Permanent Neonatal Diabetes Mellitus Due to a C96Y Heterozygous Mutation in the Insulin Gene. A Case Report

Anish Ahamed1, Ambika Gopalakrishnan Unnikrishnan1, Sanket Sharad Pendsey1, Sheela Nampoothiri2, Nisha Bhavani1, Valliyaparambil Pavithran Praveen1, Harish Kumar1, Rohinivilasam Vasukutty Jayakumar1, Vasantha Nair1, Sian Ellard3, Emma L Edghill3

Departments of 1Endocrinology and 2Pediatric Genetics, Amrita Institute of Medical Sciences. Cochin, India.

3Institute of Biomedical and Clinical Science, Peninsula Medical School. Exeter, United Kingdom

*Corresponding Author:
Ambika Gopalakrishnan Unnikrishnan
Department of Endocrinology and Diabetes
Amrita Institute of Medical Sciences
Elamakkara PO
Phone +91-484.280.1234-ext-1099; +91- 484.220.5343
Fax +91-484-280-2131
E-mail [email protected]

Received July 17th, 2008 - Accepted September 30th, 2008

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Context Neonatal diabetes is a rare disorder with an incidence of 1 in 215,000-500,000 live births with 50% of them having permanent neonatal diabetes mellitus. Case report We present a case of permanent neonatal diabetes mellitus due to a C96Y (c.287G>A; p.Cys96Tyr) heterozygous mutation in the insulin (INS) gene. Both the patient and his father (who had childhoodonset insulin-requiring diabetes) were found to be carriers of a heterozygous missense mutation C96Y in exon 3 of the INS gene. It has been hypothesized that these mutations disrupt the folding of the proinsulin molecule and result in a misfolded protein or retention of the protein in the endoplasmic reticulum, resulting in endoplasmic reticulum stress and beta cell apoptosis. Subjects with this form of diabetes will need lifelong insulin therapy. Conclusion Insulin gene mutations appear to be an important cause of neonatal diabetes worldwide. This is the first report of a case from the Indian subcontinent. It is important to carry out genetic tests for mutations linked to pancreatic beta cell dysfunction in all patients with persistent neonatal diabetes mellitus in order to decide on therapy


Diabetes Mellitus; India; Mutation


Neonatal diabetes is defined as hyperglycemia occurring within the first few months of life, lasting more than 2 weeks [1]. It is categorized into permanent neonatal diabetes and transient neonatal diabetes. Heterozygous activating mutations in the KCNJ11 and ABCC8 genes which encode the Kir 6.2 and SUR1 subunits of the ATPsensitive potassium (KATP) channels that control insulin secretion are the commonest causes of permanent neonatal diabetes and a rarer cause of transient neonatal diabetes respectively [2, 3]. Other rare genetic causes of neonatal diabetes include mutations in insulin gene (INS), hepatocyte nuclear factor 1B (HNF1B), pancreatic and duodenal homeobox 1(PDX 1), pancreas specific transcription 2 factor, 1a (PTF1A), forkheadbox P3 (FOXP3), eukaryotic translation initiation factor 2- alpha kinase 3 (EIF2AK3), and glucokinase gene [3, 4]. Recently, missense mutations in the genes encoding insulin and its precursors, preproinsulin and proinsulin, have also been reported as causes of permanent neonatal diabetes mellitus [5]. Patients with transient neonatal diabetes due to chromosome 6q24 abnormalities are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis. It is vital to identify KATP channel mutations as most of these patients do not require insulin and achieve better glycemic control with sulphonylureas.

We hereby report a case of permanent neonatal diabetes, diagnosed to have an ABCC8 mutation, who has been successfully switched over to sulphonylurea.


A two-month-old female baby, born to non consanguineous parents, was referred to Amrita Institute of Medical Sciences, Cochin, India for diabetic ketoacidosis. Antenatal period was uneventful with no history of gestational diabetes mellitus. Family history was unremarkable except that maternal grandmother had diabetes. The baby was born at full term by normal vaginal delivery with weight of 2.5 kg. Postnatal period was uneventful except for diabetic ketoacidosis.

On examination, the weight was 4.2 kg (25th percentile) and length 55 cm (50th percentile). Her vitals were stable. She had no dysmorphic features. Rest of the systemic examination was normal.

Complete blood counts were normal with no evidence of ketonuria. Fasting blood glucose was 156 mg/dL (reference range: 70-110 mg/dL) and 2- hour postprandial glucose 300 mg/dL (reference range: 100-140 mg/dL) with a glycated hemoglobin of 7.9%. (reference range: 4.0-5.9%). Structural diseases of pancreas were ruled out by ultrasonography of abdomen. Glutamic acid decarboxylase-65 antibody (GAD-65) and insulinoma-associated antibody (IA-2) were negative; the fasting C-peptide was 1 ng/mL, (reference range: 1-3 ng/mL). As the onset was less than 6 months with autoimmune markers being negative, genetic tests for mutation in KATP channel were carried out. This revealed a heterozygous missense mutation in exon 29 of ABCC8. The mutation is a substitution of a T for C at nucleotide 3596, i.e. c.3596C>T which results in the substitution of leucine for proline at amino acid 1199, i.e. P1199L. Testing of the parents showed that the mutation had risen de novo. The baby was initially put on neutral Hagedorn (NPH) insulin 2 units daily with bolus of short acting insulin until the results of the genetic analysis were made available, following which she was switched over to glibenclamide.

