 1 out of 128,844 European chromosomes in
gnomAD27), a feature consistent with a disease-
causing role. Although the serine residue at posi-
tion 263 was not highly conserved, multiple in
vitro functional studies have shown that the
p.Ser263Pro variant negatively affects the stabil-
ity of the glucokinase enzyme.26,28-30 As a result,
this variant met criteria to be classified as
“likely pathogenic.”31 As mentioned previously, a
diagnosis of GCK-MODY is consistent with this
patient’s clinical features. On subsequent testing
of additional family members, the same “likely
pathogenic” variant was identified in the patient’s
father and second child, both of whom had
documented hyperglycemia.
Discussion of M a nagemen t
Dr. Udler: In this patient, the diagnosis of GCK-
MODY means that it is normal for her blood
glucose level to be mildly elevated. She can stop
taking metformin because discontinuation is not
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of m e dic i n e
expected to substantially alter her glycated hemo-
globin level15,32 and because she is not at risk for
complications of diabetes.14 However, she should
continue to maintain a healthy lifestyle. Although
patients with GCK-MODY are not typically treat-
ed for hyperglycemia outside of pregnancy, they
may need to be treated during pregnancy.
It is possible for a patient to have type 1 or
type 2 diabetes in addition to MODY, so this
patient should be screened for diabetes accord-
ing to recommendations for the general popula-
tion (e.g., in the event that she has a risk factor
for diabetes, such as obesity).1 Since the mild
hyperglycemia associated with GCK-MODY is
asymptomatic (and probably unrelated to the
polyuria that this patient had described in the
past), the development of symptoms of hypergly-
cemia, such as polyuria, polydipsia, or blurry
vision, should prompt additional evaluation. In
patients with GCK-MODY, the glycated hemoglo-
bin level is typically below 7.5%,33 so a value
rising above that threshold or a sudden large
increase in the glycated hemoglobin level could
indicate concomitant diabetes from another cause,
which would need to be evaluated and treated.
This patient’s family members are at risk for
having the same GCK variant, with a 50% chance
of offspring inheriting a variant from an affected
parent. Since the hyperglycemia associated with
GCK-MODY is present from birth, it is necessary
to perform genetic testing only in family mem-
bers with demonstrated hyperglycemia. I offered
site-specific genetic testing to the patient’s par-
ents and second child.
Dr. Meridale V. Baggett (Medicine): Dr. Powe,
would you tell us how you would treat this pa-
tient during pregnancy?
Dr. Camille E. Powe: During the patient’s first
pregnancy, routine screening led to a presump-
tive diagnosis of gestational diabetes, the most
common cause of hyperglycemia in pregnancy.
Hyperglycemia in pregnancy is associated with
adverse pregnancy outcomes,34 and treatment
lowers the risk of such outcomes.35,36 Two of the
most common complications — fetal overgrowth
(which can lead to birth injuries, shoulder dysto-
cia, and an increased risk of cesarean delivery)
and neonatal hypoglycemia — are thought to be
the result of fetal hyperinsulinemia.37 Maternal
glucose is freely transported across the placenta,
and excess glucose augments insulin secretion
from the fetal pancreas. In fetal life, insulin is a
 Case Records of the Massachuset ts Gener al Hospital

potent growth factor, and neonates who have A Hyperglycemic Mother, B Hyperglycemic Mother,
hyperinsulinemia in utero often continue to se- Fetus without GCK-MODY Fetus with GCK-MODY
crete excess insulin in the first few days of life.
In the treatment of pregnant women with diabe-
tes, we strive for strict blood sugar control (fast-
ing blood glucose level, <95 mg per deciliter
↑Glucose ↑Glucose
[<5.3 mmol per liter]; 2-hour postprandial blood
glucose level, <120 mg per deciliter) to decrease
the risk of these and other hyperglycemia-asso-
↑Glucose ↑Glucose
ciated adverse pregnancy outcomes.38-40
GCK variant
In the third trimester of the patient’s first
↑Insulin Normal insulin
pregnancy, obstetrical ultrasound examination
revealed a fetal abdominal circumference in the
Excess growth Normal growth
76th percentile for gestational age and polyhy-
dramnios, signs of fetal exposure to maternal
hyperglycemia.40-42 Case series involving families
with GCK-MODY have shown that the effect of
maternal hyperglycemia on the fetus depends on
whether the fetus inherits the pathogenic GCK C Euglycemic Mother, D Euglycemic Mother,
variant.43-48 Fetuses that do not inherit the maternal Fetus without GCK-MODY Fetus with GCK-MODY
variant have overgrowth, presumably due to fetal
hyperinsulinemia (Fig. 2A). In contrast, fetuses
that inherit the variant do not have overgrowth
and are born at a weight that is near the average Normal Normal
for gestational age, despite maternal hyperglyce- Glucose Glucose

