Case report
Monogenic diabetes and type 1 diabetes mellitus:
a challenging combination
Dr Suma Uday1
Abstract
Registrar, Department of Paediatric Diabetes and
Endocrinology
The co-existence of maturity onset diabetes of the young (MODY) due to a glucokinase gene
(GCK) mutation and type 1 diabetes mellitus (T1DM) is rarely diagnosed. We present a family
with GCK mutation, where one member also has T1DM. We highlight the challenges faced in
the management of a child with dual diagnosis, due to the higher threshold for activation of
counter-regulatory hormones in GCK mutations. Fluctuations in blood glucose (BG) levels and
significant hypoglycaemia on attempts at normalising BG levels complicate management in
these patients. Resetting the threshold for hypoglycaemia and target BG, combined with
insulin pump therapy, enabled us to significantly reduce hypoglycaemia and improve quality of
life. The population prevalence of GCK-MODY is 1.1 in 1000. T1DM neither predisposes to nor
protects from GCK-MODY; one would therefore expect the prevalence of GCK-MODY to be the
same in T1DM patients.
In conclusion, it is important to recognise the co-existence of T1DM and GCK-MODY as
symptoms of hypoglycaemia at BG levels usually considered ‘within target’ pose management
challenges. A combined diagnosis warrants careful consideration of BG target. Copyright ©
2014 John Wiley & Sons.
Practical Diabetes 2014; 31(8): 327–330
Dr Fiona M Campbell2
Consultant Paediatrician, Children and Young People’s
Diabetes Service
Julie Cropper2
Paediatric Diabetes Specialist Nurse, Children and
Young People’s Diabetes Service
Dr Maggie Shepherd3
Honorary Reader
1
Leeds Children’s Hospital, Leeds, UK
Leeds Children’s Hospital, St James’s Multi-specialty
Day Hospital, Leeds, UK
3
University of Exeter Medical School and Royal Devon
and Exeter NHS Foundation Trust, Exeter, Devon, UK
2
Correspondence to:
Dr Suma Uday, Department of Paediatric Diabetes
and Endocrinology, Leeds Children’s Hospital,
Great George Street, Leeds LS9 7TF, UK;
email: [email protected]
Received: 29 July 2014
Accepted in revised form: 20 August 2014
Key words
type 1 diabetes mellitus; maturity onset diabetes of the young; GCK-MODY;
monogenic diabetes; glucokinase gene mutation
Introduction
Maturity onset diabetes of the young
(MODY) is a form of monogenic diabetes that is inherited in an autosomal dominant fashion. Mutations
within the glucokinase (GCK) gene
account for around 20% of UK
MODY and are characterised by
mild, stable hyperglycaemia. Type 1
diabetes mellitus (T1DM), in contrast, is an autoimmune condition
caused by auto-antibodies against
pancreatic islet cells, leading to betacell destruction. A combination of
the two conditions is very rarely diagnosed despite the population prevalence of 1.1 in 1000 for GCK-MODY.
We share the challenges faced in
the management of a child with a
dual diagnosis of T1DM and GCKMODY and discuss some key considerations in the management of
these children.
Case description
A 14-month-old Caucasian boy presented with polyuria and polydipsia
to his local hospital. His blood glucose (BG) was 23mmol/L, he was
ketotic and his HbA1c was 13%
(119mmol/mol). He was suspected
to have T1DM and was commenced
on insulin therapy. Islet cell and
PRACTICAL DIABETES VOL. 31 NO. 8
glutamic acid decarboxylase (GAD)
antibodies were positive.
Three months later, his older sibling aged three years presented with
similar symptoms and T1DM was
suspected. His hyperglycaemia (BG
8.6mmol/L) and ketonuria resolved
promptly with insulin therapy. Islet
cell and GAD antibodies were
negative. His HbA1c was 6.6%
(49mmol/mol). Negative antibodies
and minimal insulin requirements
prompted consideration of monogenic diabetes. On oral glucose tolerance test, fasting BG was
6.5mmol/L and 2-hour post glucose
load BG was 6.6mmol/L. His insulin
was stopped.
