A 14-year-old girl is found on routine screening to have persistent fasting blood glucose of 110 mg/dL. She is asymptomatic, has no ketosis, and shows no autoantibodies. Her mother and maternal grandfather have similar mild hyperglycemia. Which enzyme defect best explains this finding?

• A Glucagon receptor mutation blunting hepatic glucose output
• B Heterozygous HNF-1alpha mutation impairing insulin gene expression
• C Pancreatic beta cell autoimmunity destroying insulin secretion
• D Glucokinase mutation causing reduced hepatic glucose phosphorylation ✓

Explanation

MODY type 2 results from heterozygous glucokinase mutations. Because glucokinase sets the glucose threshold for insulin release (Km approximately 10 mmol/L), its reduced activity shifts this threshold upward, producing stable, mild, lifelong fasting hyperglycemia that rarely needs treatment. The autosomal dominant family history across three generations fits MODY. HNF-1alpha mutations (MODY 3) cause more severe hyperglycemia with marked sensitivity to sulfonylureas, and the absence of autoantibodies excludes type 1 diabetes.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.