mia, presumably because the variant results in

decreased insulin secretion (Fig. 2B). Fetuses that
inherit GCK-MODY from their fathers and have
euglycemic mothers appear to be undergrown,
most likely because their insulin secretion is lower
than normal when they and their mothers are
euglycemic (Fig. 2D). Because fetal overgrowth
and polyhydramnios occurred during this pa-
tient’s first pregnancy and neonatal hypoglyce-
mia developed after the birth, the patient’s first
child is probably not affected by GCK-MODY.
In accordance with standard care for preg-
nant women with diabetes who do not meet
glycemic targets after dietary modification,38,39
the patient was treated with insulin during her
pregnancies. In her second pregnancy, treatment
was begun early, after hyperglycemia was de-
tected in the first trimester. Because she had not
yet received the diagnosis of GCK-MODY during
any of her pregnancies, no consideration of this
condition was given during her obstetrical treat-
ment. Whether treatment affects the risk of hyper-
glycemia-associated adverse pregnancy outcomes
in pregnant women with known GCK-MODY is
controversial, with several case series showing
that the birth weight percentile in unaffected
neonates remains consistent regardless of wheth-
Normal glucose Normal glucose
GCK variant
Normal insulin ↓Insulin
Normal growth Decreased growth
Figure 2. Effect of Fetal GCK-MODY on the Relationship between Maternal
Blood Glucose Level and Fetal Growth.
Pathogenic variants that lead to GCK-MODY, when carried by a fetus,
change the usual relationship of maternal hyperglycemia to fetal hyperinsu-
linemia and fetal overgrowth. GCK-MODY–affected fetuses have lower in-
sulin secretion than unaffected fetuses in response to the same maternal
blood glucose level. In a hyperglycemic mother carrying a fetus who is un-
affected by GCK-MODY, excessive fetal growth is usually apparent (Panel
A). Studies involving GCK-MODY–affected hyperglycemic mothers have
shown that fetal growth is normal despite maternal hyperglycemia when a
fetus has the maternal GCK variant (Panel B). The goal of treatment of ma-
ternal hyperglycemia when a fetus is unaffected by GCK-MODY is to estab-
lish euglycemia to normalize fetal insulin levels and growth (Panel C);
whether this can be accomplished in the case of maternal GCK-MODY is
controversial, given the genetically determined elevated maternal glycemic
set point. In the context of maternal euglycemia, GCK-MODY–affected fe-
tuses may be at risk for fetal growth restriction (Panel D).

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 The n e w e ng l a n d j o u r na l of m e dic i n e

er the mother is treated with insulin.44,45 Evidence
suggests that it may be difficult to overcome a
genetically determined glycemic set point in
patients with GCK-MODY with the use of phar-
macotherapy,15,32 and affected patients may have
symptoms of hypoglycemia when the blood
glucose level is normal because of an enhanced
counterregulatory response.49,50 Still, to the ex-
tent that it is possible, it would be desirable to
safely lower the blood glucose level in a woman
with GCK-MODY who is pregnant with an unaf-
fected fetus in order to decrease the risk of fetal
overgrowth and other consequences of mildly
elevated glucose levels (Fig. 2C).46,47,51 In con-
trast, there is evidence that lowering the blood
glucose level in a pregnant woman with GCK-
MODY could lead to fetal growth restriction if
the fetus is affected (Fig. 2D).45,52 During this
patient’s second pregnancy, she was treated with
insulin beginning in the first trimester, and her
daughter’s birth weight was near the 16th per-
centile for gestational age; this outcome is con-
sistent with the daughter’s ultimate diagnosis of
GCK-MODY.
Expert opinion suggests that, in pregnant
women with GCK-MODY, insulin therapy should
be deferred until fetal growth is assessed by
means of ultrasound examination beginning in
the late second trimester. If there is evidence of
fetal overgrowth, the fetus is presumed to be
unaffected by GCK-MODY and insulin therapy is
initiated.53 After I have counseled women with
GCK-MODY on the potential risks and benefits
of insulin treatment during pregnancy, I have
sometimes used a strategy of treating hypergly-
cemia from early in pregnancy using modified
glycemic targets that are less stringent than the
targets typically used during pregnancy. This
strategy attempts to balance the risk of growth
restriction in an affected fetus (as well as mater-
nal hypoglycemia) with the potential benefit of
glucose-lowering therapy for an unaffected fetus.
Fol l ow-up
Dr. Udler: The patient stopped taking metformin,
and subsequent glycated hemoglobin levels re-
mained unchanged, at 6.2%. Her father and
5-year-old daughter (second child) both tested
positive for the same GCK variant. Her father had
a BMI of 36 and a glycated hemoglobin level of
7.8%, so I counseled him that he most likely had
type 2 diabetes in addition to GCK-MODY. He is
currently being treated with metformin and life-
style measures. The patient’s daughter now has a
clear diagnosis to explain her hyperglycemia, which
will help in preventing misdiagnosis of type 1 dia-
betes, given her young age, and will be impor-
tant for the management of any future pregnan-
cies. She will not need any medical follow-up for
GCK-MODY until she is considering pregnancy.
Fina l Di agnosis
Maturity-onset diabetes of the young due to a
GCK variant.
This case was presented at the Medical Case Conference.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. Andrew Hattersley and Dr. Sarah Bernstein for
helpful comments on an earlier draft of the manuscript.

