GCK mutation can lead to various clinical phenotypes based on the severity. It encodes the enzyme glucokinase. Glucokinase acts as a glucose sensor in the beta cells and catalyzes the conversion of glucose to glucose-6-phosphate. A heterozygous mutation leads to an upward shift in the threshold for insulin secretion, resulting in mild fasting hyperglycemia. In contrast, a homozygous mutation completely abolishes the glucose threshold for insulin secretion, leading to permanent neonatal diabetes. We present three cases of GCK mutation in which genetic testing was crucial to rule out other potential diagnoses.

Case 1

A 35-year-old male presented with five years duration diabetes. He was on 500 mg of Metformin daily with persistently elevated fasting glucose levels (120-140 mg/dl). He was non-obese (Body mass index 24 kg/m²). His fasting blood sugar level was 135 mg/dL, and post-breakfast blood sugar was 158 mg/dL, with an HbA1c of 6.6%. Additionally, he had pedal edema with proteinuria (24 hours urine protein 428 mg/day). His serum creatinine was 0.98 mg/dl and eGFR 108 ml/min/1.73 m². USG abdomen revealed a relatively small-sized left kidney measuring 64 x 35 mm. His father also had mild adult diabetes with the age of onset at 38 years. Looking at his young age, family history, fasting hyperglycemia, and renal involvement, we advised whole exome sequencing to rule out any monogenic diabetes. The test revealed GCK gene mutation (c.796G>A, p.Glu266Lys). The proteinuria appears non-diabetic, and further investigations, including renal biopsy, is planned. The genetic analysis helped us to think of different etiology for his renal co-morbidity.

Case 2

This patient was the previous patient’s daughter. She was diagnosed with Type 1 diabetes 1 week back on basal units of insulin therapy. Even with four units of glargine insulin, she was getting fasting hypoglycemia. One week prior, her fasting blood sugar was detected at t 124 mg/dl, and post-meal blood glucose was 138 mg/dl with HbA1C 6.2%. Her GAD-65 antibody was negative, and fasting C-peptide was 1.4 pg/ml. Due to the father being an index case and a strong family history of diabetes in 3 consecutive generations, we recommended targeted gene sequencing to identify the related MODY gene mutations (Figure 1). The sequencing revealed a heterozygous inactivating missense variation c.796G>A (p.Glu266Lys) with autosomal recessive inheritance. The parents were informed that this condition is a mild form of diabetes and that the patient does not require treatment.

Figure 1: Pedigree chart showing GCK mutation across three generations.

This pedigree illustrates the autosomal dominant inheritance pattern of a heterozygous GCK gene mutation. The index case (proband) is marked with an arrow (→). Affected individuals (  = male,  = female) across three generations show a history of early-onset, non–insulin-dependent hyperglycemia consistent with GCK-MODY (MODY2). Unaffected individuals are represented as open symbols ( = female, = male). The diagram demonstrates vertical transmission through multiple generations, suggestive of familial monogenic diabetes.

Case 3

A two-year-old boy was brought with persistent hyperglycemia despite being on insulin. He had been diagnosed with type 1 diabetes at six months of age, without ketoacidosis. His fasting blood glucose was 160 mg/dl and post breakfast blood glucose was 230 mg/dl, with HbA1c at 8.9%. He was on a basal-bolus insulin regimen. Pancreatic autoantibodies (GAD, IA2, ZnT8) were negative. General and physical examination was normal. Parents were concerned about the potential risk of diabetes in their future children. Due to the early onset and antibody negativity, genetic testing was performed, which revealed a homozygous inactivating mutation in the GCK gene at c.547G >T, which causes substitution of valine to leucine, confirming Permanent Neonatal Diabetes Mellitus (PNDM). Both parents were found to be heterozygous carriers. The diagnosis clarified the etiology, confirmed the need for lifelong insulin, and allowed for targeted family counselling. This case highlights the importance of early genetic testing in infantile diabetes.

