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 Table of Contents  
Year : 2021  |  Volume : 1  |  Issue : 4  |  Page : 260-262

Permanent neonatal diabetes mellitus in an Indian infant due to a novel mutation in the glucokinase gene

1 Department of Pediatrics, MGM Medical College, Warangal, Telangana, India
2 Division of Neonatology, Department of Pediatrics, Sri Krishna Children's Hospital, Warangal, Telangana, India

Date of Submission10-Jun-2021
Date of Decision29-Oct-2021
Date of Acceptance06-Nov-2021
Date of Web Publication29-Nov-2021

Correspondence Address:
Dr. Gouda Ankula Prasad Kartikeswar
Sri Krishna Children's Hospital, Hanamkonda, Warangal - 506 001, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_177_21

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Background: Neonatal diabetes mellitus (NDM) is a rare condition, usually genetic in etiology, that presents with hyperglycemia requiring insulin within the first 6 months of life. Most cases of permanent NDM are caused by mutations in the KCNJ11 or ABCC8 gene, which are involved in the potassium adenosine triphosphate channels. Clinical Description: A 1.88 kg female infant product of a consanguineous marriage was delivered at term by cesarean section for oligohydramnios and intrauterine growth retardation. There was a strong family history of DM involving the mother, father, and grandparents. Clinical examination was normal. Routine blood sugar monitoring identified hyperglycemia at 1 and 3 h. There was no clinical or laboratory evidence of sepsis. Management: Persistent hyperglycemia continued that necessitated the administration of insulin from the 1st day onward. The abdominal ultrasonogram was normal. C-peptide was low, indicating poor endogenous insulin production. Genetic analysis revealed a novel mutation in the glucokinase (GCK) gene (p. Glu178Asp). A brief trial of sulfonylureas (glibenclamide) was ineffective. The infant attained control, although with considerable difficulty, on a mixture of NPH and long-acting insulin. After 5 months of follow-up, she is thriving well. Conclusion: GCK mutation is a rare but important cause of NDM. To the best of our knowledge, this is the first Indian infant to be reported with a GCK gene mutation.

Keywords: Glucokinase mutation, intrauterine growth retardation, neonatal diabetes

How to cite this article:
Surender K, Kartikeswar GA, Mounika V, Baske K. Permanent neonatal diabetes mellitus in an Indian infant due to a novel mutation in the glucokinase gene. Indian Pediatr Case Rep 2021;1:260-2

How to cite this URL:
Surender K, Kartikeswar GA, Mounika V, Baske K. Permanent neonatal diabetes mellitus in an Indian infant due to a novel mutation in the glucokinase gene. Indian Pediatr Case Rep [serial online] 2021 [cited 2022 Jan 20];1:260-2. Available from: http://www.ipcares.org/text.asp?2021/1/4/260/331369

Neonatal diabetes mellitus (NDM) is defined as insulin-requiring hyperglycemia within the first 6 months of life, and is usually associated with intrauterine growth restriction and low birth weight.[1] NDM and maturity-onset diabetes of the young (MODY) are the two main forms of monogenic diabetes, i.e., DM resulting from a mutation or mutations in a single gene.[2] NDM can either be transient (TNDM) or permanent (PNDM). The majority of cases are TNDM, which resolve within a median of 18 months, and mostly (70%) are due to mutations in chromosome 6q24.[3] In contrast, almost 40% of PNDM are caused by mutations in the gene encoding the Kir6.2 subunit of the adenosine triphosphate (ATP)-sensitive potassium channel (KCNJ11).[4] The most common gene mutation reported in an Indian case series was the ABCC8 mutation.[5] Other reported mutations are in the genes encoding insulin promoter factor-1 (IPF1) and glucokinase (GCK).[6] GCK is a key regulator of glucose metabolism in pancreatic beta cells, and homozygous inactivating GCK mutations result in a complete deficiency of the glycolytic enzyme.

