MODY2 is due to mutations in the glucokinase gene (GCK; OMIM 138079) on chromosome 7p15-p13.  This is the only MODY gene that does not regulate the expression of other genes. Rather, the GCK gene is required for glucose metabolism and insulin secretion.  Thus, the clinical course of MODY2 patients differs from the prognosis associated with other types of MODY.

 

Glucokinase alerts pancreatic beta cells that glucose is present, and therefore acts as a glucose sensor.  Mutations in this gene reduce the beta-cell secretory response to glucose, which leads to chronic hyperglycemia. 

 

MODY2 is characterized by a mild stable fasting hyperglycemia with a decline in pancreatic islet cell function over time.  It has also been associated with gestational diabetes, T2D, and possibly T1D.  Many patients with MODY2 are treated with diet alone. Approximately 200 genetic variants have been identified, including VNTR polymorphisms, nonsense and missense mutations.  MODY2 accounts for ~15% of all MODY cases.