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Neonatal Diabetes-From Insulin to Oral Hypoglycemic Agent: Case Report

Sridevi A Naaraayan1*, Poovazhagi Varadharajan2, Raghavan V Dhakshayani1, and Rema Chandramohan1

1Institute of Child Health and Hospital for Children, Madras Medical College, Chennai, India

2Government Medical College, Omandurar Govt. Estate, Triplicane, Chennai, India

*Corresponding Author:
Sridevi A Naaraayan
Institute of Child Health and Hospital for Children
Madras Medical College, Chennai, India
Tel: 9884279417
E-mail: childdoctorsri@yahoo.co.in

Received date: March 06, 2017; Accepted date: March 21, 2017; Published date: March 26, 2017

Citation: Naaraayan SA, Varadharajan P, Dhakshayani RV, Chandramohan R (2017) Neonatal Diabetes-From Insulin to Oral Hypoglycemic Agent: Case Report. Diabetes Case Rep 2: 121

Copyright: © 2017 Naaraayan SA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes that occurs in first 6 months of life with an incidence of 1 in 100,000 to 500,000 live births [1]. It is one of the disorders in which the role of genetic analysis is not limited to confirmation of the diagnosis, but also required for selecting the appropriate therapy. Patients with certain mutations like the ones involving KCNJ11 and ABCC8 genes respond to oral sulfonylurea [2]. Successful switch over from subcutaneous insulin to oral sulfonylurea has been previously reported by various authors [3,4]. In this case report, we present our experience on transferring three patients with genetic mutations from insulin to oral glibenclamide in last three years.

Introduction

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes that occurs in first 6 months of life with an incidence of 1 in 100,000 to 500,000 live births [1]. It is one of the disorders in which the role of genetic analysis is not limited to confirmation of the diagnosis, but also required for selecting the appropriate therapy. Patients with certain mutations like the ones involving KCNJ11 and ABCC8 genes respond to oral sulfonylurea [2]. Successful switch over from subcutaneous insulin to oral sulfonylurea has been previously reported by various authors [3,4]. In this case report, we present our experience on transferring three patients with genetic mutations from insulin to oral glibenclamide in last three years.

Case Report

The clinical characteristics of the three patients are given in Table 1. The genetic report and transfer from insulin to glibenclamide are discussed individually and follow up details are shown in Table 2.

Characteristic Case 1 Case 2 Case 3
Age at presentation (days) 100 75 143
Gender Male Male Female
Mode of presentation Non- DKA DKA DKA
Gestational age Pre-term Term Term
Birth weight (grams) 1700 2250 2560
Consanguinity nil nil nil
Family history of diabetes Maternal grandfather Maternal grandmother nil
HbA1c at presentation (%)   13.1 12.5 7.2
C peptide at presentation(ng/ml) 0.51 0.04 1.4
Insulin dose prior to transfer (u/kg/day) 0.75 1.57 1

Table 1: Clinical characteristics of the patients.

Patient Duration of follow up Present glibenclamide dose HbA1c Growth Development
Before transfer After transfer
Case 1 22 months 0.18 6 5.1 Severe Acute Malnutrition Global developmental delay
Case 2 14 months 0.3 8.5 5 Normal Normal
Case 3 9 months 0.12 8.7 5.4 Normal Normal

Table 2: Follow up details of the patients.

Case 1: This boy was heterozygous for missense mutation pA90V in ABCC8 gene involving SUR1 (Sulfonylurea receptor 1) subunit of pancreatic ATP sensitive potassium channel (KATP) which he had inherited from his mother, who was a carrier. He was started on glibenclamide on 197th day of life in a dose of 0.1 mg/kg/dose twice a day and the dose was increased gradually while insulin dose was decreased. His blood sugar stabilized at glibenclamide dose of 0.4 mg/kg/dose twice a day on day 7 of treatment when insulin could be omitted. On follow up, his glycemic control improved substantially without any episode of hypoglycemia.

Case 2: This boy was heterozygous for ABCC8 missense mutation pR1380C in SUR1 subunit of KATP channel while both his parents were negative. He was transferred to oral glibenclamide on 139th day of life. The starting dose was 0.1 mg/kg/dose twice a day which was gradually escalated while decreasing the insulin dose. He maintained stable glucose levels at glibenclamide dose of 0.5 mg/kg/dose twice a day on day 8 when insulin could be omitted. Improvement in glycemic control was obvious on regular follow up.

Case 3: This girl had heterozygous KCNJ11 missense mutation pVal328Met involving Kir 6.2 subunit of KATP channel. Genetic analysis of her biological parents could not be done as she was an adopted child and her parents were untraceable. She was switched over to oral glibenclamide on 133th day of life with a starting dose of 0.1 mg/kg/dose twice a day. Her insulin dose was reduced as her glibenclamide dose was stepped up. She maintained stable glucose levels at a glibenclamide dose of 0.2 mg/kg/dose twice a day and her insulin could be omitted on day 5 of switch over. She is being followed up periodically and is showing improvement in glycemic control.

Discussion

This case report describes the clinical presentation, treatment and follow up details of three infants who presented to our center in last three years with diabetes and were found to have mutations involving KATP channel gene. Genetic testing will allow diagnosis of a specific type of monogenic diabetes in over 80% of patients who present with diabetes within six months of age [5]. KATP channels are hetero octameric complexes formed by four pore-forming Kir 6.2 subunits and four SUR1 regulatory subunits encoded by genes KCNJ11 and ABCC8 respectively [6]. Mutations in these genes prevent KATP channel closure and hence insulin secretion in response to hyperglycemia and are common causes of permanent neonatal diabetes mellitus [7,8]. One of our patients with ABCC8 mutation had developmental delay suggestive of intermediate form of DEND (developmental delay, epilepsy and diabetes mellitus) syndrome as described in literature [9]. Approximately 90% of patients with mutations in KATP channel genes can be transferred from insulin onto sulfonylurea tablets [2,10]. The sulfonylurea of choice is glibenclamide in usual dose of 0.5 mg/kg/day, but doses up to 2.3 mg/kg/day have been reportedly used [11]. The only common side effect reported to date in children is transient diarrhea which was not encountered in our patients [12]. In most patients, the dose of sulfonylurea required for achieving initial glycemic control can be reduced over a period of time as evidenced in our patients [2]. As noted in our patients, the glycemic control improves substantially without increasing the risk of hypoglycemia following transfer from insulin to oral hypoglycemic agents. This improved glycemic control and absence of hypoglycemic episodes are essential pre-requisites for normal growth and development of these infants.

Hence ISPAD guidelines recommends genetic testing for all patients diagnosed with diabetes in first six months of life as the results may change the treatment modality and improve glycemic control and hence the quality of life.

Key Messages

• Genetic analysis of infants presenting with diabetes within first six months of life is mandatory.

• Switching over from insulin to oral glibenclamide in patients with mutation involving KATP channel gene results in better glycemic control.

Acknowledgements

The authors express their sincere thanks to Professor Hettersley AT and Professor Ellard S of Royal Devan and Exeter NHS Foundation Trust, UK for their help in the genetic studies and guidance in the management.

The authors are also thankful to PUNCH charity, India for sponsoring the shipment of blood samples to UK.

The authors also thank Surendra diagnostics for help rendered in shipping the samples to UK.

References

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