The GCK gene consists of twelve exons and is located on chromosome 7p13. It has two tissue-specific promoters, leading to differential expression in pancreatic beta cells and hepatocytes [1]. Glucokinase catalyzes the ATP-dependent phosphorylation of glucose to glucose-6-phosphate, the rate-limiting step for glycolysis. Pancreatic β-cells release insulin in response to rising blood glucose levels. Glucose enters the beta cells through the GLUT2 transporter and is converted to glucose-6-phosphate, which generates ATP. The increase in ATP causes the closure of K-ATP channels, leading to cell depolarization and subsequent insulin release [2]. Glucokinase has a high Km, allowing it to be active only at physiologically high glucose levels; this is why insulin is not secreted during fasting [2]. β-cells initiate insulin secretion at ~5 mmol/L (60 mg/dl). In activating GCK mutations, the threshold drops to 2-3 mmol/L (36-54 mg/dl), causing the release of insulin at lower levels, leading to persistent hyper-insulinemic Hypoglycemia (PHHI). In inactivating mutations, the threshold increases to 7-8 mmol/L (126-144). In GCK-MODY (heterozygous inactivating GCK mutations), the glucose threshold for insulin secretion is raised, causing mild fasting hyperglycemia. Postprandially, glucose levels exceed the threshold, triggering near-normal insulin secretion. Hence, hyperglycemia remains stable, mild, and non-progressive, with a low risk of complications [3]. In homozygous GCK, glucokinase activity is severely impaired or absent, preventing β-cells from sensing glucose and triggering no insulin secretion even at high glucose levels. This leads to permanent neonatal diabetes mellitus (PNDM), presenting with severe hyperglycemia from birth and requiring lifelong insulin [3]. MODY includes at least 14 subtypes, with MODY 3 (HNF1A) being the most common, but the prevalence of MODY 2 (GCK) is rising due to increased genetic testing and awareness [4]. MODY 2 causes mild fasting hyperglycemia and does not require any treatment. In the first case, the child was misdiagnosed with type 1 diabetes despite having a negative autoimmune antibody workup. She was started on insulin treatment, which led to frequent episodes of hypoglycemia. Genetic testing revealed a heterozygous inactivating missense variant, c.796G>A (p.Glu266Lys). Based on these results, the parents were counselled about the condition, and the insulin treatment was discontinued. The child does not require any medications except during pregnancy. The patient's father had type 2 diabetes and exhibited proteinuria (428 mg/dl), which was initially considered a complication of diabetes. However, the discovery of a GCK mutation in the child raised suspicion of MODY2 (Maturity Onset Diabetes of the Young Type 2). We recommended whole exome sequencing, which confirmed that the child had the same mutation with autosomal recessive inheritance. This finding prompted us to consider a non-diabetic condition for renal involvement. Upon evaluation, it was noted that he had a small left kidney. Since MODY2 is typically a mild form of diabetes without significant complications. Further workup is planned in collaboration with a nephrologist, including renal biopsy, to rule out non-diabetic kidney disease. Genetic testing ultimately helped clarify the diagnosis. The third case was labelled as type 1 diabetes because of the age and high blood glucose levels. The child required basal-bolus insulin therapy. However, as a dictum, all persistent neonatal diabetes should be subjected to genetic testing, and he was advised to undergo the same. Due to a homozygous inheritance from both parents, his glucokinase activity is suppressed, making him behave like a person with type 1 diabetes. Comparison of clinical presentation, genetic mutations, and final diagnosis among three patients with GCK mutations, highlighting the phenotypic spectrum from heterozygous MODY 2 to homozygous PNDM. Mentioned in table 1.

Table1: Clinical and Genetic Profile of 3 GCK Mutation Patients.

This table summarizes the clinical presentation, genetic findings, and final diagnosis in three individuals from the same family. Cases 1 and 2, a father and his daughter, presented with mild fasting hyperglycemia and were found to harbor the same heterozygous c.796G>A (p.Glu266Lys) mutation in the GCK gene, consistent with MODY 2 (GCK-MODY). Case 3, a younger sibling, presented with insulin-requiring diabetes in the neonatal period and was found to have a homozygous c.547G>T (p.Val183Leu) mutation, confirming the diagnosis of Permanent Neonatal Diabetes Mellitus (PNDM) due to a homozygous GCK mutation. This family demonstrates the spectrum of glycemic phenotypes associated with heterozygous versus homozygous GCK mutations.

These 3 cases highlight that GCK inactivating mutation is not an uncommon condition. It should always be considered in different situations when clinical pointers prompt us to consider it.

Acknowledgments: Nil

Conflict of Interest: Nil

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