We report a case of PNDM that was due to a novel mutation (Glu178Asp) in the GCK gene. To the best of our knowledge, this is the first Indian infant with a GCK gene mutation.

  Clinical Description Top

A full-term female baby, product of a third-degree consanguineous union, was born to a 25-year-old primigravida by elective cesarean section under spinal anesthesia. The indications were oligohydramnios and intrauterine growth retardation (IUGR), as identified by ultrasonography. There were no maternal or environmental risk factors for sepsis immediately preceding the delivery. The antenatal period had been uneventful, except that the mother had contracted COVID-19 infection during the second trimester, which resolved with no major medical issues requiring hospitalization. In addition, the mother had been diagnosed with diabetes just before she conceived and required insulin throughout her pregnancy. Her blood sugars were well controlled with the last trimester HbA1c of 6%. There was no history suggestive of polyhydramnios. The baby's weight was 1880 g and the Apgar score was 8 and 9 at 1 and 5 min, respectively. The family history was significant [Figure 1]. The father also had DM, having been diagnosed at the age of 28 years, and on oral hypoglycemic agents for 3 years. The paternal grandmother and maternal grandfather, who were siblings, were also diabetic.
Figure 1: Three-generation pedigree chart of the index case

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On examination, the baby was small for gestational age (SGA) with a birth weight of 1880 g (0.28 centile), length 45 cm (5.99 centile), and head circumference of 31 cm (0.94 centile). A Ponderal Index of 2.06 was indicative of symmetric IUGR. Vitals were stable, there were no apparent congenital malformations, and the systemic examination was normal. Breastfeeding was initiated successfully, and the baby was roomed in with her mother. Blood sugar monitoring was initiated as per hospital protocol for babies born to diabetic mother, and found to be >200 mg/dl, at 1 and 3 h.

Management and outcome

The causes that were considered for hyperglycemia were transient insulin deficiency commonly seen in SGA babies and the possibility of stress hyperglycemia due to unrecognized early-onset neonatal sepsis. The baby was shifted to the neonatal intensive care unit, where a sepsis screen and blood culture were sent, the baby was started on empirical antibiotics and intravenous 5% dextrose. The sepsis screen was negative. Hyperglycemia persisted throughout the 1st day of life, with venous values as high as 320 mg/dL, despite being on a glucose infusion rate of only 2.1 mg/kg/min. There was no acidosis, and the urinary ketones were negative. This prompted us to start an insulin infusion with rates adjusted according to the blood glucose levels. The baby became euglycemic at 0.04 IU/kg/h. Nasogastric milk feeds were started on the 2nd day and breastfeeding on the 3rd day (Hence the insulin requirement increased). Investigations were proceeding simultaneously. The abdominal ultrasound revealed a normal size pancreas, whereas the C-peptide levels for assessing pancreatic β cell function were low, 0.39 ng/ml (normal: 1.1–4.4 ng/mL). Further management was planned in consultation with a pediatric endocrinologist. The infant was gradually shifted from regular insulin to NPH insulin infusion and discharged on twice-daily injections (2 IU/kg/day), after being advised regarding regular blood sugar monitoring and home care.

In view of the significant family history, consanguinity, and persistent hyperglycemia, a gene panel for MODY and neonatal diabetes was sent. This revealed a homozygous missense variation in exon 5 of the GCK gene (chr7:g.44189616T>G; depth: 562x), which lies in the hexokinase domain of the GCK protein. It is known to result in amino acid substitution of aspartic acid for glutamic acid at codon 178 (p. Glu178Asp). The mutation is autosomal recessive in inheritance and is associated with permanent neonatal diabetes. The parental genetic study was not done despite counseling due to financial restraints. The final diagnosis was NDM due to a mutation in the GCK gene.

