Heterozygous inactivating mutations in GCK [OMIM#138079] have been described in patients with maturity onset diabetes of the young type 2 (GCK-MODY) [OMIM#125851], which is characterized by mild fasting hyperglycemia. Hyperglycemia is present at birth but often only detected later in life, when individuals undergo routine screening tests. Affected individuals rarely, if ever, show progression of disease, or develop the microvascular or macrovascular complications typically associated with diabetes. These patients typically therefore can be managed by diet alone, and treatment with oral medications or insulin can actually cause poorer outcomes as patients have an altered counter-regulatory response to hypoglycemia. Homozygous inactivating GCK mutations are associated with permanent neonatal diabetes mellitus (PNDM). In addition, heterozygous activating mutations in GCK have also been observed, which lead to hypoglycemia.
GCK encodes for the enzyme glucokinase, which has a central role in the regulation of blood glucose and acts as a “glucose sensor” in pancreatic β-cells. Mutations in GCK associated with GCK-MODY typically result in a modest decrease in glucokinase activity, which in turn leads to mild fasting hyperglycemia.
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