Glucokinase catalyzes the phosphorylation of glucose to glucose-6-phosphate. Its unique kinetic properties result in the rate of glucose phosphorylation being proportional to the physiologic glucose concentration. This means that the beta cell and hepatocyte can respond appropriately to fluctuations in the degree of glycemia. In the pancreatic beta cell, glucokinase acts as “the glucose sensor”  ensuring insulin release is appropriate to the blood glucose concentration.
Molecular genetics of glucokinase MODY
Coding or intron/exon boundary mutations were first found in the glucokinase gene in French and English MODY pedigrees in early 1992 [5,6]. Over 200 different heterozygous loss-of-function mutations have now been described, all causing a similar clinical picture. Expression studies show that the mutations in MODY families may alter the enzyme’s affinity or activity for glucose metabolism or phosphorylation or alter structure or stability [7–10]. Homozygous loss-of-function glucokinase mutations are a rare cause of insulin-requiring diabetes presenting in the neonatal period . Gain-of-function mutations cause congenital hyperinsulinism .
Phenotype of glucokinase MODY
Subjects with GCK-MODY have fasting hyperglycemia that is present from birth and shows very little deterioration with age . Byrne and colleagues have shown, using graded glucose infusions, that heterozygous mutations in GCK cause a right shift in the insulin response curve leading to a re-setting of the fasting glucose set point . So the majority of GCK-MODY subjects have high fasting plasma glucose within a tight range (5.5–8 mmol L−1). There is maintained glucose homeostasis as shown by the small increment in plasma glucose at two hours during an oral glucose tolerance test, albeit at a higher set point than in normal subjects . The HbA1c is raised in people with GCK-MODY with a median value of 50 mmol mol−1 that, as in normal subjects, deteriorates with age ; over half of cases exceed the diagnostic criteria for diabetes. HbA1c values above 64 mmol mol−1 would suggest an alternative diagnosis and marked worsening of the glycemia suggests that the patient has developed type 1 or type 2 diabetes in addition to their GCK mutation. Subjects with GCK-MODY do not get significant microvascular complications . The incidence of macrovascular complications appears similar to the background Population.
As GCK mutations cause mild asymptomatic hyperglycemia most cases of GCK-MODY are diagnosed following incidental] testing of blood glucose, or following routine screening in pregnancy. A correct diagnosis is important in young people who might otherwise be thought to have type 1 diabetes. Persistent, stable mild hyperglycemia, lack of beta-cell autoantibodies and mild hyperglycemia in a parent (when tested) all support a diagnosis of GCK-MODY. Differentiating GCK-MODY from T2DM can be more difficult; however, supporting clinical evidence for GCK-MODY includes lack of obesity or features of insulin resistance, or results obtained from an oral glucose tolerance test, when the glucose increment at 2 hours is usually <3mmol L−1 . Fasting plasma glucose below 5.5mmol L−1 is rare in GCK-MODY outside pregnancy.
Patients with GCK-MODY do not usually require treatment except in pregnancy (see later) . If a patient is being treated with insulin or other hypoglycemic agents, it is usually possible to stop treatment when a diagnosis of GCK-MODY is made. However, if the HbA1c has ever exceeded 64mmol L−1, this should be done with caution, as it is possible for someone to have both a GCK mutation and type 1 or type 2 diabetes.
GCK-MODY and pregnancy
Women with glucokinase mutations are frequently first found to have hyperglycemia during screening in pregnancy. GCK-MODY represents about 3% of patients with gestational diabetes . Correctly identifying GCK-MODY is important because these women have a different clinical course both within and outside pregnancy compared to “standard” gestational diabetes.
The aim of treatment of diabetes in pregnancy is to minimize the risk of fetal and maternal complications. This is usually achieved by strict control of the mother’s blood glucose to prevent fetal macrosomia. However, in GCK-MODY pregnancies, the need to reduce maternal blood glucose is not absolute. This is because the fetus has a 50% chance of inheriting the GCK mutation from the mother, and the presence of the GCK mutation in the fetus influences the fetus’ sensing of maternal glucose. Therefore, if the fetus does not inherit the GCK mutation it will respond to maternal hyperglycemia by excess insulin production and therefore excess growth, whereas if the fetus does inherit the GCK mutation it will sense the maternal hyperglycemia as normal, produce normal amounts of insulin and have normal growth (see Figure 28.4) . In this latter setting, aggressively lowering maternal glycemia may adversely affect fetal growth . As it is not usually possible to determine the fetal genotype, the decision on whether to treat the mother should be based on fetal growth. If the abdominal circumference is greater than the 75th centile insulin may be used but early delivery is the most successful strategy (see Figure 28.5).
A mother with a GCK mutation will need no pharmacologic treatment postpartum even if she has received very high insulin doses in pregnancy.This is in contrast to subjects with nonglucokinase gestational diabetes where deterioration to T2DM is usually seen over the following 10 years.