|Year : 2018 | Volume
| Issue : 2 | Page : 65-67
Successful transition to sulphonylurea therapy from insulin in a child with permanent neonatal diabetes due to a KCNJ11 gene mutation
Venkatesan Radha1, Bhuvanagiri Ramya2, Sundaramoorthy Gopi1, Babu Kavitha1, Somayajula Preetika2, Kalpana Thai2, Ranjit Unnikrishnan3, Viswanathan Mohan3, Prasanna Kumar Gupta2
1 Madras Diabetes Research Foundation, WHO Collaborating Centre for Non-communicable Diseases Prevention and Control, ICMR Centre for Advanced Research on Diabetes, Chennai, Tamil Nadu, India
2 Dr. Mohan's Diabetes Specialities Centre, WHO Collaborating Centre for Non-Communicable Diseases Prevention and Control and IDF Centre of Excellence in Diabetes Care, Chennai, Tamil Nadu, India
3 Madras Diabetes Research Foundation, WHO Collaborating Centre for Non-communicable Diseases Prevention and Control, ICMR Centre for Advanced Research on Diabetes; Dr. Mohan's Diabetes Specialities Centre, WHO Collaborating Centre for Non-Communicable Diseases Prevention and Control and IDF Centre of Excellence in Diabetes Care, Chennai, Tamil Nadu, India
|Date of Web Publication||10-May-2018|
Dr. Venkatesan Radha
Madras Diabetes Research Foundation, ICMR Centre for Advanced Research on Diabetes, Dr. Mohan's Diabetes Specialities Centre, WHO Collaborating Centre for Non-communicable Diseases Prevention and Control and IDF Centre of Excellence in Diabetes Care, No. 4, Conran Smith Road, Gopalapuram, Chennai - 600 086, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes mellitus that occurs in the first 6 months of life. It is a rare condition with a prevalence of 1 in 100,000–500,000 live births. We report a 3-month-old girl child with high blood glucose levels. She was diagnosed with diabetes mellitus during the 28th day of life and was on treatment with insulin. She was admitted for the control of high blood glucose levels during which she was started on multiple daily insulin treatment, but the control had been poor. As the age of onset is <6 months of life, genetic analysis has been done. It revealed the presence of a heterozygous mutation p. Gly334Val (p. G334V) in KCNJ11 gene which confirmed the diagnosis of NDM. The child was successfully shifted from insulin to sulfonylureas, and the blood glucose levels are well maintained.
Keywords: Gene mutation, insulin, neonatal diabetes, sulphonylurea
|How to cite this article:|
Radha V, Ramya B, Gopi S, Kavitha B, Preetika S, Thai K, Unnikrishnan R, Mohan V, Gupta PK. Successful transition to sulphonylurea therapy from insulin in a child with permanent neonatal diabetes due to a KCNJ11 gene mutation. J Diabetol 2018;9:65-7
|How to cite this URL:|
Radha V, Ramya B, Gopi S, Kavitha B, Preetika S, Thai K, Unnikrishnan R, Mohan V, Gupta PK. Successful transition to sulphonylurea therapy from insulin in a child with permanent neonatal diabetes due to a KCNJ11 gene mutation. J Diabetol [serial online] 2018 [cited 2019 Feb 20];9:65-7. Available from: http://www.journalofdiabetology.org/text.asp?2018/9/2/65/232228
| Introduction|| |
Neonatal diabetes mellitus (NDM) is defined as diabetes diagnosed within the first 6 months of life. This condition can be either permanent, requiring lifelong insulin therapy, or transient where the condition can remit during infancy but mostly relapse later in life. Permanent NDM (PNDM) and transient neonatal diabetes mellitus are rare conditions with an incidence of 1 in 300000 live births.,
We describe here an infant with PNDM due to a mutation in KCNJ11 gene that encodes the pore-forming subunit KIR6.2 of the pancreatic ATP-sensitive potassium (K-ATP) channel, who was shifted successfully from insulin injections to oral sulphonylurea (SU).
