Download Neonatal Hyperglycemia and Diabetes Mellitus

M Polak1, 2, K Busiah1, 2, H Cavé3, A Bonnefond4, A Simon2,
I Flechtner2, A Dechaume4, N Pouvreau3, B Gerard4,
R Scharfmann1, P Froguel4, M Vaxillaire4.
French Network for the Study of NDM
INSERM U8451, Endocrinologie gynécologie et diabétologie pédiatriques2,
Université Paris Descartes, AP-HP, Hôpital Necker Enfants Malades ;
Biochimie génétique3, AP-HP, Hôpital Robert Debré, Paris ;
CNRS 8090 Institut Pasteur4, Lille.
Neonatal Hyperglycemia and Diabetes Mellitus
Presentation, mechanisms and new genes
Neonatal diabetes Mellitus
Introduction
Rare conditions
~ 1 : 100000 à 250.000
Various etiologies
• Immense progress made in the last 5 years
• Although rare
• Model to understand some aspects of normal development or
function
• Some genetic anomalies present in these patients may explain cases
of diabetes occuring later even at adult age
Difficult to manage
• Experienced team
Neonatal diabetes Mellitus
Clinical Presentation
2 main groups have been identified : permanent and
transient
A precise description of the clinical presentation of these
rare diseases was obtained through a multicenter study
in France
This cohort was collected retrospectively over a 30 years
period
Metz et al, Polak J of Ped 2002
Neonatal diabetes Mellitus Study
Features at birth and at diagnosis
PNDM
n = 21
TNDM
n = 29
Gestational age
(weeks)
39.2 ± 1.6
38.2 ± 2.2
p = 0.15
Birth weight (g)
2 497 ± 690
1 987 ± 510
p < 0.006
Birth length (cm)
47.5 ± 2.4
44.3 ± 3.4
p < 0.006
Head
circumference (cm)
33 ± 1.9
31.5 ± 1.8
p < 0.02
Intra-uterine
growth retardation
n = 7/19
36 %
n = 20/27
74 %
p < 0.03
Birth defects in 2 patients
- 1 TNDM patient with macroglossia
- 1 PNDM patients with heart defect
P value
Neonatal diabetes Mellitus Study
Features at birth and at diagnosis
PNDM
n = 21
TNDM
n = 29
P value
Gestational age
(weeks)
39.2 ± 1.6
38.2 ± 2.2
p = 0.15
Median age (days)
at diagnosis
(range)
27 (1-127)
6 (1-81)
p < 0.01
Initial insulin dose
(unit/kg/day)
1.4 ± 1.2
0.6 ± 0.25
p < 0.006
Neonatal Diabetes
Transient cases: chromosome 6
anomalies, promotor insulin gene,
Potassium channel
Permanent cases: insulin gene coding
sequences, Potassium channel
• Pancreatic Agenesis
• Glucokinase gene mutation
• IPEX
• Wolcott - Rallison Syndrome
• GLIS 3 (with hypothyroidism)
K+(ATP) channels in glucose metabolism
Link glucose metabolism – insulin secretion
Glucose
Glucose
Blood Glucose
Increase
INSULIN
SECRETION
Insulin
Glucose
Glucose
LOW
METABOLISM
Ca2+
Ca2+
ATP
Ca2+
MgADP
ATP
K+
MgADP
- 70 mV
Dépolarization
Hyperpolarization
K+
Closed K+(ATP) channel
Low glucose
High glucose
Normal Subject
Introduction: Kir6.2, potassium channel and
beta cell insulin secretion
NEJM 2004; 350:1817
A Gloyn et al., in A Hattersley laboratory reported in an ethnically diverse patient
cohort that heterozygous activating mutations in the KCNJ11 gene encoding
the Kir6.2 subunit of the pancreatic beta-cell potassium ATP (KATP) channel
cause PNDM and that some of these mutations are also associated
with developmental delay, muscle weakness and epilepsy
N Engl J Med 2004; 350:20
Kir6.2, the beta cell and permanent neonatal diabetesmellitus:
KCNJ11 mutations exist in about 50% of PNDM
NEJM 2004; 350:1817
The effect of drugs which increase insulin secretion
Were studied in these patients
Effects of sulfonylureas on beta cell
Ewan R Pearson*, Isabelle Flechtner*, Pal Njolstad* et al. NEJM 2006; 355: 467-477
Continuous glucose monitoring: child M.
Insulin pump
Glibenclamide
HbA1c
HbA1c under insulin 8,5%
(7,65-8,55)
HbA1c under sulfonylureas 6,4%
(6,19-6,61)
decrease of 1,7%
(12 weeks, p<0,001)
Identical levels at 1 year (n=12)
6% at 15 months (n=4)
5,7% at 2 years (n=1)
No increase in hypoglycemia
(CGMS®)
Physiopathology
Mutations in the ABCC8 gene/ SUR1in nine families
Andrey P. Babenko*, Michel Polak* ; N Engl J Med 2006; 355:456-66
PND12 (L213R)
NN
NN
PND16 (I1424V)
TND16 (L582V)
I
NA
NN
NN
2
1
1
2
NA
4
3
5
II
NM
NM
TND13 (C435R)
NA
TND19 (R1379C)
NN
NM
NM
1
NN
2
III
NM
NN
NN
6
NN
NM
TND28 (H1023Y)
NM
NN
6
NM
NM
I
TND17 (R1379C)
TND34 (R1182Q)
II
NA
NN
NN
NM
16
2
1
NM
NA
NN
3
NM
NM
4
G
III
NM
NN
TND36 (L582V)
1
2
3
4
5
6
7
IV
NN
NN
NA
NA
NM
NA
NA
NM
1
NN
V
NM
NM
Treatment with sulfonylureas
4 probands transferred from Insulin oral sulfonylureas
Proband
Mutation
Dominant
/de novo
Age at exam
[remission]
(year)
Insulin
(U/kg/day)
At transfer
Sulfonylurea
PND12
L213R
de novo
4.75
0.12
Glibenclamide
10 mg/j
I1424V
de novo
16.5
0.88
Glibenclamide
15 mg/j
R1379C
de novo
15.7
[6]
1.2
Glibenclamide
15 mg/j
H1023Y
de novo
16
[16]
0.5
Glipizide
10 mg/j
O
PND16
O
TND19
O
+
TND28
O
Father of TND 13 (C435R) was also transferred successfully
After 24 years of insulin injections
Dominant SUR1 mutations account for a significant fraction (~ 15%) of neonatal
diabetes cases, effectively treatable with oral hypoglycemic agents
Hôpital Necker
M. Polak
K Busiah
Biochimie
A Simon
génétique, Hôpital
JJ. Robert
Robert Debré,
I. Flechtner
Paris
P. Czernichow
H. Cave,
Equipe soignante
N Pouvreau,
B Gerard
S. Pereira,
C. Liger
Hormonologie
D Chevenne
CNRS 8090
Institut Pasteur,
Lille
M. Vaxillaire
P. Froguel
A. Bonnefond
A. Dechaume
U845 INSERM
R. Scharfmann
ENDOCRINOLOGUES DIABETOLOGUES
PEDIATRES
France
Pascal BARAT
Sylvie NIVOT ADAMIAK
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