References
1. American Diabetes Association. 2.
Classification and diagnosis of diabetes:
Standards of Medical Care in Diabetes — 2019.
Diabetes Care 2019;​42:​Suppl 1:​S13-S28.
2. Cowie CC, Rust KF, Byrd-Holt DD,
et al. Prevalence of diabetes and high risk
for diabetes using A1C criteria in the U.S.
population in 1988-2006. Diabetes Care
2010;​33:​562-8.
3. Radin MS. Pitfalls in hemoglobin A1c
measurement: when results may be mis-
leading. J Gen Intern Med 2014;​29:​388-94.
4. Bullard KM, Cowie CC, Lessem SE,
et al. Prevalence of diagnosed diabetes in
adults by diabetes type — United States,
2016. MMWR Morb Mortal Wkly Rep
2018;​67:​359-61.
5. Liese AD, D’Agostino RB Jr, Hamman
RF, et al. The burden of diabetes mellitus
among US youth: prevalence estimates
from the SEARCH for Diabetes in Youth
Study. Pediatrics 2006;​118:​1510-8.
6. Pieralice S, Pozzilli P. Latent autoim-
mune diabetes in adults: a review on clin-
ical implications and management. Dia-
betes Metab J 2018;​42:​451-64.
7. Stenström G, Gottsäter A, Bakhtadze
E, Berger B, Sundkvist G. Latent autoim-
mune diabetes in adults: definition, prev-
alence, beta-cell function, and treatment.
Diabetes 2005;​54:​Suppl 2:​S68-S72.
8. Fathallah N, Slim R, Larif S, Hmouda
H, Ben Salem C. Drug-induced hypergly-
caemia and diabetes. Drug Saf 2015;​38:​
1153-68.
9. Hattersley AT, Greeley SAW, Polak M,
et al. ISPAD Clinical Practice Consensus
Guidelines 2018: the diagnosis and man-
agement of monogenic diabetes in chil-
dren and adolescents. Pediatr Diabetes
2018;​19:​Suppl 27:​47-63.
10. Shields BM, Shepherd M, Hudson M,
et al. Population-based assessment of a
biomarker-based screening pathway to aid
diagnosis of monogenic diabetes in young-
onset patients. Diabetes Care 2017;​ 40:​
1017-25.
11. Fajans SS, Bell GI. MODY: history, ge-
netics, pathophysiology, and clinical deci-
sion making. Diabetes Care 2011;​34:​1878-
84.
12. Shields BM, Hicks S, Shepherd MH,
Colclough K, Hattersley AT, Ellard S.
Maturity-onset diabetes of the young
(MODY): how many cases are we missing?
Diabetologia 2010;​53:​2504-8.
13. Fajans SS, Bell GI, Polonsky KS. Mo-

752 n engl j med 382;8 nejm.org  February 20, 2020

The New England Journal of Medicine

Downloaded from nejm.org at NEJM TRIAL INDONESIA on February 22, 2020. For personal use only. No other uses without permission.
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
 Case Records of the Massachuset ts Gener al Hospital