The baby has been on regular follow-up since discharge. Initially, domiciliary blood sugar monitoring revealed intermittent hyperglycemia, despite the high dose of NPH insulin. Therefore, it was decided to give the baby a trial of a concurrent oral sulfonylurea (glibenclamide at 0.5 mg/kg/day). However, this proved to be ineffective in achieving good control. Finally, a long-acting insulin, Levemir (insulin detemir), was added at 3 months. Currently, she is 5 months old, weighs 6 kg, and is more or less maintaining normal blood sugar levels on this regime. There are a few areas of lipodystrophy at the injection sites. She has attained age-appropriate developmental milestones and her neurodevelopment examination is normal.

  Discussion Top

Only a few cases of GCK-PNDM had been described globally. An exhaustive literature search could not identify any Indian case report with a GCK mutation. GCK is a key regulatory enzyme in glycolysis in the pancreatic beta-cell. It forms the rate-limiting step in glycolysis because of its low affinity for glucose and lack of feedback inhibition from its product, glucose-6-phosphate. This allows GCK to function as a glucose sensor, and control insulin release. Availability of excess glucose produces excess ATP, which causes closure of ATP-sensitive potassium channel (K-ATP). Closure of these channel causes membrane depolarization and calcium influx which, in turn, cause insulin secretion.[7] In cases of GCK mutation, though the K-ATP channel is normal, there is defective glucose sensing, resulting in insufficient ATP generation and nonclosure of the K-ATP channel. As GCK controls insulin release, homozygous inactivating GCK mutations result in a more severe phenotype, presenting at birth as PNDM. Heterozygous inactivating mutations of the GCK gene are associated with GCK-MODY, also known as MODY2. Defective glucose sensing results in a higher set point for glucose homeostasis, causing mild, asymptomatic fasting hyperglycemia. In people with GCK-MODY, the prevalence of macrovascular complications is probably similar to that in the general population, and they do not develop significant microvascular complications even after long-standing mild hyperglycemia. Heterozygous activating GCK mutations have been associated with hypoglycemia. Therefore, identification of a GCK mutation has implications in the clinical course and clinical management of the disorder.[7] The severity of diabetes is directly related to the functional severity of the GCK mutation. Some mutations like that of R397 L result in a less severe phenotype that may respond well to sulphonylureas, whereas some mutations (i.e., of T228M) show less improvement.[6] In our case, sulfonylurea did not prove beneficial for the short duration for which it was given. Thus, besides the routine aspects of genetic counseling, establishing a genetic diagnosis in patients with PNDM is important for directing the course of pharmaceutical management.

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.


All authors thankful to the parents of the child for their co-operation, and help of other doctors and nursing staff of Sri Krishna Children Hospital.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Shield JP, Gardner RJ, Wadsworth EJ, et al. Aetiopathology and genetic basis of neonatal diabetes. Arch Dis Child Fetal Neonatal Ed 1997;76:F39-42.  Back to cited text no. 1
Hattersley A, Bruining J, Shield J, et al. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2009;10 Suppl 12:33-42.  Back to cited text no. 2
Temple IK, Gardner RJ, Mackay DJ, et al. Transient neonatal diabetes: Widening the understanding of the etiopathogenesis of diabetes. Diabetes 2000;49:1359-66.  Back to cited text no. 3
Edghill EL, Flanagan SE, Ellard S. Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11. Rev Endocr Metab Disord 2010;11:193-8.  Back to cited text no. 4
Ganesh R, Suresh N, Vasanthi T, et al. Neonatal diabetes: A case series. Indian Pediatr 2017;54:33-6.  Back to cited text no. 5
Turkkahraman D, Bircan I, Tribble ND, et al. Permanent neonatal diabetes mellitus caused by a novel homozygous (T168A) glucokinase (GCK) mutation: Initial response to oral sulphonylurea therapy. J Pediatr 2008;153:122-6.  Back to cited text no. 6
Gloyn AL. Glucokinase (GCK) mutations in hyper-and hypoglycemia: Maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. Hum Mutat 2003;22:353-62.  Back to cited text no. 7


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