| Case Report|| |
A 3-month-old girl child presented with uncontrolled high blood glucose levels. She was the first born child of a non-consanguineous marriage. She was born by a normal vaginal delivery of preterm gestation with a low birth weight of 2 kg. Antenatal, natal and post-natal periods were uneventful. The baby remained well until an episode of fever on the 28th day of life, during which she was investigated and diagnosed to have diabetes. The mother did not report any previous relevant medical conditions such as gestational diabetes mellitus. At the time of admission to our centre, the baby had a BMI of 13.7 kg/m 2. It was observed that the birth centile of the baby is <3rd centile (http://www.who.int/childgrowth/standards/weight_for_age_field/en) and the Z score was 3. Head circumference of the baby was not available. She was started on multiple daily insulin (MDI) treatment, but glycaemic control remained poor. Investigations showed random blood sugar of 371 mg/dl, serum beta-hydroxybutyrate of 0.08 mmol/L, HbA1c of 7.7%, blood urea of 26 mg/dl and serum creatinine of 0.3 mg/dl. Haemogram revealed white blood cell count of 11740 cells/mm 3 and haemoglobin of 10.2 gm/dl (normocytic normochromic anaemia). Liver function tests were normal. Ultrasound of abdomen revealed thinned out/hypoplastic pancreas; however, faecal elastase/stool fat estimation was not done. Metabolic encephalopathy also was observed. Serum electrolytes were normal. Thyroid function tests were normal. C-peptide assay showed a stimulated value of 0.6pmol/ml, indicating poor pancreatic beta-cell reserve. Glutamic acid decarboxylase antibody was negative: <1.0 IU/ml. As the age at onset of diabetes was <6 months, we arrived at the diagnosis of neonatal diabetes. Genetic analysis was performed by Sanger sequencing for genes implicated in neonatal diabetes which revealed the presence of a heterozygous mutation p. Gly334Val (p. G334V) in KCNJ11 gene, which has earlier been shown to be associated with response to SU therapy. The child was started on with glibenclamide a dose of 0.6 mg/kg/day and was increased to 1 mg/kg/day, and the insulin was tapered and eventually stopped. Later, as she was getting hypoglycaemia with glibenclamide, the dose of glibenclamide was reduced to 0.05 mg/kg twice daily.
| Discussion|| |
Among the mutations causing PNDM, heterozygous mutations in the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) and ATP-binding cassette, subfamily C, member 8 (ABCC8) genes are the most common causes.,, These mutations impair the ability of the channel to close in response to metabolically generated ATP, thereby preventing glucose-induced insulin secretion from pancreatic beta-cells. SU drugs directly close KATP channels and facilitate insulin release in response to food. This results in improved glycaemic control.
In this child, the Gly334Val mutation was identified which has been predicted to be deleterious and damaging when bioinformatics tool such as MutationTaster was used. In such cases, SU drugs are the best choice. Oral glibenclamide, a non-selective sulfonylurea, is effective in closing the K + ATP channels in the beta-cells, muscle, and brain. The mutated channels in the nerve muscle and brain are responsible for the neurological symptoms which may be present in some of these cases. The initiation of oral sulfonylurea was done as a rapid inhospital procedure over a period of 1 week. To begin with, sulfonylurea was started with 0.6 mg/kg/day along with a gradual tapering off of insulin before discharging the child. The child now continues to be on SU drug for the past 2 years and is doing well. However, not all patients with mutations in the KCNJ11 or ABCC8 genes are SU sensitive; there has been a report of unsuccessful sulfonylurea therapy in a NDM patient with a different mutation (p. Gly334Asp, c. 1001G >A) in the same amino acid codon  [refer supplementary information for protocol of shifting of treatment [Additional file 1]].
SU treatment is superior to insulin treatment in many PNDM due to mutations in KCNJ11 gene. Screening of KCNJ11 and ABCC8 gene for mutations in patients with PNDM is justified due to the improvement in glycaemic control and the quality of life after switching over to SU from insulin.
We would like to acknowledge Dr. Ajit Kumar Sardar, Institute of Child Health, Calcutta, for referring this case.
This study was supported by funding from the Indian Council for Medical Research, New Delhi, India, through the projects “Genetic Analysis of Maturity Onset diabetes of young (MODY) and Neonatal diabetes in India” and “Changing treatment profile in Monogenic forms of Diabetes such as Neonatal Diabetes and MODY by Translational Genomics Research” awarded to Radha V.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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