lecular mechanisms and clinical patho-
physiology of maturity-onset diabetes of
the young. N Engl J Med 2001;​345:​971-
80.
14. Steele AM, Shields BM, Wensley KJ,
Colclough K, Ellard S, Hattersley AT. Prev-
alence of vascular complications among
patients with glucokinase mutations and
prolonged, mild hyperglycemia. JAMA
2014;​311:​279-86.
15. Stride A, Shields B, Gill-Carey O, et al.
Cross-sectional and longitudinal studies
suggest pharmacological treatment used
in patients with glucokinase mutations
does not alter glycaemia. Diabetologia
2014;​57:​54-6.
16. Isomaa B, Henricsson M, Lehto M,
et al. Chronic diabetic complications in
patients with MODY3 diabetes. Diabeto-
logia 1998;​41:​467-73.
17. Stride A, Vaxillaire M, Tuomi T, et al.
The genetic abnormality in the beta cell
determines the response to an oral glu-
cose load. Diabetologia 2002;​45:​427-35.
18. Shepherd M, Shields B, Ellard S, Rubio-
Cabezas O, Hattersley AT. A genetic diag-
nosis of HNF1A diabetes alters treatment
and improves glycaemic control in the ma-
jority of insulin-treated patients. Diabet
Med 2009;​26:​437-41.
19. Pearson ER, Starkey BJ, Powell RJ,
Gribble FM, Clark PM, Hattersley AT.
Genetic cause of hyperglycaemia and re-
sponse to treatment in diabetes. Lancet
2003;​362:​1275-81.
20. Østoft SH, Bagger JI, Hansen T, et al.
Glucose-lowering effects and low risk of
hypoglycemia in patients with maturity-
onset diabetes of the young when treated
with a GLP-1 receptor agonist: a double-
blind, randomized, crossover trial. Diabe-
tes Care 2014;​37:​1797-805.
21. MODY Probability Calculator. Exeter,
United Kingdom:​Diabetes Genes, 2019
(https://www​.diabetesgenes​.org/​mody​
-­probability​-­calculator/​).
22. Shields BM, McDonald TJ, Ellard S,
Campbell MJ, Hyde C, Hattersley AT. The
development and validation of a clinical
prediction model to determine the prob-
ability of MODY in patients with young-
onset diabetes. Diabetologia 2012;​55:​1265-
72.
23. Naylor RN, John PM, Winn AN, et al.
Cost-effectiveness of MODY genetic test-
ing: translating genomic advances into
practical health applications. Diabetes
Care 2014;​37:​202-9.
24. Johnson SR, Carter HE, Leo P, et al.
Cost-effectiveness analysis of routine
screening using massively parallel se-
quencing for maturity-onset diabetes of
the young in a pediatric diabetes cohort:
reduced health system costs and im-
proved patient quality of life. Diabetes
Care 2019;​42:​69-76.
25. Cao H, Shorey S, Robinson J, et al.
GCK and HNF1A mutations in Canadian
families with maturity onset diabetes of
the young (MODY). Hum Mutat 2002;​20:​
478-9.
26. Sagen JV, Odili S, Bjørkhaug L, et al.
From clinicogenetic studies of maturity-
onset diabetes of the young to unraveling
complex mechanisms of glucokinase regu-
lation. Diabetes 2006;​55:​1713-22.
27. Genome Aggregation Database (gno-
mAD) (https://gnomad​.broadinstitute​.org/​).
28. Zelent B, Odili S, Buettger C, et al.
Mutational analysis of allosteric activa-
tion and inhibition of glucokinase. Bio-
chem J 2011;​440:​203-15.
29. Fenner D, Odili S, Hong H-K, et al.
Generation of N-ethyl-N-nitrosourea (ENU)
diabetes models in mice demonstrates
genotype-specific action of glucokinase
activators. J Biol Chem 2011;​286:​39560-72.
30. Negahdar M, Aukrust I, Johansson
BB, et al. GCK-MODY diabetes associated
with protein misfolding, cellular self-­
association and degradation. Biochim Bio-
phys Acta 2012;​1822:​1705-15.
31. Richards S, Aziz N, Bale S, et al. Stan-
dards and guidelines for the interpreta-
tion of sequence variants: a joint consen-
sus recommendation of the American
College of Medical Genetics and Genom-
ics and the Association for Molecular Pa-
thology. Genet Med 2015;​17:​405-24.
32. Shepherd MH, Shields BM, Hudson M,
et al. A UK nationwide prospective study
of treatment change in MODY: genetic
subtype and clinical characteristics pre-
dict optimal glycaemic control after dis-
continuing insulin and metformin. Dia-