Concomitantly, his younger sibling aged two months was also found
to have fasting hyperglycaemia
(8mmol/L) during investigation for
failure to thrive. Further family history revealed an accidental discovery
of raised BG level in the paternal
grandfather at 41 years of age; he
was thought to have type 2 diabetes
and was diet controlled. This
prompted a BG check on the father,
who had fasting hyperglycaemia
(8.6mmol/L).
Hyperglycaemia in three generations of the family prompted genetic
COPYRIGHT © 2014 JOHN WILEY & SONS
327
Case report
Monogenic diabetes and type 1 diabetes
investigation for monogenic diabetes. All family members with
hyperglycaemia tested positive for a
heterozygous deletion on exons 5
and 6 of the glucokinase gene on
chromosome 7, confirming the coexistence of T1DM and GCK-MODY
in the index case (Figure 1).
Challenges
The index case was initially managed
on multiple daily injections (MDI) at
his local hospital. However, this
proved to be very challenging, as
attempts to normalise BG levels
resulted in recurrent episodes of disabling hypoglycaemia with going
pale, limp and having seizures. He
was referred to our centre for tertiary care and consideration of continuous subcutaneous insulin infusion
(CSII), with a view to improving glycaemic control and reducing the frequency of hypoglycaemic episodes.
Male: GCK gene mutation
positive
Male: GCK gene mutation positive +
type 1 diabetes
Unaffected male
Unaffected female
Figure 1. Family tree demonstrates members with positive glucokinase gene mutation in three
generations and our patient with GCK-MODY and type 1 diabetes
Management and progress
Following referral to our centre, he
was commenced on CSII. The family
received intense education and CSII
was optimised by adjusting hourly
basal rates based on BG readings
and use of dual wave (square wave)
bolus to prevent late post-prandial
BG rise. His glycaemic control
improved
following
this,
as
expected. However, he continued to
have episodes of hypoglycaemia,
although with slightly reduced frequency. We undertook diagnostic
continuous glucose monitoring
(CGM) on the father (Figure 2) and
our patient (Figure 3) to determine
BG targets. The father’s lowest BG
was 5.5mmol/L. Our patient was less
than five years of age at the time; we
therefore set the lower limit of his
BG at 6.5mmol/L, which was
1mmol/L higher than the father’s
lower limit. Any BG <6.5mmol/L
was treated as hypoglycaemia. The
frequency of disabling hypoglycaemia and hypoglycaemic seizures
reduced significantly following this.
The parents reported improved
quality of life. He showed a gradual
improvement in HbA1c (Figure 4).
His total daily insulin requirement remained stable between
0.75–0.85 units/kg/day.
Despite
good adherence to treatment,
it was not possible to achieve
the usual T1DM target HbA1c of
328
PRACTICAL DIABETES VOL. 31 NO. 8
Sweets
15
10
5
Alcohol
0
00.00 02.00 04.00 06.00 08.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 00.00
Wed 22 Thu 23
Jun
Jun
# Sensor values
97
288
High SG (mmol/L)
15.2
13.5
Low SG (mmol/L)
6.7
5.4
Average SG (mmol/L) 10.4
8.7
Standard dev.
2.5
1.6
MAD %
50.5
11.7
# Valid calibrations
2
3
Fri 24
Jun
288
12.0
6.8
8.4
0.9
18.4
2
Sat 25 Sun 26 Mon 27 Tues 28 Average/
Jun
Jun
Jun
Jun
total
284
288
137
0
1382
14.0
11.9
9.3
N/A
15.2
7.0
4.9
5.1
N/A
4.9
9.7
8.5
6.8
N/A
8.7
1.7
1.5
1.1
N/A
1.7
11.8
4.3
3.8
N/A
14.4
2
3
1
0
13
Figure 2. Continuous glucose monitoring in the affected parent showing average blood glucose of
8.7±1.7mmol/L
<58mmol/mol (<7.5%) as a consequence of co-existing GCK-MODY.
The HbA1c in the father and the
sibling were 48–54mmol/mol, which
is consistent with the HbA1c
reported in patients with GCK mutations. We expect the HbA1c in our
patient to be consistently high due
to the dual diagnosis. However, the
overall trend in HbA1c gradually
improved during the four-year follow up period.
