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Indian Pediatr 2013;50:
737 |
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Infantile Onset Diabetes Mellitus
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Inder Pal Singh Kochar
Apollo Hospital, Sarita Vihar, Delhi, India.
Email:
[email protected]
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Diabetes mellitus is an etiologically
heterogeneous disorder. Monogenic forms of diabetes mellitus cover a
heterogeneous group of diabetes which are uniformly caused by a single
gene mutation and are characterized by impaired insulin secretion of the
pancreatic beta cell. It is estimated that they account for up to 5% of
all cases of diabetes mellitus, which are often not diagnosed or are
misclassified as type 1 or 2 diabetes. However, accurate diagnosis is
important because of the special implications for treatment, prognosis
and family risk. The knowledge of typical clinical features such as mode
of inheritance, age at diagnosis and impaired insulin secretion, as well
as genetic testing establishes the diagnosis of MODY, mitochondrial
diabetes and neonatal diabetes. In particular, diabetes occurring under
6 months of age—usually termed neonatal diabetes—appears to be
predominantly monogenic.
The neonatal diabetes phenotype encapsulates numerous
subtypes, wherein most etiologies involve a severe disruption in
b-cell
function. Neonatal diabetes can be permanent and require lifelong
treatment, or may be transient, in which case the diabetes may
spontaneously remit (or be so mild as not to require treatment), but
will often relapse, usually during adolescence. Nearly half of all cases
of permanent neonatal diabetes are due to activating mutations in KCNJ11 or
ABCC8; their diabetes can be remarkably well controlled by oral
sulfonylurea instead of injected insulin [1,2]. In most such cases,
transition from insulin to sulfonylurea therapy is best done during an
inpatient admission using published guidelines [2], with advice sought
from recognized centers with extensive experience. Although the
resulting treatment is clearly easier and the level of diabetes control
better, many questions still remain to be clarified:
1. How sustainable will the treatment with oral
sulfonylureas be, and will age, obesity, or other factors eventually
require supplemental insulin or other medications? In this regard, a
single case has been fortuitously treated for over 50 years [1].
Furthermore, literature reports [3,4] all continue to do well and
give reason for optimism, but only time and careful tracking of
long-term outcome will tell.
2. How often will patients have hypoglycemia, and
what happens to their blood sugar levels during illness, procedures,
or hospitalization, especially if oral medications cannot be taken?
3. To what extent will neurodevelopmental effects
be improved or even prevented by sulfonylurea treatment? In this
regard a notable study recently confirmed that mice with brain
expression of a mutant form of the protein encoded by KCNJ11 (Kir6.2)
have a neurologic phenotype reminiscent of patients with the same
mutation (V59M) [5].
In this issue, Varadarajan, et al. [6] report
a series of 40 cases with infantile onset diabetes mellitus (IODM) and
their long-term follow up which is the first in our country. The study
lucidly highlights the issue of IODM and the paucity of its recognition.
More so, it highlights the need for genetic evaluation in this select
group of diagnosis. We expect that within a few years, important
breakthroughs will be made in mapping cases of diabetes with a
suspected, but still unsolved monogenic basis.
Competing interest: None stated; Funding:
Nil.
References
1. Gloyn AL, Pearson ER, Antcliff JF, Proks P,
Bruining GJ, Slingerland AS, et al. Activating mutations in the
gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and
permanent neonatal diabetes. N Engl J Med. 2004;350:1838-49.
2. Pearson ER, Flechtner I, Njølstad PR, Malecki MT,
Flanagan SE, Larkin B, et al. Switching from insulin to oral
sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl
J Med. 2006;355:467-77.
3. Stoy J, Greeley SAW, Paz VP, Ye H, Pastore AN,
Skowron KB, et al. Diagnosis and treatment of neonatal diabetes:
a United States experience. Pediatr Diabetes. 2008;9:450-9.
4. Iafusco D, Bizzarri C, Cadario F, Pesavento R,
Tonini G, Tumini S, et al. No beta cell desensitisation after a
median of 68 months on glibenclamide therapy in patients with KCNJ11-associated
permanent neonatal diabetes. Diabetologia. 2011;54:2736-8.
5. Clark RH, McTaggart JS, Webster R, Mannikko R,
Iberl M, Sim XL, et al. Muscle dysfunction caused by a KATP
channel mutation in neonatal diabetes is neuronal in
origin. Science. 2010;329:458-61.
6. Varadarajan P, Sangaralingam T, Senniappan S,
Jahnavi S, Radha V, Mohan V. Clinical presentation and long term outcome
of 40 children with infantile onset diabetes mellitus in South India.
Indian Pediatr. 2013;50:759-63.
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