In our case, the child is on regular follow up and is presently on 3.75 mg/day of glibenclamide with glycated hemoglobin of 6.8% and C-peptide of 2.7 ng/mL, 3 months after starting oral hypoglycemic agent.


Activating mutations in Kir 6.2 and SUR1 subunits of the KATP channels account for one third to one half of cases of permanent neonatal diabetes. Mutations in ABCC8 gene is thought to account for 10% of all cases of neonatal diabetes [6] and frequently cause transient neonatal diabetes. ABCC8 mutations may be either dominantly or recessively acting and 40 different mutations have been reported in patients with neonatal diabetes[7, 8].

The KATP channel is an octamer complex of four regulatory sulphonylurea receptors (SUR) embracing pore forming inwardly rectifying potassium channel (Kir). This channel is normally inhibited by binding of adenine nucleotides to subunit Kir 6.2 which closes the channel and activated by nucleotide binding or hydrolysis on SUR1 which opens the channel. The balance of these opposing action determines the low open channel probability (P0), which controls excitability of pancreatic beta cells.

It is postulated that activating mutations in these channels reduce the sensitivity to inhibitory actions of ATP and increases sensitivity to stimulatory actions of ADP which causes KATP channel to remain open, thereby inhibiting insulin release. Sulphonylurea stimulates insulin secretion by binding to SUR1 subunit, thereby closing KATP channel by ATP independent mechanism.

Babenko et al. described seven ABCC8 mutations with milder phenotypes. Four mutations were familial and showed vertical transmission [6]. L213R and I1424V mutations were associated with permanent neonatal diabetes and other five with transient neonatal diabetes. These patients were diagnosed within first 6 months of life, presented with low birth weight (from less than 3 to 67 percentile) and hyperglycemia with absence of islet cell antibody. Two patients presented with ketoacidosis (H1023Y and I1424V) and four patients with minor neurological symptoms.

Compared to babies with Kir 6.2 mutations, those with SUR1 mutation revealed no significant difference in the prevalence of low birth weight, age at diagnosis or severity of hyperglycemia. However, babies with insulin gene mutations had higher birth weight than those with channel mutations.

The preliminary investigations in our case ruled out type 1 diabetes. Hence, a genetic analysis was done which revealed heterozygous missense mutation (P1199L) in exon 29 of ABCC8 gene, which results in substitution of leucine for proline. This mutation had arisen de novo and is a new mutation not reported so far from India. In our patient, the baby was later switched over to 0.1 mg/kg/day of glibenclamide, which was slowly titrated as per the protocol compiled by Hattersley and Asheroft [2]. A more detailed version of the protocol for transferring patients with diabetes due to Kir 6.2 or SUR1 mutation is available in the website. This protocol was for Kir 6.2 mutations, but is also applicable for patients with SUR1 mutations [9]. The sulphonylurea commonly used is glibenclamide at a high dose of 0.5 mg/kg/day which later can be tapered over time.

Rafiq et al. followed 27 patients with SUR1 mutation for two months after switching over to OHA and found that 85% could be successfully transferred to OHA without need for insulin [9]. Glycated hemoglobin in them fell from 7.2% to 5.5% (P=0.01). However, long term follow up is needed to see whether improved glycemic trends continue. In seven patients sulphonylureas other than glyburide were tried (i.e., gliclazide, glipizide, tolbutamide). In the study by Rafiq et al., four patients could not be successfully switched over to OHA. Two of them had neurological abnormalities and the other two received their molecular genetic diagnosis later in life [9]. Three patients reported side effects due to sulphonylurea. One had transitory diarrhoea, the other had nausea which resolved spontaneously. One severe hypoglycemic episode was reported, requiring reduction in the dosage of sulphonylurea.

When compared with Kir 6.2 mutations, patients with SUR1 mutation needed lesser dose of sulphonylurea (0.26 vs. 0.45 mg/kg/day) and may represent an increased endogenous insulin secretion [9]. Permanent neonatal diabetes due to an insulin gene mutation has been reported earlier from India [10]. To our knowledge, ABCC8 mutations are rare causes of permanent neonatal diabetes and this is the first case from India. This case has a hitherto undescribed novel mutations.


S.E. is a Wellcome Trust (London, United Kingdom) senior investigator. Genetic testing is available in Exeter (United Kingdom) laboratory for any patient diagnosed with diabetes of less than 9 months of age, free of charge. Please see for details.

Conflict of interest

The authors have no potential conflict of interest


  1. Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larki B, et al. The Neonatal Diabetes International Collaborative Group. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006; 355:467-77. [PMID 16885550]
  2. Wang J, Takeuchi T, Tanaka S, Kubo SK, Kayo T, Lu D, et al. A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. J Clin Invest 1999; 103:27-37. [PMID 9884331]
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