Although his threshold for treatment of hypoglycaemia has been
reset as he has grown older, it still
remains higher than the usual threshold at 5.5mmol/L. Hypoglycaemia
episodes are now extremely rare. Use
of CGM in conjunction with a low
glucose suspend feature enabled
insulin pump has been encouraged,
especially overnight.
Discussion
Glucokinase is a key regulatory
enzyme in the pancreatic beta-cell. It
plays a crucial role in the regulation
of insulin secretion. Heterozygous
COPYRIGHT © 2014 JOHN WILEY & SONS
Case report
Monogenic diabetes and type 1 diabetes
24-hour analysis – sensor, insulin and settings
Breakfast
Lunch
Dinner
Glucose (mmol/L)
20.0
15.0
10.0
7.8
3.9
2.2
00
1.6
1.2
04
06
08
10
12
14
16
18
20
22
4.0
Basal rate
3.2
Bolus insulin
2.4
1.6
0.8
0.4
0.25 0.30 0.35 0.35 0.30
0.15 0.10 0.10 0.10 0.10 0.15 0.20 0.15 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.15
0.15 0.15
0.8
0
0
Sensitivity
(mmol/L/U)
Carb ratio
(g/U)
00
Bolus insulin
(U, active 4 hr)
Basal rate (U/hr)
2.0
02
10.0
25
20
25
27
25
Figure 3. Continuous blood glucose monitoring in the index case while on an insulin pump demonstrating huge fluctuations in blood glucose levels and
an average sensor blood glucose reading of 8.6±3mmol/L
PRACTICAL DIABETES VOL. 31 NO. 8
110
Reset threshold for
hypoglycaemia treatment
HbA1c
100
HbA1c (mmol/mol)
inactivating mutations in GCK
causes GCK-MODY and is characterised by mild, stable fasting hyperglycaemia (5.5–8mmol/L); this is
present from birth but often discovered incidentally.1 Despite persistent
hyperglycaemia, the prevalence of
micro- and macrovascular complications in this group of patients is
very low.2
There are currently 187 children
and young adults under the age of
19 years with a genetic diagnosis of
GCK-MODY in the United Kingdom
(established by direct communication with the central testing laboratory in Royal Devon and Exeter
Hospital, Exeter). This gives a point
prevalence of approximately 1 in
81 000 in children and young
people under the age of 19 years as
per the 2011 census, Office for
National Statistics. The population
prevalence of GCK-MODY is said to
be 1.1 in 1000.3 There is no evidence
to suggest that GCK-MODY either
protects or pre-disposes to T1DM;
hence, one would expect the prevalence to be 1.1 in 1000 in individuals
90
80
70
60
50
40
Feb May Aug Nov Feb May Aug Nov Feb May Aug Nov Feb May Aug Nov Feb May
2009
2010
2011
2012
2013
Figure 4. Trend in HbA1c following continuous subcutaneous insulin infusion and resetting threshold
for treatment of hypoglycaemia
with T1DM as well. The 2011–2012
National Paediatric Diabetes Audit
reported that there are approximately 25 000 children and young
people under the age of 19 years
with diabetes in the UK. Ninetyseven percent of these patients
have T1DM, giving an approximate
number of 24 000. Based on the
prevalence of 1.1 in 1000, we would
expect approximately 26 children
with T1DM under the age of 19 years
to have co-existent GCK-MODY.