betologia 2018;​61:​2520-7.
33. Steele AM, Wensley KJ, Ellard S, et al.
Use of HbA1c in the identification of pa-
tients with hyperglycaemia caused by a
glucokinase mutation: observational case
control studies. PLoS One 2013;​8(6):​e65326.
34. The HAPO Study Cooperative Research
Group. Hyperglycemia and adverse preg-
nancy outcomes. N Engl J Med 2008;​358:​
1991-2002.
35. Crowther CA, Hiller JE, Moss JR,
McPhee AJ, Jeffries WS, Robinson JS. Ef-
fect of treatment of gestational diabetes
mellitus on pregnancy outcomes. N Engl
J Med 2005;​352:​2477-86.
36. Landon MB, Spong CY, Thom E, et al.
A multicenter, randomized trial of treat-
ment for mild gestational diabetes. N Engl
J Med 2009;​361:​1339-48.
37. Pedersen J. Diabetes and pregnancy:
blood sugar of newborn infants. Copen-
hagen:​Danish Science Press, 1952:​230.
(Ph.D. thesis.)
38. Committee on Practice Bulletins —
Obstetrics. ACOG practice bulletin no.
190: gestational diabetes mellitus. Obstet
Gynecol 2018;​131(2):​e49-e64.
39. American Diabetes Association. 14.
Management of diabetes in pregnancy:
Standards of Medical Care in Diabetes — 2019.
Diabetes Care 2019;​42:​Suppl 1:​S165-S172.
40. Committee on Practice Bulletins —
Obstetrics. ACOG practice bulletin no. 201:
pregestational diabetes mellitus. Obstet
Gynecol 2018;​132(6):​e228-e248.
41. Bochner CJ, Medearis AL, Williams J
III, Castro L, Hobel CJ, Wade ME. Early
third-trimester ultrasound screening in
gestational diabetes to determine the risk
of macrosomia and labor dystocia at term.
Am J Obstet Gynecol 1987;​157:​703-8.
42. Buchanan TA, Kjos SL, Montoro MN,
et al. Use of fetal ultrasound to select
metabolic therapy for pregnancies com-
plicated by mild gestational diabetes. Di-
abetes Care 1994;​17:​275-83.
43. Hattersley AT, Beards F, Ballantyne E,
Appleton M, Harvey R, Ellard S. Muta-
tions in the glucokinase gene of the fetus
result in reduced birth weight. Nat Genet
1998;​19:​268-70.
44. Spyer G, Macleod KM, Shepherd M,
Ellard S, Hattersley AT. Pregnancy out-
come in patients with raised blood glu-
cose due to a heterozygous glucokinase
gene mutation. Diabet Med 2009;​26:​14-8.
45. Dickens LT, Letourneau LR, Sanyoura
M, Greeley SAW, Philipson LH, Naylor
RN. Management and pregnancy out-
comes of women with GCK-MODY en-
rolled in the US Monogenic Diabetes Reg-
istry. Acta Diabetol 2019;​56:​405-11.
46. Bacon S, Schmid J, McCarthy A, et al.
The clinical management of hyperglyce-
mia in pregnancy complicated by maturity-
onset diabetes of the young. Am J Obstet
Gynecol 2015;​213(2):​236.e1-236.e7.
47. Hosokawa Y, Higuchi S, Kawakita R,
et al. Pregnancy outcome of Japanese pa-
tients with glucokinase-maturity-onset di-
abetes of the young. J Diabetes Investig
2019;​10:​1586-9.
48. Bitterman O, Tinto N, Franzese A, et al.
Glucokinase deficit and birthweight: does
maternal hyperglycemia always meet fetal
needs? Acta Diabetol 2018;​55:​1247-50.
49. Chakera AJ, Hurst PS, Spyer G, et al.
Molecular reductions in glucokinase activ-
ity increase counter-regulatory responses
to hypoglycemia in mice and humans
with diabetes. Mol Metab 2018;​17:​17-27.
50. Guenat E, Seematter G, Philippe J,
Temler E, Jequier E, Tappy L. Counter-
regulatory responses to hypoglycemia in
patients with glucokinase gene muta-
tions. Diabetes Metab 2000;​26:​377-84.
51. Fu J, Wang T, Liu J, Wang X, Li M, Xiao
X. Birthweight correlates with later meta-
bolic abnormalities in Chinese patients
with maturity-onset diabetes of the young
type 2. Endocrine 2019;​65:​53-60.
52. Spyer G, Hattersley AT, Sykes JE, Stur-
ley RH, MacLeod KM. Influence of mater-
nal and fetal glucokinase mutations in
gestational diabetes. Am J Obstet Gynecol
2001;​185:​240-1.
53. Chakera AJ, Steele AM, Gloyn AL, et al.
Recognition and management of individ-
uals with hyperglycemia because of a het-
erozygous glucokinase mutation. Diabe-
tes Care 2015;​38:​1383-92.
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