However, to the best of our knowledge there are only two genetically
confirmed cases, including our
COPYRIGHT © 2014 JOHN WILEY & SONS
329
Case report
Monogenic diabetes and type 1 diabetes
Key points
l Co-existence of type 1 diabetes (T1DM) and GCK-MODY is currently rarely diagnosed
despite the reported population prevalence of GCK-MODY of 1.1 in 1000. GCK mutations
do not protect from or predispose to T1DM, therefore one would expect to find
co-existence in 1.1 in 1000 T1DM patients
l It is important to recognise the co-existence of these conditions as symptoms of
hypoglycaemia at blood glucose levels usually considered ‘within target’ pose
management challenges. Counter-regulatory response to hypoglycaemia is activated at a
higher plasma glucose concentration in GCK-MODY. The target blood glucose for these
patients should therefore be set at a higher level than in patients who have T1DM alone
l Identifying relevant family history is key in recognising monogenic diabetes. Planned longterm follow up of families with dual diagnosis of T1DM and GCK-MODY would allow us
to determine optimal management strategies and assess future risks of microvascular and
macrovascular complications
patient, with a combined diagnosis
of GCK-MODY and T1DM in the
UK (established through the central
genetic testing laboratory in
Exeter). Individuals are often misdiagnosed as having other forms of
diabetes depending on the timing of
detection of hyperglycaemia.1 In this
case, our patient’s older sibling was
thought to have T1DM and his
grandfather was misdiagnosed as
having type 2 diabetes.
The counter-regulatory response
to hypoglycaemia is activated at a
higher plasma glucose concentration
in those with GCK-MODY. This may
be secondary to decreased glucokinase activity in hypothalamic
neuronal cells, or to alterations of
glucose sensing in pancreatic alphacells and liver cells.4 It would be useful to demonstrate the changes in
counter-regulatory hormones using
clamp studies; unfortunately, we were
unable to do this due to ethical
issues. In patients with GCK-MODY,
there is a lack of glycaemic response
to pharmacologic agents as the
genetic subtype determines the
treatment response.5 The use of
hypoglycaemic agents in GCK-MODY
suppresses endogenous insulin to
maintain BG at a higher level.5
However, in patients with a dual
diagnosis of T1DM, where there is a
lack of endogenous insulin, use of
high doses of insulin to lower BG
levels may render patients symptomatically hypoglycaemic at BG levels
considered to be within target, hence
complicating management. Consequently, the targets should be set at
a higher level to match that of
GCK-MODY, with fasting values
between 5.5–8mmol/L considered
acceptable. We chose to set the lower
threshold to be 5.5mmol/L in
our patient based on the father’s
BG levels.
Although the frequency of hypoglycaemic episodes reduced after
commencing CSII, marked improvement was noted only after resetting
the threshold for treatment of hypoglycaemia. Overall glycaemic control
improved with age over a four-year
follow up period with fewer fluctuations in BG, as one would expect
in any young child with T1DM. It has
been demonstrated that counterregulatory response to hypoglycaemia is activated at a higher
plasma glucose concentration in
those with GCK-MODY; however, it is
not known whether neuroglycopaenia also occurs at a higher circulating
glucose in GCK-MODY than in persons with normal glucokinase activity. Further studies in patients with
dual diagnosis are required to
explore this.
The effect of persistent hyperglycaemia in patients with a dual diagnosis is unknown. There is no literature
on the long-term effect of micro- and
macrovascular complications in this
group of patients and these require
further investigation.
Acknowledgements
We would like to thank:
– Our patient and his family.
– Kevin Colclough, Clinical Scientist,
Molecular Genetics Laboratory,
Royal Devon & Exeter Hospital, for
help with data.
– All members of the diabetes team at
our patient’s local hospital where he
was initially diagnosed and managed.
Declaration of interests
There are no conflicts of interest
declared. No funding was received
for this work. MS is supported by the
NIHR Exeter Clinical Research
Facility.
Written consent has been
obtained from the patient’s family.
References
1. Murphy R, et al. Clinical implications of a molecular
genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 2008;
4(4):200–13.
2. Steele AM, et al. Prevalence of vascular complications among patients with glucokinase mutations
and prolonged, mild hyperglycemia. JAMA 2014;
311:279–86.
3. Chakera A, et al. The 0.1% of the population with
glucokinase monogenic diabetes can be recognized
by clinical characteristics in pregnancy: the Atlantic
Diabetes in Pregnancy cohort. Diabetes Care
2014;37(5):1230–6.
4. Guenat E, et al. Counterregulatory responses to
hypoglycemia in patients with glucokinase
gene mutations. Diabetes Metab 2000;26(5):
377–84.
5. Stride A, et al. Cross-sectional and longitudinal
studies suggest pharmacological treatment
used in patients with glucokinase mutations does
not alter glycaemia. Diabetologia 2014;57(1):54–6.
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